EP4618987A1

EP4618987A1 - Methods for prevention and treatment of cardiovascular disease by modulating or inhibiting cannabinoid receptor 1

Info

Publication number: EP4618987A1
Application number: EP23848600.5A
Authority: EP
Inventors: Joseph-Kevin IGWE
Original assignee: Joyboy Igwe LLC
Current assignee: Joyboy Igwe LLC
Priority date: 2022-12-13
Filing date: 2023-12-13
Publication date: 2025-09-24
Also published as: WO2024129891A1

Abstract

Administration of receptor antagonists, inverse agonists, allosteric modulators, or signaling specific inhibitors of cannabinoid receptor 1 (CB1) prevents and treats disease conditions and complications in patients, including those associated with various cardiovascular disease therapies. Patients having a history of cannabis use are particularly at risk for severe complications. For methods involving cardiovascular disease therapies, such as percutaneous coronary intervention, coronary artery bypass surgery or stent placement, administration of the inhibitors or modulators of CB1 during the peri-operative, intra-operative, and/or post-operative period results in improved outcomes for the patient.

Description

METHODS FOR PREVENTION AND TREATMENT OF CARDIOVASCULAR DISEASE BY MODULATING OR INHIBITING CANNABINOID RECEPTOR 1 BACKGROUND [0001] This application claims priority to U.S. Provisional Patent Application Serial No. 63/387160, filed December 13, 2022, entitled “Use of Rimonabant and other CB1 antagonists or reverse agonists as singular and/or adjunct medication therapy for the treatment/prevention of arterial microembolization, atherosclerosis, thrombosis, and/or ISR among patients who are or will receive procedural intervention and treatment/modulation of cardiovascular risk factors related to coronary artery disease and/or ischemic heart disease and/or other diseases,” the entire contents of which are hereby incorporated by reference. [0002] This disclosure relates to prevention and treatment of conditions and diseases through administering compounds that act as modulators or inhibitors of cannabinoid receptor 1 (CB1). [0003] Cannabis has become increasingly legalized for recreational and medicinal use. Currently 22 states (including the District of Columbia) allow non-medical adult use of cannabis, and 38 states permit the use of medical cannabis. According to the CDC (Centers for Disease Control), 48 million people used cannabis at least once in 2019. It is also estimated that 2 million US adults who have cardiovascular disease have used cannabis at least once. [0004] The latest guidelines recommend the use of dual anti-platelet therapy (DAPT) with PY12 and antiplatelet therapy (i.e., clopidogrel and aspirin) for the secondary prevention of adverse cardiovascular complications following PCI or coronary artery bypass grafting (CABG). Antiplatelet therapy is also recommended among those with ischemic cardiomyopathy. However, no policies or medical therapies have been approved for use that target mechanisms associated with modulation of disease secondary to microembolization seen with difficult procedural manipulation and angioplasty, or risk modification for cannabis users generally or with CAD specifically, and while utilization of drug eluting stent (DES) has decreased PCI complications, coronary artery in-stent restenosis (ISR), stent thrombosis, stent occlusion, atheromatous microembolization, etc. are still significant complications intrinsic to the procedure itself and associated with subsequent derangements in the activation of the CB1 receptor in response to injury, the procedural and clinical consequences of which are not understood. [0005] Unfortunately, the clinical role and outcomes associated with endocannabinoids in the treatment of obesity and other cardiovascular disease risk factors has not been explored extensively due to regulations related to medical experimentation using Schedule I drugs and adverse side effects associated with prior CB1 antagonist Rimonabant. SUMMARY [0006] The present disclosure relates generally to methods of preventing and treating diseases and conditions, including those associated with cardiovascular disease therapies and other diseases associated with activation or overactivation of cannabinoid receptor 1 (CB1), through administering compounds that modulate or inhibit CB1. [0007] Perioperative utilization of CB1 receptor antagonist/inverse agonist/allosteric modulators/signaling specific inhibitor/cannabinoformins ameliorates disease conditions and complications associated with percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) surgery. Similarly, CB1 antagonism/inverse agonism for patients with history of cannabis use, and, more generally, for those with history of PCI, to decrease risk of subsequent acute myocardial infarct or other complications associated with DES, metal stent, or other intravascular stent placement represents a viable therapeutic option. These therapies and the various clinical utility at different stages of the treatment and therapeutic process of management of ischemic and micro- or macrovascular cardiomyopathy can have far reaching effects for many diverse patient groups. As such, the benefits and the outcomes of these methods extend beyond those with cannabis use due to similar pathology to patients with concomitant diabetes mellitus and obesity. [0008] Utilizing real world data from the National Inpatient Sample (NIS) database, it is noted that active cannabis use disorder (CUD-A) is associated with 53.08% higher odds of stent thrombosis among patient receiving percutaneous coronary intervention (PCI) without history of PCI presenting with primary hospital diagnosis of ST-elevation myocardial infarction (STEMI) (1.53,[1.01- 2.31], p=0.04); and 43% higher odds of in-stent restenosis among patients with history of PCI presenting with primary diagnosis of non-ST-elevation myocardial infarction (NSTEMI) between 2016-2020 (OR: 1.43, [1.12-1.66], p=0.05). Obesity with complicated diabetes (diabetes mellitus type I or diabetes mellitus type II (DM)) is associated with 35.22% higher odds of stent thrombosis among patients receiving PCI without history of prior PCI before index admission and admitted with primary hospital diagnosis of STEMI (OR: 1.35, [1.00- 1.83], p=0.05); 45.69% higher odds of in-stent restenosis among patient receiving PCI with history of prior PCI before index admission and admitted with primary hospital diagnosis of STEMI (OR: 1.46, [1.07-1.98], p=0.02); 58.95% higher odds of in-stent restenosis among patients receiving PCI without history of PCI presenting with primary diagnosis of STEMI between 2016-2020 (OR: 1.59, [1.25 - 2.02], p≤0.001); 31.63% higher odds of in-stent restenosis among patients receiving PCI with history of PCI presenting with primary diagnosis of NSTEMI (OR: 1.32, [1.18-1.47], p≤0.001); and 80.33% higher odds of in-stent restenosis among patients receiving PCI without history of PCI presenting with primary diagnosis of NSTEMI (OR: 1.80, [1.66-1.96], p≤0.001) between 2016-2020. [0009] Notably, cannabis users and obese patients with complicated diabetes (Ob-DM) are at increased risk of stent failure; and both populations--cannabis users and Ob-DM-- separately are associated with increased peri-procedural and post-procedural risk for adverse outcomes (stent thrombosis; in-stent restenosis) with markedly similar patterns in the incidence of stent thrombosis acutely among the STEMI group with no history of PCI and receiving PCI during index admission (2.19% (N=120/5,470) vs 1.36% (N=3,195/235,715), p=0.019; 1.89%(N=220/11,645) vs 1.36% (N=3,195/235,715), p=0.031, respectively); and the incidence of in-stent restenosis chronically (defined as subsequent acute myocardial infarction (AMI) ≥ 4 weeks from prior AMI) among the NSTEMI group with history of PCI (8.68% (N=495/5,680) vs 6.44% (N=23,190/360,130), p=0.002; 8.59% (N=3,475/40,470) vs 6.44% (N=23,190/360,130), p≤0.001, respectively); and without significantly different incidence between the two groups regarding in-stent restenosis for those with Ob-DM with vs without history of cannabis use (10.00% vs 13.02%, p=0.351, respectively), or alternatively, for those with cannabis use with vs without Ob-DM (1.56% vs 2.09%, p=0.351). [0010] Real world evidence establishes and reveals a fundamental relationship between CB1 activation, and the incidence of adverse event (AE) defined as in-stent thrombosis and/or stenosis, noting comparable incidence of AE among those with increased CB1 tone which is associated with pathological inhibition of insulin function on lipoprotein phospholipase (LPL) function, adipocyte growth, and inflammation. [0011] Cannabinoid receptor introduction. The cannabinoid receptor belongs to the class A G protein-coupled receptor (GPCR) family, which consists of seven transmembrane helices (TMs), three intracellular loops (ICLs), and three extracellular loops (ECLs). In the absence of any ligand, the GPCR instantiates in a dynamic equilibrium between the inactive R and active R* state. When GPCR binds to a ligand, it undergoes a conformational change which in turn affects residue interactions between transmembrane proteins and the functional capacity and characteristics associated with GPCR-ligand binding. The full or partial ligand binding of the receptor is thought to increase the probability of the receptor converting R*. Moreover, both diffusion across the lipid membrane and/or tight ligand binding at GPCR activation sites as in rhodopsin for an induced fit mechanism may occur. However, there is a possibility that both mechanisms are operational, but to different extents or proportions. Importantly, the transduction of imminent signals through CB1 receptor-dependent and -independent mechanisms are demonstrated across multiple cellular landscapes with differential localization across subcellular organelles and cytoplasmic domains within the cell and at the cellular membrane and across divergent organ systems and signaling pathways. Mechanistically, the mechanism by which CB1 receptors and other GPCRs function involves a rotamer toggle switch motif, referred to as the “toggle switch” or “transmission switch,” which translates ligand-receptor interactions and GPCRs interactions into functional downstream effects. The toggle switch drives the movement of neighboring helices and modulates the interaction and binding stability of ligand-helix coupling. The toggle switches of the β₂ adrenergic receptor (β₂AR) and the A2A adenosine receptor (A_2AAR) mediate the helical movement of transmembrane-helix (TM) domain 5 and TM6 through the rearrangement of inter-helical interactions in TM3, TM5, and TM6, and interactions between TM1 and TM7 are involved in CB1 receptor ligand functionally biased activity for MI-1891. Additionally, hydrogen bond interactions between G-protein coupled receptors transmembrane proteins between helices function in the stabilization of conformational positioning across active and inactive CB1 conformational states. Moreover, different conformations of GPCR mediate agonist-induced protein activation and β-arrestin recruitment; and specific phosphorylation patterns at the C terminus of G-protein coupled receptors (GPCR) which in turn mediate β-arrestin recruitment to GPCR and modulate intracellular functions. These different phosphorylation patterns themselves are induced by GPCR kinases (GRKs). As such, biased agonist function in the preferential activation of conformations linked with G protein or β-arrestin signaling, respectively. [0012] Endocannabinoid System (ECS) Modulation. Metabolism: Acute and chronic storage and downstream effects based on ligand binding efficacy. Two of the most abundant cannabinoids within cannabis are Δ9-tetrahydrocannabinol (THC), the principal psychoactive component of cannabis, and cannabidiol. THC functions as a cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) partial agonist, while cannabidiol is a non-competitive negative allosteric modulator of CB1 and CB2, with reports indicating that it potently modulates cannabinoid receptor responses to THC and endogenous cannabinoid 2^arachidonylglycerol. Cannabinoid receptors (CB₁ and CB₂) are distributed in multiple tissue beds and cell types. Cannabinoid effects related to activation of the CB1 receptor modulate sympathetic activation, cytokine production, and interleukin (IL) production. On the other hand, its function at CB₂ receptors, localized primarily in immune cells – the tonsils, spleen, PBMC (Peripheral Blood Mononuclear Cells), microglia, and thymus—and function as an inhibitor of adenylate cyclase highlight its role in regulation of inflammation. Additionally, multiple studies have confirmed the presence of CB₂ mRNA and protein activation components across different human lymphocytes. [0013] The plasma half-life of THC is approximately 1-3 days in occasional users and 5- 13 days in chronic users; and cannabidiol half-life is 18-32 hours. However, both cannabidiol and THC are highly lipophilic with a long elimination half-life within adipocytes, and under normal conditions, they passively diffuse from fat back into blood. THC can be observed in fat cells biopsy up to 28 days after last use, and the presence of THC has been reported in the urine among chronic, heavy users after 77 days, despite extended periods of abstinence. Notably, the accumulation, storage, and release of THC and its metabolites in adipose tissue, and its serum concentrations over time and in specific settings are not stagnant. Sympathetic activation of catecholamine- induced lipolysis may enhance the transient shifts in the serum THC concentrations, increasing over time in relation to extent and duration of ACTH stimulation or food deprivation. As such, the functional activity of THC may not be limited to its acute effects, and its functional components stored in adipocytes and released into the serum may function to modulate the endocannabinoid system (ECS) long after last use. In this respect, the long-term storage and release of THC may play a role in the modulation of outcomes among those receiving percutaneous coronary intervention among those patients hospitalized with AMI. [0014] Functional State- and Organ-specific Effects of the Cannabinoid 1 Receptor Modulate Cellular Response and Adipocyte Inflammation. The state-dependent functional activity of the ECS modulates downstream signaling pathways within the cell such that its effects and the plasticity of its responses within different organ systems represents an interplay between internal and external stimuli, rapidly altering receptor availability and expression patterns in response to physiological inflammatory perturbations. As such, the differences in PCI-related outcomes between the cannabis use population and others is likely reflective of the underlying functional activity of cannabis and its constituent cannabinoids. [0015] THC belongs to a family of plant-based phytocannabinoids with functional activity at the cannabinoid receptor as well as modulation of intracellular and extracellular calcium ion channels such as TRPV2, among others. However, other endogenous cannabinoids (arachidonoylethanolamide (anandamide [AEA]) and 2-arachidonoylglycerol (2-AG)), phytocannabinoids, and synthetic cannabinoids also function as bioactive lipid mediators capable of modulating cannabinoid receptor responses within liver, skeletal muscle, heart, gut, bones, and adipose tissue. Cannabinoids exert their immunosuppressive properties through (1) induction of apoptosis, (2) inhibition of cell proliferation, (3) inhibition of cytokine and chemokine production, and (4) induction of regulatory T cells (T regs). In this regard, modulation of the ECS and the immunosuppressive properties of phytocannabinoids within peripheral B-cell and T-cell lymphocytes support the findings described herein. [0016] What is more, the association between mitochondrial dysfunction in pathologic metabolic disorders such as obesity and diabetes and the pathological importance of the CB1 receptor in COVID-19 disease presentation; the dose-dependent associated effects of THC on mitochondrial oxidative energy production and the modulation of insulin sensitivity or insulin resistance; and the functional modulation of the renin-angiotensin system associated with ECS modulation such that modulates angiotensin-II expression highlight central mechanisms by which THC or other cannabinoids are expected to interact and modulate COVID-19 disease and other viral infection [0017] The mitochondrial CB1 receptor (mtCB1) has previously been described as an integral component involved in complex-I-dependent oxygen consumption, the alteration of which by THC reduces the intramitochondrial levels of cAMP and results in decreased protein kinase A (PKA)-dependent complex I phosphorylation and lowered mitochondrial respiration. Moreover, COVID-19 affects molecular pathways involved in energy metabolism, with other reports noting localization of viral targets within the endoplasmic reticulum and mitochondria as well as increased risk for insulin resistance during the acute-phase of infection and long-term following COVID-19 disease resolution. Aligned with these findings are reports indicating that the cannabinoid receptor localizes to punctate regions within the mitochondria and endoplasmic reticulum, and specifically cannabinoid receptor 1 distribution, prevalence, and function within white adipocytes among obese patients in whom there is a more significant baseline endoplasmic reticulum and mitochondrial dysfunction which is associated with increased activation of inflammatory transcription factors, many of which have been implicated in COVID-19 disease pathology. [0018] Moreover, the associated clinical outcomes related to COVID-19 disease for obese patients with complicated diabetes (Ob-DM) specifically highlights the pathophysiological role of the CB1 receptor in disease modulation, and it implicates CB1 activation by COVID-19 disease and modulation by endogenous CB1 ligands such as AEA or 2-AG or exogenous ligands such as THC in clinical and cardiovascular presentation and outcomes. Obese patients with complicated diabetes specifically have been associated with increased tonic activity of the CB1 receptor and a baseline dysfunctional regulation of URP and associated mitochondrial and endoplasmic reticulum stress response within adipocytes such that the cellular state represents a putative fertile soil for instantiation of COVID-19-related pathways; and the introduction of SARS-CoV-2, which itself is associated with upregulation of these pathways, potentiates these effects. [0019] Due to viral host-transcriptomic modification an associated URP response leading to an increase in activation of IRE1α, one of three stress sensing proteins within the ER, is not increased and subsequent cell death does not occur. However, while IRE1α activity itself is not upregulated by COVID-19, and its absence among IRE1α knockout mice does not affect COVID- 19 infection, the other two remaining stress-related proteins, PKR-like eukaryotic initiation factor 2a kinase (PERK) and activating transcription factor-6 (ATF-6), are not affected. The constitutional activation of PERK is associated with inhibition of translation of inhibitor of nuclear factor-κB (NFkB) (IkB) protein which in turn leads to NFkB induction of pro-inflammatory targets. Additionally, the UPR-induced upregulation of chaperone proteins leads to increased reactive oxygen species production and accumulation secondary to Ero1p and Erv2p enzyme- driven oxidation reduction reactions in the formation of disulfide bonds utilizing molecular oxygen as the final electron recipient, and these ROS themselves may either potentiate UPR activation or act as primary inducer of the UPR response. The induction of these inflammatory responses and the importance of inflammation in insulin resistance are factors associated with obesity; as are the modulatory effects to ion channel function associated with different pathological states in cardiomyopathy, many of which align with the functional activity of various conformational isoforms of the active CB1 receptor in ion channel activation. Moreover, in X-box binding protein 1 (XBP-) (transcription factor involved in IRE1α-related induction of cell death) heterozygous mice—a corollary to pathways noted in COVID-19 disease in so far as XBP-1 is not activated due to inhibition of IRE1α pathways—exposed to high fat diet the result was hyperglycemia, hyperinsulinemia, and impaired glucose and insulin tolerance compared to wild-type mice, and, at the adipocyte itself, increased phosphorylation of PERK and IRE1α and increased c-Jun N- terminal kinase (JNK) activity, coupled with the loss of insulin sensitivity. What is more, free fatty acids (FFAs) themselves can induce JNK activation and subsequent insulin resistance in 3T3-L1 adipocytes. [0020] Cannabinoids and Immune Cell Function. Cannabinoid Receptor 1 and the Heart. An elevated leukocyte count is associated with poor clinical outcomes in both acute myocardial infarction and in the setting of heart failure. Energy and metabolism are heavily implicated in the acute and chronic changes within cardiovascular system and the significant number of insulin receptors within cardiac tissue and the immune cells therein implicate these changes in the efficiency of energy production, metabolic rate, mitochondrial respiration, and cellular changes–pathological or adaptive—in response to the intracellular and extracellular interaction. [0021] What is more, the modulation of innate and adaptive immunity within acute and chronic dysfunction effectuates significant changes in the immune-metabolic state, modulating cytokine production and inflammatory response along divergent cellular and metabolic pathways. These changes in the immune-metabolic ecosystem are central to cardiovascular response and resolution to injury, so much so that these changes within the environment themselves effectuate a shift in the localized ecosystem. Moreover, local inflammatory response is amplified through the neuro-immune axis which increases local inflammatory mediators and cellular response to inflammation. These cellular changes are translated across metabolic pathways as oxidation of lipids and glycolysis by CD4 + helper T cells, B-cells, dendritic cells, and other immune cells modulate the response to inflammation. Moreover, hypoxia and hypoxia inducible factor, decreased availability of amino acids, and altered neuro-muscular interactions potentiate inflammation. [0022] CD4+ T helper (Th) 1 cells are increased following myocardial infarction and the depletion of these cells following coronary ligation ameliorates pathological remodeling and ventricular dysfunction; with similar finds for CD8+ T cells in experimental models. The activation of these T-cell receptors promotes glycolytic metabolism through upregulation of Glut,1,7 and T cell differentiation; and support INF-gamma cytokine production and CD8+ T cell granzyme B expression. Moreover, the increased presence of Th17 cells following MI is mediated through mammalian target of rapamycin (mTOR)-dependent HIF-1α activation which modulates metabolic activity to increase glycolytic pathways. What is more, the functional role of IL-6 in the promotion of differentiation in naïve CD4+ T cells highlights the role of the CB1 receptor in linking innate and acquired immune response. The combination of IL-6 with transforming growth factor (TGF)-β is indispensable for Th17 differentiation from naïve CD4+ T cells, while it functionally inhibits the Foxp3+ T cells (Tregs) differentiation. Notably, Treg function in the attenuation of cardiac and ventricular remodeling and improve healing mechanisms after AMI, and their presence following MI may be dependent upon extracellular nutrients such as leucine, required for T-cell differentiation and the presence of which stimulates mTOR mediated reprogramming in favor of Th1 and Th17 development after uptake by T-cells in the setting of MI. [0023] Additionally, the recruitment and functional activation of B-cells following ischemic events leads to the increased production of cytokines such as CCL7 and increase recruitment of inflammatory monocytes and inflammatory macrophage activation; as well as the presentation of (self) antigens to B-cells and subsequent production of antibodies/immunoglobulins which target the cardiac tissue itself. The increased production of CCL7 is also mediated by transcriptional activation by the glycolysis regulator HIF-1α. What is more, the production of IL-10, enriched in the B-cells within the pericardial adipose tissue, is cardioprotective. The fatty acid oxidation of short-chain fatty acid butyrate enhances the production of IL-10 from B cells. Moreover, the stimulation of T-cell and B-cell differentiation into T-follicular helper-cells and Ab-producing plasma cells; and the production of IL-21 which regulates immunoglobulin synthesis and IgG4 production specifically are mediated through IL-6. The result of these imbalanced processes precipitates hypergammaglobulinemia and autoantibody production. This shift in phenotypic immunoglobulin expression or production and shift to fatty acid oxidation induced by CB1 modulation may counteract the adverse outcomes associated with B-cell anticardiac or other IgG antibody production and favor regulatory function. Moreover, in antagonizing the CB1 receptor, the functional improvement of cardiac and non-cardiac metabolic pathways can be salvaged. These aberrant pathways are characterized by dysfunctional lipid accumulation, metabolism, and cardiac peroxisome proliferator-activated receptor (PPAR)α and PPAR^ signaling which may contribute to the development of heart failure. [0024] CB1-related Signal Transduction. In these and other interactions, the CB1 receptor functions as one of the central mediators of cellular energetics, helix and loop G-protein coupled receptor interaction, stability, and subsequent signaling pathway potency or duration. For example, dopamine and other chemokines have been reported to form heterodimers with CB1 and beta-arrestin in cellular injury. Moreover, CB1 forms heterodimers, oligomers, homodimers, vs other with other molecules such as B2-AR and serotonin, both of which function in vascular or endothelial rigidity; atherosclerotic content; and relative cellular response (to B2-AR agonists) among those with major depressive disorder or heart failure. The modulation of the cellular cascade associated with the CB1 receptor may moderate serum, endothelial, and vascular characteristics generally and in the setting of inflammation or injury or procedural manipulation. These modulatory effects and the strength of signaling pathways resultant from ligand-dependent conformational changes and associated selective affinity for other transmembrane GPCR helix/loops by the CB1 receptor characterizes inflammation as such; it imparts to inflammation its “character” and instantiates it. Finally, interactions between the CB1 receptor and β-arrestin-1 have been characterized, and conflicting results exist regarding β-arrestin-1 recruitment to CB1. However, β-arrestin-1 recruitment has been corroborated by structural studies of β-arrestin-1 interaction with a synthesized CB1 C-terminus, while others indicate that CB1 inverse agonist associate with and modulate activity through β-arrestin-2. What is more, in binding to GPCR, β- arrestin-1 functions may function as a scaffold for a pathway leading to the phosphorylation of MAPK extracellular signal-regulated kinase (ERK) following CB1 binding. [0025] Importantly, these GPCR function across cellular types and produce downstream effects which potentiate and/or reciprocate the functional activities of counterbalanced mechanisms. For example, β-arrestin-2 can negatively regulate β-3 adrenergic receptor activity by increasing its internalization and thereby antagonizing the browning/beiging of white adipocytes in response to sympathetic activation. Notably, β-arrestin-1 knockout mice may develop increased myostatin levels in brown adipocytes which subsequently inhibited satellite cell development and resulted in the development of insulin resistance; while β-arrestin-2 knockout mice are resistant to high-fat, diet-induced weight gain and the associated metabolic deficits, including impaired glucose tolerance and insulin resistance, highlighting the importance of β-arrestin in potentiation of signaling pathways associated with the CB1 as well as cellular localization and trafficking. These effects may be related to the potency of the two isoforms to engender cellular effects and localization of the β-arrestin molecules, with β-arrestin-1 expressing a nuclear localization domain and β-arrestin-2 a cytoplasmic localization domain. Additionally, the functional role of β-arrestin- 1 or β-arrestin-2 in Beta-2-adrenergic receptor (B2-AR) and the angiotensin II type 1A receptor (AT(1A)-R) desensitization and downregulation in β-arrestin-1 or β-arrestin-2 knockout mice highlights the functional modulation of the Beta-2-Adrenergic receptor by CB1: [0026] Both β-arrestin-1-knockout mice and β-arrestin-2-knockout (KO) mice cells showed similar impairment in agonist-stimulated B2-AR and AT(1A)-R desensitization, when compared with their wild type control cells; and the β-arrestin-1/ β-arrestin-2- KO cells were even further impaired. In contrast, β-arrestin-2-knockout cells and not β-arrestin-1- nor β-arrestin-1/ β- arrestin-2-KO cells significantly decreased sequestration (87% reduction) of B2-AR; and agonist- stimulated internalization of the AT(1A)-R was only slightly reduced in the β-arrestin-1-KO but was unaffected in the β-arrestin-2-KO cells. Notably, the study demonstrates a significantly more potent (approximately 100-fold more potent) ability of β-arrestin-2 to sequester the B2-AR compared to β-arrestin-1. [0027] The impaired down-regulation of B2-AR among β-arrestin-1/ β-arrestin-2 knockout but not among single knockout cells highlights redundancies within the β-arrestin cellular function, but it also highlights the functional potential of the receptor modulation focused on the β-arrestin-2 to indirectly potentiate signaling effectuated by the B2-AR. By indirectly inhibiting signaling cascades that induce sequestration through β-arrestin-2 without down- regulation of β-arrestin-1 signaling, the functional activity of the associated B2-AR signaling cascade can be increased or prolonged by prevention of sequestration. The associated effects of β- arrestin-2 knockout mice and not β-arrestin-1 knockout may relate to its cytoplasmic localization; differences in isoform potency; and potency or duration of ligand-receptor signaling cascades. As such, the impaired B2-AR sequestration among β-arrestin-1/ β-arrestin-2 knockouts, the slight reduction in β-arrestin-1 knockout, and significant reduction in β-arrestin-2 knockout highlight a mechanism through which the CB1 receptor-β-arrestin-2 complex may potentiate signaling pathways by B2-AR desensitization (a loss in cellular signaling without a net change in receptor number) indirectly by inhibiting subsequent cellular signaling cascades or directly by increasing down-regulation/sequestration (a net loss in receptors). [0028] Notably, the modulation of B2-AR pathways through activation of G protein- coupled receptor (GPCR)-kinase (GRK)-2 may inhibit Gαs-mediated G protein-coupled receptor (GPCR)-kinase (GRK)-5 signaling and lead to subsequent desensitization and internalization of the receptor. GRK2 plays a diverse role in fibrosis-associated pathways. FIG. 1 shows a representation of various pathways impacted by GRK2. The phosphorylation of GRK2 by different kinases (PKA) also modifies kinase activity and substrate selection. GRK2 can regulate many downstream molecules and participates in the multiple signaling pathways; activates PI3K/Akt; and inhibits Akt/eNOS (endothelial nitric oxide synthase) pathway to lower NO production. Activation of ERK1/2 pathway contributes to apoptosis. GRK2 promotes ERK1/2 phosphorylation, while ERK1/2 inhibits GRK5 phosphorylation. GRK2 and NF-κB can advance their activation through each other. Meanwhile, GRK2 inhibits Epac1/Rap1 pathway and inhibits the release of inflammatory cytokines. However, GRK2 promotes the phosphorylation of STAT1/3, which promotes the accumulation of inflammatory cytokines and contributes to the occurrence and development of fibrotic diseases. [0029] Moreover, knockout of GRK-5 significantly enhances aldosterone-dependent mineralocorticoid (MR) transcriptional activity; but GRK5 overexpressing cells virtually abrogated aldosterone-dependent MR transcriptional activity in H9c2 cardiomyocytes. Additionally, B2-AR- dependent GRK5-mediated MR phosphorylation in cultured adult rat ventricular myocytes (ARVMs) functions in the inhibition of aldosterone-dependent MR transcriptional activity and functions through a PLCβ-Ca2+-CaM signaling pathway; while GRK2 antagonizes these signaling pathways, leads to phosphorylation and desensitization of agonist- activated, antiapoptotic G protein-coupled estrogen receptor (GPER) at the plasma membrane, and promote heart failure through MR-mediated activation of GRK-2-dependent apoptosis and MR-mediated GRK5 nuclear accumulation-dependent hypertrophy in transgenic mouse hearts in vivo. These effects are mediated by MR-induced, proto-oncogene tyrosine-protein kinase Src (c- Src)-dependent cardiac angiotensin II type I receptor (AT-1R) transactivation. These findings indicate that GRK5-induced phosphorylation of the cardiac MR leads to inhibition of its aldosterone-dependent transcriptional activity, and a GRK2-mediated pathway antagonizes Gα_s in potentiating fibrosis and cardiac dysfunction. [0030] Utilization of the CB1 antagonist/inverse agonist as a method of treatment to prevent the increased endothelin production and fibrosis in cardiac fibroblasts and myocytes can effectively disinhibit the production of Epac1, the exchange protein directly activated by cAMP which has been shown to inhibit cardiac fibroblast activation and fibrosis. Moreover, in ischemic contexts which favor GRK2/Hsp90 interaction, GRK2 localizes to cardiac mitochondrial fractions following ERK1/2 phosphorylation, and the upregulation of GRK2 is associated with mitochondrial-dependent death pathways signaling and facilitates calcium-induced opening of the mitochondrial permeability transition pore. Additionally, in ischemia/reperfusion mouse models involving mutual inhibition of GRK2 and eNOS, the cardiac cells of transgenic mouse models with increased GRK2 exhibited an impairment of the cardioprotective eNOS pathway and reduced NO bioavailability. As such, functional inhibition of these pathways through antagonists/inverse agonists/allosteric modulators of the CB1 receptor represent viable treatment options to improve patient outcomes. [0031] The activation of these receptor cascades by CB1 agonists such as THC inhibits stimulation of fibroblast Gαs-protein signaling pathways mediated by IL-6 production and G protein-coupled receptor (GPCR)-kinase (GRK)-5 activation which are responsible for fibroblast proliferation mediated by the B-2-AR and potentiates GRK2-mediated signaling pathways. The functional role of THC in stabilization of and increased transmission switch and conformational stability of CB1 with ligand binding, and the known functional association between CB1 receptor- Beta-arrestin heterodimers and interaction with GRK2 establishes a mechanism by which these events occur. These interactions and the functional inhibition of GRK5 and IL-6-mediated B2-AR- dependent downstream effectors such as the mineralocorticoid receptor OPN—which also indirectly increases vasopressin/aldosterone-mediated signaling pathways within the vasculature; and the functional interaction of CB1 receptor- or CB1 receptor antagonist-mediated signaling with receptor tyrosine kinases or their downstream targets such as EGFR represents a molecular and cellular mechanism by which CB1 functions and through which antagonism can have powerful results to patient outcomes. Lastly, in human embryonic kidney cells the co-expression of CB1 and B2-AR altered the signaling properties of CB1 receptors, resulting in increased G-alpha(i)- dependent ERK phosphorylation, but decreased non-Galpha(i)-mediated CREB phosphorylation. The CB(1) receptor inverse agonist AM251 (N-(piperidin-1-yl)-5-(4- iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide) was able to attenuate beta(2)-adrenoceptor-pERK signaling in cells expressing both receptors, while the CB(1) receptor neutral antagonist O-2050 ((6aR,10aR)-3-(1-methanesulfonylamino-4-hexyn-6-yl)-6a,7,10,10a- tetrahydro-6,6,9-trimethyl-6H-dibenzo[b,d]pyran) did not. [0032] Moreover, in antagonism/inverse agonism/allosteric modulation/signaling specific inhibition/biased inhibition of the CB1 receptor, there may also be benefits to cardioprotective mechanisms with therapy alone and/or in concert with other cardioprotective medical therapies. For example, prior research indicates that allosteric modulators of the Beta-1-arrestin biased signaling of carvedilol can increase the cardioprotective mechanisms of the medication. Furthermore, at higher doses (>1 µM) rimonabant-dependent and rimonabant-independent mechanism may potentiate hormone sensitive lipase (HSL) effects on native adipocytes but also lipid droplets (LD) in excess of 25% of the maximal effect of isoproterenol, in contrast with low dose rimonabant which had no effect on LD. Notably, CB1-independent lipolysis was noted in rat models following a single dose of rimonabant (30mg/kg). [0033] Among those receiving PCI, utilizing CB1 antagonism/inverse agonism/allosteric modulation during procedural intervention represents a novel and powerful treatment modality for clearing atherosclerotic plaques, particularly because of the intrinsic risks associated with the procedure such as coronary microembolization and subsequent development of or prior history of microvascular dysfunction. Indeed, the increased odds of subsequent AMI during index admission among obese or cannabis patients relates to this physiologic action of the CB1 receptor. [0034] Finally, the CB1 receptor-stimulated ERK activation provides cellular selectivity, variable and sensitive modulation of metabolic responses which are dependent upon agonist binding characteristics, and CB1 receptor-stimulated, ligand-independent, transactivation of multiple receptor tyrosine kinases (RTKs). Chronically, CB1 activation increases the relative, proportional cellular extent of MAPK activation and ERK1/2 phosphorylation in hippocampal tissue. Moreover, selectively biasing the receptor target to CB1 inverse agonists may potentiate cardioprotective pathways that promote cell survival and decreased inflammation, such as that associated with the phosphorylation of CREB; and decrease fibrosis and chronicity of IL-6-related inflammatory signaling pathways; and modulate THC/CB1 receptor induced JNK/inflammatory transcriptional activation which is dependent upon Gai/o proteins, phosphatidylinositide 3-kinase, and Ras. Notably, gene expression and protein production of fibrogenic chemokines, monocyte chemotactic protein-1 (MCP-1, also known as C-C motif ligand 2 [CCL2]) and C-X-C motif chemokine 12 (CXCL12), are attenuated by the deletion of CB1 in murine models of bleomycin- induced fibrosis. [0035] The compilation of these findings indicates that the CB1 receptor functions to powerfully modulate B2 receptors. So much so, that the co-localization of the CB1 and B2-AR receptors shifts GPCR expression from Gαs (B2 profile/GRK5) to Galpha(i)-dependent ERK phosphorylation (CB1 profile/GRK2 profile) but decreased non-Ga(i)-mediated CREB phosphorylation. This functional pathway at the vascular smooth muscle cell is the causal mechanism of stent failure. The induction of innate and adaptive inflammatory cascades associated with the CB1 receptor potentiates VSMC migration and proliferation; IL-6 production; increased neutrophilic content and friability of atherosclerotic plaques; inhibition of Gαs mediated cardioprotective pathways; and neointimal hyperplasia chronically and stent thrombosis acutely. The evidence of these risks is validated. By utilizing CB1 modulation as a mechanism for treating and/or prevention of these deleterious outcomes, patient morbidity and mortality outcomes related to procedural stent implantation and other procedures may improve. [0036] The effect on a range of cannabinoid-dependent signaling pathways was measured via pERK1/2 (Gα_i/o mediated), β-arrestin-1 recruitment to CB1 (by BRET), phosphorylation of CREB (pCREB; suggested to be Gα_s mediated), phosphorylation of phospholipase C (pPLCβ3; suggested to be Gα_q mediated), and phosphorylation of Akt (pAkt) (Gβγ mediated). The signaling bias was calculated relative to WIN55,212-2 signaling. [0037] These preferential signaling pathways and the potency of the downstream signals they effectuate are modulated by interactions between one another, other proteins and transmembrane receptors which in turn influence conformational ligand binding states, instantiations of ligand binding activity and energy requirements therein, and other ligand-binding and receptor-receptor interactions; the duration of signal transduction, number and type of secondary effectors (nuclear/transcriptional/translational/cytoplasmic/cell membrane); the degree of down-regulation or desensitization and internalization associated with ligand-receptor binding; and the binding affinity of the CB1 ligand among available conformational states relative to other CB1 ligands and allosteric modulators. The capacity of ligands to function as either agonist or antagonist at the CB1 receptor is a functional relationship between the ligand binding efficiency and potency across isoform instantiations and in relation to other ligands present, and the receptor isoform itself. As such, THC can function as either an antagonist or an agonist depending upon the functional state of the organ itself and the activation state and persistence and potency of signaling cascades mediated through the receptor. Hence, the functional term “antagonist” or “agonist” should be interpreted in the context of the current organ milieu which represent an interplay between multiple signaling pathways with the goal of returning to baseline, homeostatic state, and the alteration or persistence of which induces inflammatory disease. [0038] The receptor-ligand proportional saturation, and the binding affinity and potency of the ligand-receptor conformational configuration; and the inflammatory signals derived from the inciting event/nidus of injury are interrelated. The low efficacy binding and promiscuity of the THC molecule and other cannabinoid congers with lower binding affinity than endogenous AEA during acute injury and catecholamine-induced release may stabilize conformational changes and signal transduction cascades diffusely enough to reach a “sublimation phase threshold” to transform signal transduction across a proportionally sufficient extent of the cellular landscape, coordinated across multiple cells and across a sufficient portion of cardiac epithelium; or within a sufficient portion of the atherosclerotic membrane (which itself is a dynamic architectural, cellular ecosystem); or through allosterically stabilizing transducing, helical conformations and interactions to overcome or satisfy an acute inflammatory threshold required for stent thrombosis. [0039] In contrast, the increased potency of interactions with AEA and other endogenous cannabinoids, decreased conformational-state binding promiscuity compared to THC, increased propensity towards Gβγ conformational isoforms which potentiate vascular smooth muscle cell proliferative pathways and adipocyte growth rather than pathways associated with resolution of insult, and increased, tonic activation and persistence of these signaling cascades and transient conformational isoform interactions in patients with obesity and complicated diabetes shift homeostatic balance toward GRK2-related pathways and together result in a more tempered, gradual “phase shift,” –solid to liquid to gas. Within the central nervous system, AEA is a high- affinity, partial agonist of the CB1 receptor, and almost inactive at the CB2 receptor; whereas 2- AG acts as a full agonist at both CBRs moderate-to-low affinity. Additionally, AEA is degraded by fatty acid amide hydrolase (FAAH) into free arachidonic acid and ethanolamine, whereas 2- AG is mostly hydrolyzed by monoacylglycerol lipase (MAGL) into arachidonic acid and glycerol, although several other enzymes could be involved in this process. Moreover, AEA can negatively regulate 2-AG biosynthesis which may contextualize the significant decrease in AEA during acute periods of vascular injury. The threshold signal from the inciting event (from STEMI vs NSTEMI), the characteristics of the inciting signal ligand (THC vs AEA/2-AG vs other), the metabolism/elimination characteristics of the inciting ligand intrinsic to the molecule itself (THC has a limited elimination profile compared to endogenous cannabinoids which are rapidly degraded in vivo), and the metabolism/elimination characteristics of the inciting ligand intrinsic to the organ system itself, and lower expression of FAAH-1 distinguishes the heart relative to other organ systems such as the brain, intestine, and testes; as well as expression of a second fatty acid amid hydrolase FAAH-2 present in primates and a variety of distantly related vertebrates , but not in murids (mice and rats); and higher expression of FAAH-2 relative to FAAH-1 in the heart. [0040] Moreover, the nonselective character of the THC molecule and other cannabinoid ligands may provide benefit in allowing for preferential or selective binding of the CB2 receptor and stabilization of conformational isoforms of the CB2 receptor. As such this added benefit may provide selective amelioration of adverse events associated with stimulation of the CB1 receptor and potentiate resolution of inflammatory signals. Additionally, the down regulation of signaling cascades which lead to monocyte recruitment into the inflammatory site functions to decrease the presence of granulocyte and monocyte/macrophage invasion and stimulation within these tissues; as well as modulate the presence of factors associated with their recruitment in acute inflammation and in chronic inflammatory response. [0041] In the case of cannabis use disorder (CUD) acutely, the strength of these interactions is potentiated by THC, preferentially activating GRK2 pathways over GRK5 by introducing an exogenous CB1 ligand (stored for long periods of time in the adipocyte and released through lipolysis) to a tonically mediated, sensitive equilibrium that is disrupted by acute injury. Within the heart of healthy individuals, the low efficacy interactions and signal cascade induced by THC-CB1 binding and subsequent conformational isoform stabilization is of so low consequence that their interactions are overshadowed by tonic interactions and endogenous signaling. However, in the setting of acute and precipitous tissue damage/inflammation or other stimulatory inciting signal, THC (acting as antagonist and/or agonist of R and R*) and other CB1 ligand-receptor complexes dimerize with Beta-arrestin molecules following endocytosis, and rather than down-regulation or desensitization, GRK2 stimulation potentiates signal transduction of GPCR conformational isoform interactions. By doing so, increased stimulation to GRK2 and inhibition of Gαs (and indirect stimulation of OPN and sustained up regulation of endothelial vasopressin (V2) receptors; and downregulation of Epac1) toward fibrosis and pathologizes traditional feedback loops. Because THC can be stored within the adipocyte, released through lipolysis, and potentiate initiating signal transduction without division or degradation in a manner similar to the fuel and propagation pattern of an atomic bomb mechanistically, such a release can be described as “Promethean” in character. Because this process has not been described before in the literature, the release of the THC molecule through catecholamine-induced lipolysis and the subsequent cascade of events will be referred to as a “Promethean Release.” Interestingly, and in line with this analogy, following the initial initiating event (STEMI/NSTEMI), the prolonged and sustained increase in inflammatory signals such as IL-6 following such an event result in what is akin to radiation exposure at the nidus of injury (the stent site); or, in the case of the adipocyte, it translocates and effectuates distant cardiovascular sites and translates to subsequent/secondary AMI. [0042] In another example, the functional consequences following and associated with stent implantation represent the transduction of these signals. Phosphorylation of ligand-CB1 receptor complex by G-protein kinase 2 (GRK2) may induce a greater translocation of β-arrestin- 1 or β-arrestin-2 compared to ligand-CB1 receptor complex alone and induces an internalization and desensitization of the receptor. These and other cellular interactions with CB1 receptor mediate transcriptional and translational amplification of inflammatory responses, unfolded protein response (URP), increased production of reactive oxygen species (ROS), and modulation of calcium and potassium ion channels within the adipocyte and other cells. In conjunction with these events, the cardiac fibroblast is stimulated to proliferate secondary to Gαs stimulation modulated by B2-AR activation and IL-6 interactions which induce receptor internalization and desensitization. [0043] TRP & CB1 ligands Binding Efficacy and Potency. Modulation of CB1-related Signal Transduction and Mitochondrial Fusion and Fission for treatment in Cardiac Arrythmia. THC has low efficacy binding to the CB1 receptor compared to other ligands. In terms of acute effects, both high potency and low potency ligands produce similar effects physiologically. However, chronically, the low efficacy of THC and other such similar congers results in more promiscuous CB1 interactions and activation within the organ-level ecosystem. Moreover, the limited elimination mechanisms and lipophilic nature of THC results in long periods of storage. In effect, because THC can function as both an antagonist and an agonist of the CB1 receptor depending upon the clinical context, the limited elimination and low efficacy function to alter phenotypic character of the adipocyte/atherosclerotic site at which it is stored. At the level of the adipocyte and across interactions within the vasculature, the balance between mitochondrial fusion and fission reactions catalyzes the translation of inflammatory signaling cascades within the intravascular and interstitial compartments and mediate the processes regulating apoptosis. The loss of the mitochondrial membrane potential, indicative of loss of mitochondrial function, recruits kinases PTEN-induced putative kinase 1 (PINK1) or JNK to the outer mitochondrial membrane and leads to an orchestrated processes which destabilizes the mitochondrial membrane in order to precipitate mitophagy and cell death. [0044] The phosphorylation of Akt and dynamin-related protein 1 (Drp1) at Serine637 and the associated pathways related to protein kinase A (PKA) phosphorylation promote cell viability by inhibition of mitochondrial-related signaling pathways; intracellular electrolyte imbalances which promote cell death through Drp1 oligomerization; induction of increased reactive oxygen species (ROS); inhibition of the constitutively active mitofusion protein 2 (MFN2); increased mitochondrial fission protein FIS1 and Drp1; and shift in metabolic activity among certain immune cells to glycolytic pathways among others. Moreover, the mitochondrial fission and outer mitochondrial membrane (OMM) destabilization occurs in the presence of high glucose and diabetes, inducing mitochondrial fragmentation through O-GlcNAcylation of OPA1 and Drp1 which eventually translocate to the outer mitochondrial membrane to precipitate apoptosis. The prevention of these mechanisms mediated by CB1 receptor antagonism/inverse agonism/allosteric modulation presents a potential therapeutic option for treatment of pathologies associated with or driven by mitochondrial dysfunction and/or abnormal metabolic pathways related to Akt signaling and vascular pathology such as cerebral ischemia, Parkinson’s disease, and Alzheimer’s disease among others. [0045] The CB1 receptor modulates electrochemical signaling within the vasculature and functions to increase parasympathetic pathways overall. The primary sympathetic fibers that innervate the heart synapse below the cervical vertebrae, while the parasympathetic fibers flow almost exclusively through the vagus nerve. Loss of central autonomic control is directly related to the level of spinal cord injury. High grade C-spine injury above T6 results in a dramatic shift in sympathetic and parasympathetic activity at the level of the heart as sympathetic efferent stimulation is significantly decreased, while the baroreceptors and parasympathetic afferent and efferent fibers remain intact. The resultant unopposed parasympathetic outflow is thought to be responsible for spinal cord injury (SCI) related bradyarrhythmias. However, the modulation of these neural, electrochemical pathways may also be also coordinated through endocannabinoid receptors. [0046] Mitochondrial activity is functionally important in electrochemical propagation and in development of arrythmia. Inhibition of sarcolemma K-ATP currents and prevention of action potential shortening, and the subsequent cellular calcium overload may promote gap junction closure and block re-entrant wave-fronts via cellular uncoupling. Upregulation of mitochondrial biogenesis associated with dual CB1 receptor agonist CB13 prevents the tachycardia-induced shortening of the effective refractory period in atrial cardiomyocytes and attenuates Connexin43 downregulation ex vivo which intimates the function of the receptors in cardiac electrical modulation. Within the cardiac ventricle and across the sarcolemma these interactions stall and inhibit the propagation of forward signal, and, within the intravascular compartment, CB1 operationalizes the vascular epithelium and adipocyte; and lipolysis as such and may have a role in the prevention of mitochondrial transfer from the white adipocyte to peripheral blood cell; and inhibition of mitochondrial biogenesis. By doing so, CB1 activation alters the mitochondrial phenotypic character, cellular electrochemical balance, and cellular cytokine production at the site at which its ligands such as THC are bound, stored, and released, and it produces and coordinates its effects across the body of the cardiac structures in the setting of inflammation and coronary microembolization. The modulation of this process can effectively alter cardiac repolarization and risk of arrythmia. [0047] Paroxysmal phase-4 paroxysmal atrioventricular block (PAVB) represents a repetitive block of atrial impulses to the ventricles. It usually develops in conjunction with increased atrial input to the AV conduction system; however, it may occasionally be initiated by a supraventricular pause, defined as bradycardia-dependent paroxysmal-AVB or phase-4 paroxysmal-AVB (PAVB). PAVB is postulated to be secondary to a) phase-4 block in which supraventricular or ventricular impulses reach a diseased His-Purkinje system (HPS) during phase- 4 of the action potential during which sodium channels are inactivated secondary to slow diastolic depolarization within diseased Purkinje cells b) frequency dependent changes in the magnitude of the slow inward current from normally polarized Purkinje fibers proximal to site of block leading to source-to-sink mismatch and exit block c) hyperpolarization during phase-4 shifting the membrane away from threshold potential. In addition, increased vagal tone is thought to play a role in accentuating these critical pauses needed to enhance phase-4 block. [0048] Physiologically the right atrium and ventricle have a greater density of parasympathetic innervation as well as concentration of transient outward potassium current (Ito) channels compared to the left atrium and ventricle. Parasympathetic output hyperpolarizes the cardiac membrane increasing the permeability to outgoing potassium (Ito) and decreasing the permeability to calcium during phase two of depolarization. By doing so, the effective refractory period at the sinoatrial and AV node is extended or shortened dependent upon parasympathetic inhibitory activity. Additionally, changes at the myocardium associated with this increased baseline parasympathetic tone produce ST elevations in the anterior leads and prolonged QTcB changes present as an early repolarization pattern that worsens with parasympathetic tone, higher lesions above T6, and higher-grade Frankel scores. The increased parasympathetic tone may lead to PAVB by hyperpolarizing the cell membrane, moving it away from threshold potential; and extending diastolic time intervals, precipitating slow diastolic depolarization within Purkinje fibers proximal to the area of impaired conductivity thereby facilitating PAVB. At the epi- and endocardium, the altered electrochemical baseline produces an environment in which acute or transient alterations in parasympathetic tone induce changes in the myocardial transmural voltage gradient, whereby a powerful Ito mediated action potential at the ventricular epicardium but not endocardium during early ventricular repolarization may inhibit forward propagation of the impulse or at the very least not facilitate conduction beyond the site of block. Finally, because retrograde conduction is maintained during PAVB, a ventricular escape beat resets baseline propagation across the area of block. Additionally, electrochemical modulation through premature ventricular contraction itself can significantly alter parasympathetic and sympathetic tone which may also provide a substrate for induction of arrythmia. As such, changes in I_to or I_kr or other ion channel kinetics and atrial or ventricular activation due to increased or decreased parasympathetic or sympathetic tone could provide the necessary substrate to induce cardiac arrythmia. [0049] Cannabinoid 1 receptor activation of cation channels, such as TRPA1, at vagally mediated or vagal-dominant receptors, may result in an increase in calcium currents and movement of the cardiac membrane potential closer to depolarization membrane potential acutely. This effect is more powerful in the presence of TRPV1, but TRPA1 is a necessary constituent of this process. However, chronically, the activation of the TRPA1 receptor leads to desensitization and decrease potency and calcium influx response at the vagal afferent neuron. As such, the down regulation of TRPA1 in cannabis use disorder or chronic congestive heart failure as well or other models of increased CB1 activation may similarly represent a more chronic and persistent stimulation of the cannabinoid one receptor overtime and following acute insult with the variability of those responses dependent upon the persistence, functional activity, and concentration of the constituent ligand of the CB1 receptor, as well as heterogeneity of the CB1 receptor and associated modulatory pathways within the organ itself. The subsequent result in electrical remodeling of the heart produces imbalance in autonomic signaling, dependent upon the potency and persistence systemically as in chronic cannabis use or at the nidus of insult as in ischemic cardiomyopathy and associated downregulation of the TRPA1 receptor. [0050] However, overall, there is an increase in endothelin-1 dependent fibrosis and significant perturbations to the cardiac electrophysiologic baseline. Notably, endothelin-1 functions as a nerve growth stimulator and chemoattractant of the CB1 receptor within niches during early embryonic development, and CB2 receptor functions to activate mTOR1 in neural progenitor cells. Cannabinoid receptor 1 in concert with other locally produced ECBs regulates neural progenitor (NP) proliferation, pyramidal specification, and axonal navigation. In addition, subcellularly restricted ECB production acts as an axonal growth cone signal to regulate interneuron morphogenesis. What is more, IL-6 and the CB1 receptor function synergistically in modulation of neurite outgrowth, and the net content of mature spines in excitatory neurons decrease over prolonged exposure to cannabinoidergic agonists. Aberrant cardiac autonomic function, decreased excitability among parasympathetic cardiac parasympathetic postganglionic (CPP) neurons, and increased heterogeneity of ventricular electrical impulses in CPP neurons characterizes type II diabetes mellitus rats pre- and post-MI. These changes in the CPP neuron remodeling highly correlate with the occurrence of ventricular arrhythmias acutely or in the setting of an MI-induced chronic heart failure. As such, an increased or decreased concentration of CB1- dependent signaling may function to disrupt signaling within the cardiac tissue following acute insult among at risk patient populations receiving operative intervention as well as over chronic periods of exposure precipitating increased heterogeneity of ventricular depolarizations. [0051] Due to the significant variability in autonomic innervation and density between the right and left heart, and atrium and ventricle, localized shifts in electrochemical potential can have significant and variable effects to autonomic sensitivity and response. Moreover, it should be noted that the activation of the CB1 receptor may function in “myocardial stunning,” preconditioning the heart following acute insult, as a protective mechanism against catecholamine induced tachycardia. The functional activation of the cannabinoid receptor modulation coupled to vagal afferent neurons precipitates movement closer to depolarization threshold potential. By altering frequency dependent oscillations in cellular potassium and calcium transit; and decreasing the electrochemical gradient between extracellular and intracellular environments; and decreasing stimulation needed to reach threshold potential; and shifting the membrane potential of the cell closer to the depolarization threshold, CB1 activation can increases the propensity of cells to undergo early after depolarizations. However, by coupling specifically to vagal neurons, the molecule may also inhibit forward propagation at the atria indirectly by facilitating sodium transit and depolarization thereby inactivating enough of the constituent cardiac myocytes from effectively producing signal propagation thereby preventing precipitation of atrial arrythmias through modulation of parasympathetic activity. By activating membrane ion channels and facilitating depolarization, the CB1 receptor functionally activates and inactivates ion channels following depolarization and prevents adequate depolarization and forward propagation of subsequent signaling inputs due to mismatch between depolarization threshold for forward propagation and inhibition of forward propagation at the site of CB1 receptor modulation. The weakened input signal cannot escape the area of increased CB1 modulation and aberrant electrical potentiation and abates. In contrast, the activation of these receptors at the ventricle inhibits the functional activity of the sympathetic inputs extending repolarization. However, because these effects are dependent upon the temporospatial, relative density of the ligand and receptor, the subsequent effects may produce divergent results among those with increased ligand availability; relative decreased receptor availability; and relative strength of concordant, counterbalanced signaling mechanism within the organ system. These effects at the ventricle specifically as noted above, may have significant clinical consequences in increasing the risk of ventricular arrythmia or R-on-T arrhythmia and precipitating or exacerbate arrythmia among other adverse complications. [0052] The functional activity of the CB1 receptor in modulation of vagal stimulation and electrochemical signaling through modulation of transient receptor protein cation channels, potassium, and sodium channels represents a mechanism by which arrythmia and modulation of arrhythmogenic disease presentation can be achieved. BRIEF DESCRIPTION OF THE DRAWINGS [0053] FIG.1 shows a representation of various pathways impacted by G protein-coupled receptor (GPCR)-kinase (GRK)-2 (GRK2). [0054] FIG.2 shows an illustration of consequences of CB1 activation or over-activation and dysregulation of the peripheral endocannabinoid system in high-fat diet-induced hyperglycaemia and obesity. [0055] FIG. 3 shows binding affinity and selectivity (CB2 vs. CB1) of different cannabinoid receptor ligands. [0056] FIG. 4 shows a representation of the docking of different exemplary antagonists in the CB1 crystal structure, including (A) CB1 binding pocket with rimonabant, otenabant, and taranabant. (B) chemical structures of rimonabant, otenabant, and taranabant, and (C) predicted binding modes of rimonabant, otenabant, and taranabant with CB1. DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS [0057] The present disclosure relates to treatment of conditions relating to cardiovascular diseases and therapy as well as respiratory diseases by administering compounds having a modulatory or inhibitory effect on cannabinoid receptor 1 (CB1). [0058] Cannabinoid receptor ligands may be functionally characterized, for example, according to: (i) Their effect upon adenylyl cyclase activity; and/or (ii) Their effect upon S-g-GTP binding. An inverse agonist will (i) stimulate adenylyl cyclase activity and (ii) inhibit IS-g-GTP binding. A neutral antagonist will (i) block the inhibition of adenylyl cyclase activity by a CB1 agonist and (2) block the stimulation of S-g-GTP binding by a CB1 agonist. A non-biased negative allosteric modulator will indirectly change agonist binding by interacting at a secondary site on the receptor to diminish the ability of the agonist to bind to the primary site. A biased allosteric modulator with signaling specific inhibition does not modify the orthostatic ligand binding and restricts the conformational changes that an agonist can induce by binding the CB1 receptor, thereby preferentially inhibiting one or more signaling pathways effectuated by the CB1 receptor. [0059] FIG.2 shows consequences of CB1 activation or over-activation and dysregulation of the peripheral endocannabinoid system in high-fat diet-induced hyperglycemia and obesity. The upregulation of endocannabinoid tone can have different effects on AEA and 2-AG (with subsequent differential impact on the activity of cannabinoid and TRPV1 receptors), and in a time- dependent way. “Early” is usually associated with high fat diet (HFD)-induced hyperglycemia and “sustained” with overt HFD-induced obesity. A neutral antagonist will (i) block the inhibition of adenylyl cyclase activity by a CB1 agonist and (2) block the stimulation of S-g-GTP binding by a CB1 agonist. [0060] The increased concentration of THC in adipocytes among chronic users results in significant differences between baseline THC serum concentration and stress-state THC serum concentration. The increased stress-state serum concentration occurs secondary to a catecholamine-induced lipolysis which releases THC and other cannabinoids from the adipocyte; and progressively increases CB1 ligand serum concentration over time in proportion to duration of inflammatory stimuli; and progressively increases CB1 receptor expression, membrane-receptor site availability, and transduction of signaling cascades effectuating transcriptional, translational, and epigenetic cellular changes at the nucleus, endoplasmic reticulum, mitochondria; and across organ systems/structures (neuro-immuno-metabolic axis) to orchestrate the inflammatory response to injury (or response to CB1 receptor activation ) at the muscular-vascular-neural interface and tight control over energy metabolism. Notably, prior reports indicate that the neuro-immune axis is affected by beta-2 adrenergic receptor activation, such that beta-2 activation on group 2 innate lymphoid cells result in a decrease cytokine production. By derivation, this would mean that those signals characteristic of “rest and digest” would lead to an up regulation of cytokine production from group 2 innate lymphoid cells. This upregulation of group 2 innate lymphoid cell cytokine production functions as a mediator of the inflammatory response and is highly organ-specific and dependent upon the extent of heteromerization and coupling of CB1 G-protein coupled receptors with beta-2 adrenergic receptors. Within the heart, the increased coupling of B2-AR with CB1 functions to alter contraction and chronotropy/ionotropy/lusitropy of the heart, through modulation of phosphorylation altering actin-myosin interactions and cross linkages; and ATP consumption, priming the heart in the setting of AMI to decrease threshold for CB1 neural inhibition as a protective mechanism against hypoxia secondary catecholamine-induced tachycardia; or, due to the specific localization of B2-AR within the cardiac sarcolemma and T-tubules, CB1-mediated signal propagation through connecting cardiac, paracrine signaling channels and/or interplay between concordance vs discordance of the mitochondrial effectors which in turn can precipitate or worsen systolic heart failure or diastolic heart failure (where exposure through microlesion, tear, or injury of the cardiac vasculature tissue occurs and/or secondary to increased vascular tone associated with chronically increased CB1 tone as in the obesity phenotype of diastolic heart failure or microvascular dysfunction); and decrease neuro- synaptic output at the pre-synaptic neuron, altering cellular electrochemical gradients/current through modulation of L-type calcium channel, outward potassium channel, and/or voltage-gated sodium channel (VGSC) permeability which in effect increases parasympathetic output and alters/decreases the propagation potential/propensity of cardiac electrical early after depolarization (EAD); increases the transmural dispersion of repolarization from epicardium to endocardium across the ventricular wall; and decreases risk of ventricular tachycardia and arrythmia and signal transduction generally (with prior studies noting increased CB1 density and VGSC-related activity at the neural soma (body) compared to dendrites or other sites, and the AEA-related stabilization of the inactive CB1 receptor channel state alongside blockade of VGSC (forming a negative feedback loop to inhibit continued neurotransmitter/cytokine production) ; and, in the immune system, the increased CB1 activation in setting of acute injury with or without THC administration modulates innate lymphoid cell and other cellular (adipocyte, vascular, neural, etc.) cytokine production. Specifically, within the heart, the decreased concentration of CB1 ligand-degrading enzymes FAAH and MAGL and/or increased expression and activity of CB1 increases the propensity of CB1 activation to reach threshold levels at which point the effects become clinically significant. This threshold is organ- specific and patient-specific, with patient-level health factors and organ-specific function influencing phenotypic presentation; and it is also affected by the differential localization of CB1 receptors within organ systems (heart vs immune system); and at different developmental or pathophysiologic cellular states (CB1/CB2 expression at different stages of B-cell development and among cancer lines compared to non-cancerous cell lines); and expression patterns over time, noting that CB1-related pathways and effects may implicate other intercellular ion channel interaction pathways; heteromerization and lipid rafts; and desensitization in response to chronic activation precipitating altered organ-level, CB1 receptor heterogeneity over time which may relate to increased risk of ventricular arrythmia among those patients with diabetes. [0061] The CB1 receptor was initially thought to be a B-Cell differentiator when it was first identified. Of note, the neuro-immune axis and activation of beta-2 adrenergic receptors (β2AR) was associated with modulation of cytokine production among group 2 innate lymphoid cells. Mitochondrial function powerfully modulates autoimmune reactive states. Notably, theβ2AR can adopt the active conformational state only in the presence of agonist and G-protein, and associates with β-arrestin in a biphasic mechanism at the C-terminal domain of β2AR and weak interactions with the receptor core thereafter. Finally, within the heart, the functional compartmentalization of organ-specific effects may result in cardiac fibroblast specific responses to cytokine production. [0062] The CB1 antagonists/inverse agonists/allosteric modulators modulate ERK/Akt pathways. The production of interleukin (IL)-6 stimulates fibroblast proliferation (but not migration) through a Beta-2 Adrenergic Receptor-related GRK5 pathway. The chemotactic properties of the activated and phosphorylated CB1 can associate with Beta-Arestin molecules and form signaling complexes, homo- and heterodimers/oligomers, and alter the pharmacological properties of these receptor complexes; as well as modulate autocrine and paracrine production and release of immunomodulators, lymphokines, and cytokines such as IL-6, TNF-alpha, and IL- 1-beta among others. CB1 signaling has previously been described. [0063] By directing the cardiac fibroblast to sites of injury (through the latter chemotaxis method) and stimulating IL-6 cytokine production, THC (and by derivation CB1) increases the risk for stent failure related to neo-intimal hyperplasia; and risk for coronary microembolization and new infarction site and/or stent neo-atherosclerosis; and increases endothelial dysfunction and stent thrombosis, in-stent restenosis, and in-stent occlusion; and potentiates the inflammatory response to injury and ischemia-reperfusion injury. [0064] Due to the increased concentration of CB1 ligand interactions at the level of the adipocyte and vascular interface, patients with history of cannabis use have a greater odds of presentation following PCI with STEMI compared to NSTEMI; increased metalloproteinase (MMP) concentration associated with increased monocyte activation and neutrophil prevalence and CB1 activation in adipocytes; altered angiotensin converting enzyme 2 (ACE-2), NADPH, eNOS, and cytokine production; and loose fibrin network within atherosclerotic plaques such that the plaques represent non-calcified lesions in contrast to calcified lesions. The latter frequently present among patients with longstanding diabetes and increases extracellular meshwork and stability of the atherosclerotic plaque. The relative lack of the longstanding comorbid conditions that engender inflammatory milieu and plaque stabilization within this population, leading to an increased propensity for calcification of plaques is absent among THC users, who are noted to be younger and with lower APDRG severity scores, compared to non-THC users. Moreover, these patients have increased incidence of stent thrombosis within four weeks among those with history of prior PCI; higher incidence of subsequent AMI following a prior MI; and higher incidence of STEMI vs NSTEMI compared to non-cannabis users. The increased risk of NSTEMI among those with history of PCI compared to those without history of PCI and increased risk of subsequent myocardial infarct during index hospitalization and subsequent myocardial infarction within four weeks after hospitalization among the THC subpopulation reflects the increased risk of coronary microembolization, and mirrors increased risk of subsequent AMI among the obese patient population. [0065] Notably, the chronic activation of the CB1 receptor associated with obesity with complicated diabetes in association with the low efficacy and potency which characterize binding characteristics of endogenous cannabinoids is associated with an increase incidence of in-stent restenosis chronically among obese patients with complicated diabetes, but also an increased risk for late stent thrombosis. The low efficacy and low binding interactions associated with increased CB1 tone among obese patients with complicated diabetes potentiate inflammatory, signaling cascades which progressively shifts serum milieu toward inflammation, neointimal hyperplasia and stent failure, but the potency of THC as determined by the relative increased odds for thrombosis as opposed to in-stent restenosis (as in obesity with complicated diabetes) may be related to binding efficacy of the THC molecule, serum concentration over time, clinical context, and chronicity of use (with chronic users exhibiting greater bioavailability of cannabinoids congers compared to other users). [0066] Moreover, the lower odds of composite all-cause stent-related failure among the cannabis use subpopulation with history of prior PCI presenting with STEMI highlights this concerning pathophysiological mechanism. The lower association of cannabis use disorder with composite all cause stent-related failure indicates that these patients have significantly higher odds of AMI—often STEMI—at new intravascular locations unrelated to the location of prior intravascular intervention/unrelated to the prior stent site. Compared to non-cannabis users, those with cannabis use disorder not only have an increased risk for stent failure, but also an increased risk of secondary acute myocardial infarct, subsequent myocardial infarction, and coronary microembolization with clinically significant sequela; and this is increasing over time in association with the liberalization of cannabis use policies at the state level and increased reporting within the USA among patients with coronary artery disease. These events are associated with the characteristic changes at the adipocyte, but also neural, muscular, and vascular changes as described above. [0067] What is more, patients with major depressive disorder have a decreased vascular relaxation in response to B2-AR agonists; or, in contrast, an increased relative response among patients with chronic heart failure. In addition to beta-2 adrenergic receptor heterodimerization, the CB1 receptor can also interact with other G-protein coupled receptors. For example, the associated perturbations in vascular endothelial response to serotonin; and serum and platelet-level serotonin levels among those with major depressive disorder (MDD) may explain the higher odds of stent failure among those with MDD. Or in another example, the inhibition of fatty acid amide hydrolase (FAAH) normalizes the cardiovascular function in hypertension. In this example, activation of CB1 receptors and dimerization of CB1 receptors with B2-AR result in CB-1 mediated and non-CB-1 mediated effects (ex. down regulation of IL-1beta; relaxation of venous system in response to B2-AR); membrane-related (ex. CB-1 and B2-AR co-localization, activation patterns, dimerization, and desensitization) and non-membrane-related effects (intracellular effects of CB1 receptor) to vascular tone and vascular relaxation. Increased serotonin is associated with increased incidence of left ventricular hypertrophy, hypertension, and diastolic heart failure, while low serotonin is associated with ischemic cardiomyopathy and coronary artery disease. Notably, these effects represent pathophysiological processes within the adipocyte and vascular endothelium. As such, the dimerization and/or interaction of CB1 receptors with B2-AR and serotonin/serotonin receptors may also function to mediate endothelial relaxation and metabolism at the adipocyte and vascular interface. The endocannabinoid system and CB1 receptor signaling cascade may operate through these and other mechanisms to influence the patient-specific clinical trajectory, morbidity, and/or mortality among those with cardiovascular disease; those with coronary artery disease; those with ischemic cardiomyopathy; those with microvascular disease; those with microvascular coronary dysfunction; those with peripheral vascular disease; those with ischemia-reperfusion injury; those with acute and/or chronic systolic heart failure; those with acute and/or chronic diastolic heart failure; those with major depressive disorder; those receiving selective serotonin release inhibitors; those with inflammation following insult (such as before/during/after PCI) or injury (such as after an acute myocardial infarction); those planning to receive PCI, or an alternative intravascular or surgical procedure; those at high risk of major adverse cardiovascular and cerebral events (MACCE) without CB1-related risk factor modification in need of prevention/amelioration of consequences of disease (in setting of continued inflammatory stimuli such as among those who continue to smoke cannabis or among those with non-calcified atherosclerotic lesions; those in need of treatment/amelioration of risk factors associated with MACCE; those in need of treatment/amelioration of risk factors associated with stent failure (Diabetes mellitus; obesity, cannabis use disorder, etc.); those in need of risk modification to prevent/treat stent-related failure and adverse outcomes; those with veno- thromboembolism or in need of treatment of veno-thromboembolism; those with cannabis use disorder; those in need of risk modification to prevent/treat inflammatory response, stricture formation, fibrosis, sclerosis, stricture progression, complications associated with stricture (such as bowel obstruction, volvulus, ischemia, etc.) following intravascular, surgical, and/or procedural intervention; those in need of treatment/prevention of athero-thrombo- embolization/microembolization/ development of micro-thromboemboli or at risk of adverse outcomes associated with therapeutic manipulation(s) or intervention(s); those in need of treatment/prevention of iatrogenic athero-thrombo-embolization/microembolization/ development of micro-thromboemboli; those in need of treatment/amelioration of cardiac arrythmia; those with history of PCI in need of risk modulation for the prevention/treatment of subsequent adverse events and outcomes; those receiving organ transplant to treat/prevent acute and/or chronic rejection; those with acute GVHD in need of treatment/amelioration of symptoms and treatment/prevention of adverse outcomes associated with organ transplant; those receiving PCI who would benefit from the use of CB1 antagonist coated balloons to prevent stent and procedural related complications; and/or those receiving PCI who would benefit from the use of CB1 antagonist coated stents to prevent stent and procedural related complications. [0068] Rimonabant and other CB1 antagonists may antagonize the activation of CB1 receptor by THC and other cannabinoid ligands. THC specifically activates CB1 receptors in the vascular tissues. This study identifies a suitable target and time period for modulation of major adverse cardiovascular and cerebral events and represents a contrast to prior studies and reports that cannabis/CB1 agonism is not associated with stent thrombosis or in-stent restenosis. The utilization of the medication in the correct clinical context is pivotal to its utility. Prior research findings and prior art suffered from low power (Beta/sample size) and type II error in distinguishing the risks and outcomes associated with CB1 modulation. The real-world evidence (RWE) and proof/validation of concept with established risk measurements using a validated dataset for outcome analysis that are encapsulated in the information herein should also emphasize the specificity of these outcomes to human patients or the human condition and provides clinical data to guide novel targeting which contrasts with the heavily non-human and animal-based (murine, pig, etc.) studies describing endocannabinoid system modulation. The limitation of these prior models of disease in translation to the characteristic innate differences are existent between species, between mouse and man, and notable differences related to fat distribution and function of white adipose tissue in rodents underscore these species-related differences. Moreover, due to the unpredictable nature of biological responses, genetic knockouts and cell-free systems may not accurately reflect human physiological responses, or the interplay between innate and adaptive responses to vascular insult. What is more, the significant differences in binding affinity of endogenous and exogenous CB1 ligands between rodents and humans; as well as the chronicity of signaling cascades associated with procedural intravascular angioplasty, stent implantation, or other procedural intervention implicate the variable cellular, physiologic, organ-level differences between animal and human models of disease and response to injury—particularly because these differences in CB1 ligand affinity which translate to differences in potentiation of CB1-related signaling cascades; and dissimilar expression and function of glycolytic and lipolytic enzymes such as PIM1 among others. Additionally, the noted differences innate immune responses in murine models are not in agreement with prior studies which note the importance of their role in pathophysiological responses associated with neointima formation after acute cardiac injury following ischemic events and/or procedural manipulation. [0069] As such, these animal models may not represent the accurate representation of clinical pathophysiologic outcomes for human patients. In describing clinical outcomes associated with CB1 modulation, the results herein represent novel research which utilizes real-world evidence to characterize rare cardiovascular disease outcomes and risk factors; and provides a elucidate of treatment/amelioration/prevention of adverse outcomes associated with cardiovascular disease by CB1 receptor modulation. These findings represent novel information which translate ECS-specific outcomes to human-specific/clinical disease presentation, and elucidate to those skilled in the art a method of treatment/prevention of adverse outcomes associated with procedural intervention for cardiovascular disease; and modulation of subsequent vascular and electrical remodeling through administration of a therapeutic dosage of CB1 receptor antagonist; inverse agonists; and/or allosteric modulator(s) during the peri-operative, intra- operative, and/or post-operative period. [0070] The person skilled in the art knows how to determine the affinity of a particular molecule for the cannabinoid receptor CB1 and thus, to determine if this particular molecule is an antagonist of the cannabinoid receptor CB1. Table 1 below shows affinities of the main cannabinoid ligands to CBR1. Table 1 aKi or Kd values are based on a previous meta-analysis of CB1R ligand affinities. [0071] FIG. 3 shows binding affinity and selectivity (CB2 vs. CB1) of different cannabinoid receptor ligands. White dots represent Ki values for CB 1 receptors, and the dark dots the Ki values for CB 2 receptors. Echinacea compounds A1 (22) and A2 (23) show similar Ki values as the CB 2 antagonist AM630 (21). [0072] The crystal structure of CB1 in complex with AM6538 reveals an expansive and complicated binding pocket network consisting of multiple sub-pockets and channels to various regions of the receptor. The three-arm ligand structure is common to CB1 antagonists and inverse agonists and may be critical for stabilizing the inherent flexibility of the native receptor in a non- signaling conformation. FIG.4 shows a representation of the docking of different antagonists in the CB1 crystal structure, specifically the crystal structure of CB1 in complex with AM6538. FIG. 4(A) shows CB1 binding pocket with rimonabant, otenabant, and taranabant. FIG. 4(B) shows chemical structures of rimonabant, otenabant, and taranabant. The rectangles represent previously described “arms” of the molecule termed arm 1/arm 2/arm 3. FIG.4(C) shows predicted binding modes of rimonabant, otenabant, and taranabant with CB1. The interacting residues are shown, as well as H178. Combining the 3D structure of CB1 and molecular docking of the three representative antagonists, which act as inverse agonists, rimonabant, otenabant, and taranabant, the role of each arm is clearly illustrated. Arm 1 is crucial for high affinity binding, while arm 2 extends into the long channel. An aliphatic or aromatic ring on arm 3 pushes on helices I and II, causing them to bend outward, and potentially modulating the pharmacological signaling state of the receptor. [0073] CB1 receptor activity may be qualified utilizing biochemical assay or other techniques. In some embodiments, biochemical assay or another method of qualifying CB1 receptor expression and/or activity will be utilized in the treatment of a subject receiving procedural intervention and to qualify treatment/therapy utilizing CB1 antagonists/inverse agonists/allosteric modulator before, during, or after procedural intervention for a subject in need thereof. [0074] In some embodiments, the inhibitor, antagonist or modulator of the cannabinoid receptor CB1 has an IC₅₀ for inhibiting CB1R-agonist-induced G protein [³⁵S][GTPγS] activation from about 1 nM to about 25 nM. In other embodiments, the antagonist has an IC₅₀ from about 1 µM to 1 nM, 1.0 µM to 0.1 µM, or 0.1 µM to .01 nM. In other embodiments, the allosteric modulator has an IC₅₀ for inhibiting MAPK phosphorylation of 1 nM to about 350 nM Preferably, such a cannabinoid antagonist is selective for the CB1 receptor and has an IC₅₀ for the CB1 receptor which is one-fourth or less than that of the CB2 receptor or, more preferably, is one-tenth or less than the IC₅₀ for the CB2 receptor, or even more preferably, an IC₅₀ so with respect to the CB1 receptor which is one-hundredth that for the CB2 receptor. [0075] The exemplary inhibitors, antagonists or modulators of the cannabinoid receptor CB1 can be, among others, proteins, peptides or small organic molecules. Illustrative non- limitative examples of inhibitors and/or antagonists and/or modulators of the cannabinoid receptor CB1 include the compounds of Table 2 below or pharmaceutically acceptable salts thereof. Table 2

[0076] In a particular embodiment, the inhibitor, antagonist or modulator of the cannabinoid receptor CB1 is selected from the group consisting of the compounds of Table 2 or pharmaceutically acceptable salts thereof. In preferred embodiments, the antagonist of the cannabinoid receptor CB1 is selected from 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N- (1- piperidyl)pyrazole-3-carboxamide, (6aR.10aR)-3-(1-methanesulfonylamino-4-hexyn-6-yl)- 6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzob. dpyran, N-(2S,3S)-4-(4-chlorophenyl)-3-(3- cyanophenyl)-2-bu tanyl-2-methyl-2-5-(trifluoromethyl)-2-pyridinyl oxypropanamide, 5-(4- bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1- piperidinyl)-1H-pyrazole-3-carboxamide, 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-(4-chlorophe nyl)-sulfonyl-4-phenyl-4,5-dihydro-1H- pyrazole-1- carboxamidine, (+)-N-1-bis(4-chlorophenyl)methyl-3-azetidinyl-N- (3,5- difluorophenyl)-methanesulfonamide, 1-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6- yl)- 4-(ethylamino)piperidine-4-carboxamide, and (+)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N- (1-piperidinyl)-4,5-dihydro-1H-pyrazole-3-carboxamide or a pharmaceutically acceptable salt thereof. [0077] The term “pharmaceutically acceptable salt thereof, as used herein, refers to derivatives of the compounds of Table 2 wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from 1.2-ethanedisulfonic, 2-acetoxybenzoic, 2-hy-droxyethanesulfonic, acetic, ascorbic, benzenesulfonic, benzoic, bicarbonic, carbonic, citric, edetic, ethane disulfonic, ethane Sulfonic, fumaric, glucoheptonic, gluconic, glutamic, glycolic, glycolyarsanilic, hexylresorcinic, hydrabamic, hydrobromic, hydrochloric, hydroiodide, hydroxymaleic, hydroxynaphthoic, isethionic, lactic, lactobionic, lauryl Sulfonic, maleic, malic, mandelic, methanesulfonic, napsylic, nitric, oxalic, pamoic, pantothenic, phenylacetic, phosphoric, polygalacturonic, propionic, Salicyclic, Stearic, Subacetic, Succinic, Sulfarnic, Sulfanilic, Sulfuric, tannic, tartaric, and toluenesulfonic. [0078] The pharmaceutically acceptable salts of the compounds of Table 2 can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two: generally, non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are useful. [0079] In a preferred embodiment of the invention, the antagonist of the cannabinoid receptor CB1 is the compound 5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N- (piperidin-1-yl)-1H-pyrazole-3-carboxamide (or “rimonabant” or “SR141716A) or a pharmaceutically acceptable salt thereof such as INV-200 (MRI-1891). Thus, in a particular embodiment, the invention is related with the compound 5-(4-Chlorophenyl)-1-(2,4- dichloro- phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole 3-carboxamide or a pharmaceutically acceptable salt thereof for use in the prevention or treatment of pathological conditions associated with coronary atherosclerotic disease and percutaneous coronary or alternative intravascular intervention. [0080] The term “acutely,” as used herein, refers to a method of administration in which the patient is exposed to a single dose of the antagonist of the cannabinoid receptor CB1, preferably the compound 5-(4-Chlorophenyl)-1-(2,4- dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H- pyrazole 3-carboxamide or a pharmaceutically acceptable Salt thereof, or a multiple dose but for a reduced period of time like for example 1, 2, 4, 6, 8, 10, 12, 16, 20, 24 hours or 2, 3, 4, 5, or 6 days. [0081] In a particular embodiment, the antagonist of the cannabinoid receptor CB1, preferably the compound -(4- Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1- yl)-1H-pyrazole-3-carboxamide or a pharmaceutically acceptable salt thereof is administered chronically, preferably for a period of at least 7 days. [0082] The antagonist of the cannabinoid receptor CB1, preferably the compound -(4- Chlorophenyl)-1-(2,4- dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole 3-carboxamide or a pharmaceutically acceptable Salt thereof, may be administered by any suitable administration route, such as, but not limited to, parenteral, oral, topical, nasal, rectal route. In a particular embodiment, the antagonist of the cannabinoid receptor CB1, preferably the compound -(4- Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide or a pharmaceutically acceptable salt thereof, is administered orally. In another particular embodiment, the antagonist of the cannabinoid receptor CB1, preferably the compound -(4- Chlorophenyl)- 1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H pyrazole-3-carboxamide or a pharmaceutically acceptable salt thereof is administered by parenteral route, e.g. by intravenous, intraperitoneal, intracranial, subcutaneous, intradermal, intramuscular, intrathecal or epidural administration. In a more particular embodiment, it is administered intraperitoneally. In another particular embodiment, it is administered intracranially. In another particular embodiment, it is administered intranasal. [0083] The term “therapeutically effective amount,” as used herein, refers to the sufficient amount of the compound to provide the desired effect and will generally be determined by, among other causes, the characteristics of the compound itself and the therapeutic effect to be achieved. It will also depend on the subject to be treated, the severity of the disease suffered by said subject, the chosen dosage form, administration route, etc. For this reason, the doses mentioned in this invention must be considered only as guides for the person skilled in the art, who must adjust the doses depending on the aforementioned variables. In an embodiment, the effective amount produces the amelioration of one or more symptoms of the disease that is being treated. [0084] The pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabilizer should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material will depend on the route of administration. Pharmaceutical compositions for oral administration may be in tablet, capsule, powder or liquid form. A tablet may comprise a solid carrier or an adjuvant. Liquid pharmaceutical compositions generally comprise a liquid carrier such as water, petroleum, animal or vegetable oils, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. A capsule may comprise a solid carrier such as gelatin. For intravenous, cutaneous or subcutaneous injection, the active ingredient will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has a suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as sodium chloride solution, Ringer’s solution, or lactated Ringer’s solution. Preservatives, stabilizers, buffers, antioxidants and/or other additives may be included as required. [0085] In another aspect, there is provided the use in the manufacture of a medicament a therapeutically effective amount of a pharmaceutical composition for inhibiting or modulating cannabinoid receptor 1 for administration to a patient as described herein. [0086] In a particular embodiment, the cannabinoid receptor CB1, preferably the compound -(4-Chlorophenyl)-1-(2,4- dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole 3-carboxamide or a pharmaceutically acceptable salt thereof is administered intraperitoneally at .5-1.5 mg/kg of body mass per day, for seven consecutive days or more. [0087] In a particular embodiment, the cannabinoid receptor CB1, preferably the compound -(4-Chlorophenyl)-1-(2,4- dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole 3-carboxamide or a pharmaceutically acceptable salt thereof is administered intravenously at 0.5- 1.5 mg/kg of body mass per day, for seven consecutive days. [0088] In another particular embodiment, the cannabinoid receptor CB1, preferably the compound -(4-Chlorophenyl)- 1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H pyrazole- 3-carboxamide or a pharmaceutically acceptable salt thereof is administered orally at 0.5-1.5 mg/kg of body mass per day, for seven consecutive days. [0089] In a particular embodiment, the cannabinoid receptor CB1, preferably the compound -(4-Chlorophenyl)-1-(2,4- dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole 3-carboxamide or a pharmaceutically acceptable salt thereof is administered intraperitoneally at 0.5-1.5 mg/kg of body mass per day, for seven consecutive days or more. [0090] In another particular embodiment, the cannabinoid receptor CB1, preferably the compound -(4-Chlorophenyl)- 1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H pyrazole- 3-carboxamide or a pharmaceutically acceptable salt thereof is administered intravenously at 0.5- 1.5 mg/kg of body mass per day, for seven consecutive days. [0091] In another particular embodiment, the cannabinoid receptor CB1, preferably the compound -(4-Chlorophenyl)- 1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H pyrazole- 3-carboxamide or a pharmaceutically acceptable salt thereof is administered orally at 0.5-1.5 mg/kg of body mass per day, more than seven consecutive days. [0092] In a particular embodiment, the cannabinoid receptor CB1, preferably the compound (R,E)-N-(N-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4- (trifluoromethyl)phenyl)sulfonamido)methylene)carbamimidoyl)acetamide ((S)-MRI-1891or a pharmaceutically acceptable salt thereof is administered intraperitoneally at 0.1-40 mg/kg of body mass per day, for seven consecutive days or more. [0093] In a particular embodiment, the cannabinoid receptor CB1, preferably the compound (R,E)-N-(N-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4- (trifluoromethyl)phenyl)sulfonamido)methylene)carbamimidoyl)acetamide or a pharmaceutically acceptable salt thereof is administered intravenously at 0.1-40 mg/kg of body mass per day, for seven consecutive days. [0094] In another particular embodiment, the cannabinoid receptor CB1, preferably the compound (R,E)-N-(N-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4- (trifluoromethyl)phenyl)sulfonamido)methylene)carbamimidoyl)acetamide or a pharmaceutically acceptable salt thereof is administered orally at 0.1-40 mg/kg of body mass per day, for seven consecutive days. [0095] In a particular embodiment, the cannabinoid receptor CB1, preferably the compound (R,E)-N-(N-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4- (trifluoromethyl)phenyl)sulfonamido)methylene)carbamimidoyl)acetamide or a pharmaceutically acceptable salt thereof is administered intraperitoneally at 0.1-40 mg/kg of body mass per day, for seven consecutive days or more. [0096] In another particular embodiment, the cannabinoid receptor CB1, preferably the compound (R,E)-N-(N-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4- (trifluoromethyl)phenyl)sulfonamido)methylene)carbamimidoyl)acetamide or a pharmaceutically acceptable salt thereof is administered intravenously at 0.1-40 mg/kg of body mass per day, for seven consecutive days. [0097] In another particular embodiment, the cannabinoid receptor CB1, preferably the compound (R,E)-N-(N-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4- (trifluoromethyl)phenyl)sulfonamido)methylene)carbamimidoyl)acetamide or a pharmaceutically acceptable salt thereof is administered orally at 0.1-40 mg/kg of body mass per day, more than seven consecutive days. [0098] In a particular embodiment, the cannabinoid receptor CB1, preferably the compound (R,E)-N-(N-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4- (trifluoromethyl)phenyl)sulfonamido)methylene)carbamimidoyl)acetamide ((S)-MRI-1891or a pharmaceutically acceptable salt thereof is administered intraperitoneally at 0.1-40 mg/kg of body mass per week, for three to six consecutive months. [0099] In a particular embodiment, the cannabinoid receptor CB1, preferably the compound (R,E)-N-(N-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4- (trifluoromethyl)phenyl)sulfonamido)methylene)carbamimidoyl)acetamide or a pharmaceutically acceptable salt thereof is administered intravenously at 0.1-40 mg/kg of body mass per week, for three to six consecutive months. [0100] In another particular embodiment, the cannabinoid receptor CB1, preferably the compound (R,E)-N-(N-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4- (trifluoromethyl)phenyl)sulfonamido)methylene)carbamimidoyl)acetamide or a pharmaceutically acceptable salt thereof is administered orally at 0.1-40 mg/kg of body mass per week, for three to six consecutive months. [0101] In a particular embodiment, the cannabinoid receptor CB1, preferably the compound (R,E)-N-(N-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4- (trifluoromethyl)phenyl)sulfonamido)methylene)carbamimidoyl)acetamide or a pharmaceutically acceptable salt thereof is administered intraperitoneally at 0.1-40 mg/kg of body mass per week, for more than three to six consecutive months. [0102] In another particular embodiment, the cannabinoid receptor CB1, preferably the compound (R,E)-N-(N-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4- (trifluoromethyl)phenyl)sulfonamido)methylene)carbamimidoyl)acetamide or a pharmaceutically acceptable salt thereof is administered intravenously at 0.1-40 mg/kg of body mass per week, for more than three to six consecutive months. [0103] In another particular embodiment, the cannabinoid receptor CB1, preferably the compound (R,E)-N-(N-((3-(4-chlorophenyl)-4-phenyl-4,5-dihydro-1H-pyrazol-1-yl)((4- (trifluoromethyl)phenyl)sulfonamido)methylene)carbamimidoyl)acetamide or a pharmaceutically acceptable salt thereof is administered orally at 0.1-40 mg/kg of body mass per week, for more than three to six consecutive months. [0104] Therapeutic dose refers to the required amount to achieve a desired effect, such as IC50. One skilled in the art understands the required dose required to achieve a therapeutic effect. In one embodiment the treatment dosage consists of administering a CB1 antagonist/inverse agonist/allosteric modulators/signaling specific inhibitor/cannabinoformins preferentially rimonabant (1mg/kg I.V.; 8-75mg oral rimonabant) or MI-1891 or biosimilar salt pre-operatively at an increased loading dose followed by a daily dosing regimen thereafter following procedural intervention for duration 6 months or more, for example MI-1891: 1-30 mg/kg followed by 0.5-3 mg/kg/day. In another, the subject receives the medication orally following the procedure for a shortened period of time (3 months) due to patient specific risk factors through peri-operative I.V and/or oral administration with an decreased loading dose or without a loading dose. In another embodiment the medication may be taken in IV or oral formulation in combination with other pharmaceutical preparations or alone for a limited duration of time at different administration frequencies such as twice daily I.V.; twice daily (every 12 hours) orally; every other day with or without breakfast for seven days or less; or one month or less; or three months or less, etc. Notably, as seen in a previous clinical trial, rimonabant administration can inhibit adipocyte growth in vivo. Clearance of microvascular micro-atheroembolic debris by inverse agonists, signaling specific inhibition of the cannabinoid receptor 1; and/or modulation with cannabinoformins/canabinomimetics and amelioration and/or reversal of adverse outcomes by the therapeutic administration of CB1 receptor antagonist/inverse agonist/allosteric modulator during the peri-operative period prior to intravascular intervention, during intravascular intervention, and/or after intravascular intervention depending upon the desired goal of treatment in a subject in need of treatment, and balancing the risks of adverse side effects in a treated subject associated with perturbations in wound healing and/or contraction of scar tissue and/or ventricular remodeling and/or ventricular rupture and/or ventricular aneurysm, etc.. As such, it is not only the risk of stent failure, but poignantly, the risk of secondary or subsequent acute myocardial infarct and coronary microembolization and associated sequala, in addition to stent failure at the primary stent location, which represent nidi of pathophysiological processes at which CB1 modulation, utilizing CB1 antagonist, inverse agonist, and/or allosteric modulators may have significant therapeutic/treatment benefit. [0105] It is to be further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the compositions, and that the concentration ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the claimed compositions and methods. The findings noted here represent real world evidence validating this fundamental mechanism. In order to ameliorate these adverse events and modulate procedural- and health-related outcomes for patients in whom this phenomenon occurs, described herein is a therapeutic method of treatment of a subject undergoing percutaneous coronary intervention; or any other alternative intravascular procedure; or invasive or non-invasive surgical procedure, resultant from or the result of which will be an increased inflammatory response, increased CB1 activation, and increased risk of worsening or new, major adverse cardiovascular and cerebral events or poor interventional outcomes by administration of a therapeutic amount of a CB1 antagonist, inverse agonist, and/or allosteric modulators in a subject in need thereof that will result in amelioration, prevention, and/or treatment of cardiovascular and cerebral disease as described above or in other embodiments and/or presentation of disease. The description here is not to impose a limit on the described invention and this description should not limit the alternative embodiments to which the invention may apply. [0106] Accordingly, a first preferred embodiment disclosed herein is a method for prevention and treatment of diseases associated with cardiovascular therapy in a patient through peri-procedural administration of a pharmaceutical composition for inhibiting or modulating cannabinoid receptor 1. The patient may have a history of cannabis use, but the method is effective for prevention and treatment of diseases amongst non-cannabis users as well. As used herein, a “history of cannabis use” means prior or current use of any substance or compound which binds to the cannabinoid receptor through any route of administration for any duration or at any period of time. The method may include a step of administering a first dose of the pharmaceutical composition to the patient within a first time period before or substantially concurrently with performing the cardiovascular therapy on the patient. In preferred embodiments, a first time period before performing the cardiovascular therapy can be at any time within one month before the therapy is performed and the first dose may be 0.01 to 40 mg of the pharmaceutical composition per kilogram (kg) of the patient’s body weight. [0107] The term “substantially concurrently with” as used herein means at about the same time as the therapy is performed, or at any point during the process of performing the therapy on the patient. [0108] In preferred embodiments, the pharmaceutical composition comprises a therapeutically effective amount of an inhibitor or modulator of cannabinoid receptor 1 and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, stabilizer, or mixture thereof. [0109] In additional preferred embodiments, the cardiovascular therapy comprises a medical procedure relating to treating a cardiovascular disease, such as percutaneous coronary intervention, coronary artery bypass surgery or stent placement. Examples of diseases associated with these cardiovascular therapies include coronary artery disease, coronary microembolization, atheromatous embolism, stent thrombosis, stent restenosis, stent occlusion, coronary artery bypass graft thrombosis, coronary artery bypass graft stenosis, coronary artery bypass graft occlusion, congestive heart failure, myocardial infarction, coronary artery disease, microvascular coronary dysfunction, cardiac arrhythmia, peripheral vascular disease, or combinations thereof. [0110] The term “peri-procedural” as used herein means before, during, and after the performance of the cardiovascular therapy. [0111] The pharmaceutical composition may be administered by intravenous, intraperitoneal, intracranial, subcutaneous, intradermal, intramuscular, intrathecal, intranasal or epidural administration. [0112] The method of claim 1, wherein the inhibitor or modulator of cannabinoid receptor 1 is 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1-piperidyl)pyrazole-3- carboxamide,(6aR.10aR)-3-(1-methanesulfonylamino-4-hexyn-6-yl)- 6a,7,10,10a-tetrahydro- 6,6,9-trimethyl-6H-dibenzob. dpyran, N-(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)-2-bu tanyl-2-methyl-2-5-(trifluoromethyl)-2-pyridinyl oxypropanamide, 5-(4-bromophenyl)-1-(2,4- dichlorophenyl)-4-ethyl-N-(1- piperidinyl)-1H-pyrazole-3-carboxamide, 4S-(-)-3-(4- chlorophenyl)-N-methyl-N'-(4-chlorophe nyl)-sulfonyl-4-phenyl-4,5-dihydro-1H-pyrazole-1- carboxamidine, (+)-N-1-bis(4-chlorophenyl)methyl-3-azetidinyl-N-(3,5-difluorophenyl)- methanesulfonamide,1-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6- yl)-4- (ethylamino)piperidine-4-carboxamide, and (+)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(1- piperidinyl)-4,5-dihydro-1H-pyrazole-3-carboxamide or a pharmaceutically acceptable salt thereof. [0113] In additional preferred embodiments of the method described herein, one or more subsequent doses of the pharmaceutical composition to the patient are administered to the patient within subsequent time periods after performing the cardiovascular therapy on the patient. The subsequent doses may be 0.1 to 40 mg per kg of patient body weight, and each subsequent dose may be administered at varying intermittent intervals over varying periods of time. In some preferred embodiments, the subsequent doses are administered once every one to four hours for twenty-four hours after performing the cardiovascular therapy on the patient. In additional preferred embodiments each subsequent dose is administered once a day for seven days after performing the cardiovascular therapy on the patient. In further preferred embodiments each subsequent dose is administered once a week for three to six months after performing the cardiovascular therapy on the patient. [0114] Additional preferred embodiments disclosed herein relate to a method for prevention and treatment of diseases associated with cardiovascular therapy in a patient through acute administration of a pharmaceutical composition for inhibiting or modulating cannabinoid receptor 1. Preferred embodiments of this method include administering a single dose of a preferred embodiment of the pharmaceutical composition as described herein to the patient, where the dose may be 0.01 to 40 mg per kg of patient body weight, within a time period substantially concurrently with performing the cardiovascular therapy on the patient. [0115] Additional preferred embodiments disclosed herein include a method for prevention and treatment of diseases associated with activation or overactivation of cannabinoid receptor 1 through administration of preferred embodiments of the pharmaceutical composition for inhibiting or modulating cannabinoid receptor 1 that is described herein in a single dose or in multiple doses. The diseases associated with activation or overactivation of cannabinoid receptor 1 may be COVID-19, obesity, diabetes, stroke, fibrosis, keloid formation, or combinations thereof. If the pharmaceutical composition is administered in multiple doses, the subsequent doses may be administered once every one to four hours for twenty-four hours after administering the first dose, once a day for seven days to three years after administering the first dose, or once a week for one to six months after administering the first dose to the patient. [0116] In preferred embodiments, administration of the compositions can be systemic or local, and may comprise a single injection of a therapeutically effective amount of the CB1 antagonist/inverse agonist/allosteric modulator, or repeated administrations and dosing to achieve a therapeutic effect. The formulations for such therapy may be based on the route of administration and may include liposome and micelle formulations as well as classic pharmaceutical preparations including polymer coatings, films and fiber or stents, bandages, sutures and transdermal patches. These formulations may be incorporated into a stent or other device by dip coating, electro-treated coating, plasma-treated coating, and spray coating known to those of skill in the art. A biocompatible device comprising a CB1 receptor antagonist/inverse agonist/allosteric modulators/signaling specific inhibitor/cannabinoformins compound, the device being configured for deployment into a subject's vascular system selected from the cardiovascular system, the peripheral vascular system or both, such that upon deployment of the device in said subject's vascular system, said CB1 receptor antagonist/inverse agonist/allosteric modulators/signaling specific inhibitor/cannabinoformins compound is released from the device in an amount effective to treat or prevent at least one condition specified; or a device, comprising a radially expandable wire, stent or balloon, perforated tube, catheter, intravascular needle, bioresorbable scaffold, bioresorbable polymer, or an ostial stent or balloon; a device, comprising said CB1 receptor antagonist/inverse agonist/allosteric modulators/signaling specific inhibitor/cannabinoformins compound by means of impregnation into a component of the device, coating or deposition onto a surface of the device, sequestering in holes, grooves, or pores of the device or sequestering within an inner space of the device; and/or a device, wherein said CB1 receptor antagonist/inverse agonist/allosteric modulators/signaling specific inhibitor/cannabinoformins compound is formulated into a pharmaceutical composition comprising a physiologically acceptable carrier permitting in situ release of the CB1 receptor antagonist/inverse agonist/allosteric modulators/signaling specific inhibitor/cannabinoformins compound, said release being at least at the area of insertion of the device in the vascular system. These devices may be utilized for cardiovascular stents in the coronary artery stent, intracranial stent, peripheral vascular stent, biliary stent, esophageal stent, or other stent type. Any route known to those of skill in the art for the administration of a therapeutic composition of the invention is contemplated. EXAMPLES AND SUPPORTING DATA A Quasi-Experiment: Cannabis Use, The Cannabinoid Receptor 1, and Stent Thrombosis and In-Stent Restenosis Using the National Inpatient Sample [0117] Importance: The association between cannabis use disorder (CUD) and cardiovascular outcomes among chronic ischemic heart disease and/or coronary artery disease (CAD) patients receiving percutaneous intervention (PCI) is unknown. [0118] Findings: In patients with chronic coronary artery disease, with or without prior stent placement, cannabis use was associated with significantly higher odds of stent thrombosis (STS) and in-stent restenosis (ISR) and earlier age of adverse events compared to those with no cannabis use. [0119] Meaning: Active cannabis use is a significant risk factor for peri- and post- procedural adverse events, subsequent acute myocardial infarction, and associated with higher risk for stent thrombosis, ISR, and all-cause stent failure compared to non-users. Modulation of the ECS peri-procedurally may ameliorate symptoms and decrease adverse events among those receiving PCI or other intravascular procedural manipulation or device internal implantation. [0120] Participants: Adults (^18 years-old) identified from 2016-2020 National Inpatient Sample database with ICD-10-CM codes indicating primary admission diagnosis of acute myocardial infarction (AMI: defined as ST elevation myocardial infarction (STEMI) or non-ST elevation myocardial infarction (NSTEMI)) and history of coronary artery disease with or without history of PCI prior to index hospitalization who received procedural percutaneous coronary intervention during index hospitalization. Propensity-score matching used age, primary insurance type, length of stay, hospital characteristics, comorbid conditions, medications, and population median Elixhauser sum. [0121] Main Outcome: primary outcome: Composite all-cause stent failure (stent thrombosis, in-stent restenosis, stent occlusion, Coronary Artery Bypass Graft (CABG) occlusion, CABG artery or vein atherosclerosis, CABG thrombosis; secondary outcomes: composite all- cause stenosis (in-stent restenosis, stent thrombosis, CABG stenosis, CABG thrombosis; In-stent Restenosis; Stent thrombosis [0122] Results: [0123] 20,535 patients with cannabis use disorder (CUD) and 1,043,090 without cannabis use disorder (N-CUD) were identified who met the inclusion criteria. The mean age of CUD 53.06 +/- 0.17 years old (y.o.) with 80.20% males; and 65.29y.o. +/- 0.03 with 67.62% males for N-CUD (p≤0.001 for both). Between 2016 and 2020, there was a significant positive temporal relationship between in-stent restenosis and time on multivariable linear regression (Beta-coefficient, Confidence Interval: [Lower Bound, Upper Bound], p-value, Beta-coefficient: 0.0083061, [0.007548, 0.0090641, p≤0.001). However, there was a negative temporal relationship between thrombosis and time on multivariable linear regression (Beta-coefficient: -0.0003544, [ - 0.0006432, -0.0000656], p=0.02, respectively). Mean length of stay (LOS) for CUD (3.69 ± 0.01 days) was significantly greater than that of N-CUD (3.15 ±0.05 days, p≤0.001). The total charge for CUD was ($113,184.4 ±232.36) was significantly greater than that of N-CUD ($107,825.1 ±1,430.11, p≤0.001). CUD-A was significantly associated with primary STEMI compared to primary NSTEMI (OR: 1.26, [1.18-1.35, p≤0.001); and thrombosis among those with no history of PCI or CABG presenting with primary AMI diagnosis receiving index PCI (CUD-A(N=10,565) vs those without CUD-A (N=503,055); 1.04% vs.0.68%, p≤0.05). Finally, from 2016-2020, on propensity-score matched analysis among CAD encounters with history of graft or stent presenting with primary NSTEMI or STEMI and receiving index PCI (Matched Observations=49,625), the all-cause stent failure adverse event rate was 9.75% higher for active cannabis use compared to others (ATE: .0975, [0. 0523, 0.1427], p≤0.001); and the all-cause stenosis rate (Matched Observations= 49,625) was 12.75% greater for CUD-A compared to others (ATE: 0.1275, [0.0830, 0.1719], p≤0.001). [0124] Conclusions and Relevance: Cannabis use and CB1 activation is associated with higher odds of stent failure and younger age at presentation compared to no cannabis use. Moreover, the lower incidence of adverse events among the STEMI population indicates an increased risk for non-stent related new AMI among this population likely secondary to peri- procedural microembolization. [0125] There is limited recent data on the incidence, predictors, and outcomes of acute in- hospital stent thrombosis and in-stent restenosis (STS) following AMI treated with PCI, particularly among populations at increased risk of major adverse cardiovascular events (MACE) such as those with history of cannabis use. Percutaneous intervention represents a valuable therapeutic tool in the treatment of ischemia. Atherosclerotic burden, microvascular disease, and plaque composition (i.e., non-calcified vs mixed vs calcified); prior history of vascular intervention; and architectural distribution or presence of overlying edges are particularly important. For example, complicated diabetes mellitus induces a state which represents an extreme example of vascular endothelial remodeling, and is associated with more extensive atherosclerosis, a greater propensity for forming longer lesions encapsulated by a higher density necrotic core, a smaller lumen area, and larger calcium content. These changes as well as other risk factors associated with AMI influence outcomes of adverse events among those undergoing PCI and even the subsequent type of AMI. [0126] Delta-9-tetrahydrocannabinol (THC) belongs to a family of plant-based phytocannabinoids with functional activity at the cannabinoid receptor as well as modulation of intracellular and extracellular calcium ion channels such as TRPV2, among others. However, other endogenous cannabinoids (arachidonoylethanolamide (anandamide [AEA]) and 2- arachidonoylglycerol (2-AG)); phytocannabinoids, and synthetic cannabinoids also function as bioactive lipid mediators capable of modulating cannabinoid receptor responses within liver, skeletal muscle, heart, gut, bones, and adipose tissue. Two of the most abundant cannabinoids within cannabis are THC, the principal psychoactive component of cannabis, and cannabidiol. THC functions as a cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) partial agonist, while cannabidiol is a non-competitive negative allosteric modulator of CB1 and CB2, Cannabinoid receptors (CB₁ and CB₂) are distributed in multiple tissue beds and cell types. Cannabinoid effects related to activation of the CB₁ receptor modulate sympathetic activation, cytokine production, and increased interleukin (IL) production. On the other hand, its function at CB2 receptors, localized primarily in immune cells – the tonsils, spleen, PBMC (Peripheral Blood Mononuclear Cells), microglia, and thymus—and can function as an inhibitor of adenylate cyclase as well as modulate ion channels independent of the cannabinoid receptors. [0127] The plasma half-life of THC is approximately 1-3 days in occasional users and 5- 13 days in chronic users; and cannabidiol half-life is 18-32 hours. However, both cannabidiol and THC are highly lipophilic with a long elimination half-life within adipocytes, and under normal conditions, they passively diffuse from fat back into blood. THC can be observed in fat cells biopsy up to 28 days after last use, with presence in the urine among chronic, heavy users after 77 days, despite extended periods of abstinence. Notably, the accumulation, storage, and release of THC and its metabolites in adipose tissue, and its serum concentrations over time and in specific settings are not stagnant. Sympathetic activation of catecholamine-induced lipolysis may enhance the transient shifts in the serum THC concentrations, increasing over time in relation to extent and duration of ACTH stimulation or food deprivation. As such, the functional activity of THC may not be limited to its acute effects, and its functional components stored in adipocytes and released into the serum may function to modulate the endocannabinoid system (ECS) long after last use. In this respect, the long-term storage and release of THC may play a role in modulating the effects and outcomes associated with intravascular intervention such as PCI (Percutaneous Coronary Intervention) as well as the associated procedural outcomes of disease among those patients hospitalized with acute myocardial infarction (AMI). [0128] There is limited recent data on the incidence, predictors, and outcomes of acute in- hospital stent thrombosis or in-stent stenosis (STS) following acute myocardial infarction (AMI) treated with percutaneous coronary intervention (PCI), particularly among populations at highest risk of adverse complications. Percutaneous intervention represents a valuable therapeutic tool in the treatment of ischemia. However, while ischemia has long been considered the most important predictor of major adverse cardiac events (MACEs), ischemia may not be the only clinically relevant risk factor for prediction of cardiovascular outcomes, particularly, among diabetic patients. Atherosclerotic burden, microvascular disease, and plaque composition (i.e., non- calcified vs mixed vs calcified); and architectural distribution or presence of overlying edges are particularly important. [0129] The increased risk of major adverse cardiovascular events (MACE) and strong associations between diabetes and insulin resistance both acutely and chronically among those at risk of adverse events implicates metabolic dysregulation in the pathophysiological mechanism of atherosclerotic disease. Additionally, vascular injury and coagulopathy associated with endothelial dysfunction are also implicated in adverse outcomes, with current guidelines recommending the use of dual antiplatelet therapy (DAPT) for 3-6 months following intervention. As such, it was hypothesized that the functional consequences of ECS modulation associated with cannabis use may increase inflammatory responses associated with PCI and result in worse inpatient outcomes generally among AMI-related hospitalizations when controlling for other factors, including tobacco use disorder, antiplatelet therapy, and anticoagulation therapy. Using the Nationwide Inpatient Sample (NIS) database, incidence, predictors, and outcomes of PCI for cannabis use disorder (CUD) patient encounters and non-cannabis users (N-CUD-A) patient encounters among those hospitalized from January 2016 to December 2020 was analyzed. [0130] Methods: [0131] Study Population: [0132] The National Inpatient Sample database was queried from January 2016 to December 2020 to identify all patients aged ^18 years presenting with ICD-10-CM codes indicating primary admission diagnosis of acute myocardial infarction (AMI) defined as primary admission diagnosis of ST elevation myocardial infarction (STEMI) or non-ST elevation myocardial infarction (NSTEMI) and history of coronary artery disease with or without history of PCI prior to index admission who received percutaneous coronary intervention during index hospitalization. The NIS database is the largest publicly available all-payer inpatient healthcare database designed to produce U.S. regional and national estimates of inpatient utilization, access, charges, quality, and outcomes. [0133] Definitions: [0134] Acute myocardial infarction (AMI) was identified using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10-CM) diagnosis code of STEMI/NSTEMI in the primary position on a medical claim, inclusive of inpatient hospital encounters. Similarly, cannabis use was identified using ICD-10-CM diagnosis code corresponding to history of active cannabis abuse or dependence (CUD-A; ICD-10 CM: F1210, F12120, F12121, F12122, F12129, F1213, F12150, F12151, F12159, F12180, F12188, F1219, F1290, F12920, F12921, F12922, F12929, F1293, F12950, F12951, F12959, F12980, F12988, F1299, F1220, F12220, F12221, F12222, F12229, F1223, F12250, F12251, F12259, F1228, F12280, F12288) in any position on a medical claim, inclusive of inpatient hospital encounters. [0135] Moreover, the All-Patient Refined Diagnosis Related Groups (DRGs) (APR- DRG) was used to further characterize patient encounters. The All Patient Refined DRGs incorporate severity of illness subclasses into the AP-DRGs and take into account the severity of illness, risk of mortality, and resource intensity. The APDRG Severity of Illness Subclass (APDRG-S) specifically represents the extent of physiologic decompensation or organ system loss of function, and it has been noted in prior studies to model risk of mortality. [0136] Statistical Analysis: [0137] Chi square analysis, ANOVA (Analysis of variance), multivariate regression analysis, and propensity score matched analysis were conducted to analyze significant associations between baseline characteristics, comorbid conditions; and primary outcome of interest: composite all-cause stent failure, defined as stent thrombosis, in-stent restenosis, stent occlusion, Coronary Artery Bypass Graft (CABG/graft) occlusion, CABG artery or vein atherosclerosis, CABG thrombosis; and secondary outcomes: composite all-cause stenosis, defined as in-stent restenosis, stent thrombosis, CABG stenosis, or CABG thrombosis; adverse event (AE) defined as stent thrombosis or in-stent restenosis; in-stent restenosis; stent thrombosis as defined by ICD-10 CM and PR codes. Percutaneous coronary intervention characteristics such as number of stents placed in a single coronary artery, number of arteries receiving intervention, and procedural intervention following primary PCI during index admission—none, angioplasty, stenting alone, or stent and angioplasty—were also utilized to stratify procedural intervention during index admission. STATA/MP software (Stata Corp.2021. Stata Statistical Software: Release 17. College Station, TX: Stata Corp LLC) was used for all analyses. [0138] Propensity Score Matched Analysis: To account for confounding factors related to hospital encounter and hospitalization-associated outcomes, and to establish causality of treatment effect, propensity score matching (PSM), inverse-probability weighted (IPW) match, and an augmented inverse propensity weight match were utilized for primary outcome of interest. A 0.2 caliper width was used to account for age, race, sex, length of stay (LOS), total charge (TOTCHG), hospital characteristics: hospital region, hospital bed size, location/teaching status of hospital; primary insurance payor: Medicare, Medicaid, Private, Self-Pay, Other, No Charge; median household income for patient’s ZIP code, medications, elixhauser comorbid conditions, admission year; long-term medications (aspirin(ASA) and long-term anticoagulation); population elixhauser median score; admission on the weekend, tobacco use disorder, subsequent acute inpatient STEMI or NSTEMI, number of arteries with metal stent, number of metal stents in one artery, number of arteries with DES stent, number of DES in one artery, primary procedural angioplasty status, number of DES for primary PCI procedural intervention, number of metal stents for primary PCI procedural intervention, and secondary PCI procedural status (angioplasty procedure, stent implantation, stent and angioplasty procedure). [0139] Results: [0140] 20,535 patients with cannabis use disorder (CUD) and 1,043,090 without cannabis use disorder (N-CUD) were identified who met the inclusion criteria. The mean age of CUD 53.06 +/- 0.17 years old (y.o.) with 80.20% males; and 65.29y.o. +/- 0.03 with 67.62% males for N-CUD (p≤0.001 for both). Between 2016 and 2020, there was a significant positive temporal relationship between in-stent restenosis and time on multivariable linear regression ((Beta-coefficient, Confidence Interval: [Lower Bound, Upper Bound], p-value, Beta-coefficient: 0.0083061, [0.007548, 0.0090641, p≤0.001). However, there was a negative temporal relationship between thrombosis and time on multivariable linear regression (Beta-coefficient: -0.0003544, [ - 0.0006432, -0.0000656], p=0.02, respectively). Among those with CAD with primary NSTEMI or STEMI and receiving PCI, the mean LOS for CUD-A and N-CUD-A was 3.15±0.048 and 3.69±0.012, p≤0.001, respectively. The mean TOTCHG for CUD-A and N-CUD-A was $107,104± 1,575.01 and $112,58.3±683.067, p=0.079, respectively. Among those with STEMI, the mean LOS for CUD-A and N-CUD-A was 3.44±0.10 and 3.87±0.02, p≤0.001, respectively; and the mean TOTCHG for CUD-A and N-CUD-A was $116,234.70±3,165.78 and $122,746.80±916.68, p=0.079, respectively. Among those with NSTEMI, the mean LOS for CUD-A and N-CUD-A was 3.01±0.05 and 3.62±0.01, p≤0.001, respectively; and the mean TOTCHG for CUD-A and N-CUD-A was 102,791.6±1,584.08 and 108,774.4±661.47, p≤0.001, respectively. [0141] The significant association of adverse events among those without history of PCI intimates the extent of inflammatory perturbation related to the initial procedure or vascular reactivity across a continuum of inflammation and inflammatory changes related to prior or index hospitalization intervention. Notably, on multivariable linear regression among the STEMI population irrespective of history of PCI and receiving PCI during index admission, within the interaction between primary PCI number of stents in one artery and subsequent procedural intervention, one stent, two stent, three stent, and four stent with subsequent angioplasty was associated with a significant positive temporal relationship with all-cause stent failure compared to no subsequent procedural intervention following primary PCI (Beta-Coefficient: 0.15,[0.12- 0.18], p≤0.001; Beta-Coefficient: 0.18,[0.14-0.21], p≤0.001; Beta-Coefficient: 0.18,[0.12-0.24], p≤0.001; Beta-Coefficient: 0.19,0.08-0.30], p≤0.001). Additionally, from 2016-2020, among CAD patients presenting to the hospital with STEMI-P without history of PCI and receiving PCI during index admission, CUD-A was associated with indices of secondary procedural intervention significantly different compared to others (No Catheterization or Angioplasty after Primary PCI: 88.72% vs 90.33%; Angioplasty after Primary PCI: 4.98% vs 3.95%; Stent after Primary PCI: 5.86% vs 4.83%; Stent and Angioplasty after Primary Catheterization: 0.44% vs 0.89%, p=0.04, respectively). What is more, among CAD patients younger than 50 years old (y.o.) between 2016- 2020 who received PCI during index admission, CUD-A was associated with significantly increased risk for premature AMI (defined as AMI at age <50 y.o.) with significantly greater incidence of primary STEMI compared to primary STEMI among other patients (38.53% (N=2,855/7,410) vs 35.53% (N=41,150/115,815), p=0.020). [0142] The clinical presentation is associated with the treatment outcomes and vice versa. For example, CUD-A was associated with significant association with STEMI infarctions compared to NSTEMI (OR: 1.26, [1.18-1.35, p≤0.001), and CUD-A was also associated with thrombosis among those with no history of PCI presenting with primary diagnosis of STEMI or NSTEMI receiving index PCI vs those without CUD-A (1.04% (N=10,565) vs. 0.68% (N=503,055), p≤0.05). Controlling for other factors (such as subsequent AMI during index admission, subsequent procedural intervention type, and IVUS use), and utilizing an interaction term between CUD-A and number of DES in one artery primary PCI procedure among primary NSTEMI-CAD patients receiving PCI with history of prior PCI, CUD-A individually was associated with significantly higher odds of stent thrombosis compared to others (Adjusted Odds Ratio, Confidence Interval: [Lower Bound, Upper Bound], p-value, aOR: 6.65, [1.65, 26.83], p=0.008; N=123,850); and within the interaction term, CUD-A and angioplasty was associated with significantly greater odds of thrombosis compared to those without CUD-A receiving angioplasty (aOR: 6.65 [1.65-26.82],p=0.008; N=123,850). In the same model, subsequent index AMI was associated with significantly higher odds of stent thrombosis when controlling for other factors (aOR: 5.71, [2.14, 19.25], p≤0.0016 N=123,850). [0143] Among those with primary STEMI or NSTEMI without history of prior graft or stent and receiving index PCI from 2016-2020, cannabis use was significantly associated with subsequent acute myocardial infarction (i.e., secondary diagnosis of STEMI or NSTEMI) during index admission (2.91% (285/19,315) vs 2.05% (95,10/917,800), p=0.008, respectively). Upon stratification, the significant association was persistent only among those with primary diagnosis of STEMI (3.07% (210/6840) vs 2.24%(N=6,575/294,080), p=0.04, respectively). Moreover, the incidence of stent thrombosis or stenosis was significantly higher for those with subsequent acute myocardial infarction compared to others (5.16% vs 3.77%, p=0.001, respectively). [0144] Increased CB1 Tone is Associated with Adverse Clinical Outcomes: [0145] Notably, both cannabis users and obese patients with complicated diabetes (Ob- DM) were at increased risk of stent failure; and both populations--cannabis users and Ob-DM-- separately were associated with increased peri-procedural and post-procedural risk for adverse outcomes (stent thrombosis; in-stent restenosis) with markedly similar patterns in the incidence of stent thrombosis acutely among primary STEMI-CAD patients with no history of PCI and receiving index PCI during admission and excluding each respective group from the sample analysis (CUD-A: 2.19% vs 1.36%, p=0.019; Ob-DM: 1.89% vs 1.36%, p=0.031, respectively). Similarly, the incidence of in-stent restenosis chronically (defined as subsequent AMI ^ 4 weeks from prior AMI) among the primary NSTEMI-CAD patients with history of PCI and irrespective of index PCI during admission was also similar (CUD-A: 8.68% vs 6.44%, p=0.002; Ob-DM: 8.58% vs 6.44%, p≤0.001, respectively); and without significantly different incidence between the two groups regarding in-stent restenosis for those with Ob-DM with vs without history of cannabis use (10.00% vs 13.02%, p=0.351, respectively), or alternatively, for those with cannabis use with vs without Ob-DM (1.56% vs 2.09%, p=0.351). Additionally, in 2020, among patients with primary diagnosis of STEMI and NSTEMI who received index PCI with history of graft or prior PCI, the incidence of AE among the COVID-19 subpopulation was significantly higher than that of others (25.33% (90/375) vs 13.93% (6,605/47,425), p=0.005, respectively). [0146] On univariate regression analysis, it was noted that active cannabis use disorder (CUD-A) was associated with 53.08% higher odds of stent thrombosis among patient receiving PCI without history of PCI presenting with primary hospital diagnosis of STEMI (N= 253,089.98; 1.53,[1.01- 2.31], p=0.04); and 36.40% higher odds of in-stent restenosis among patients with history of PCI presenting with primary diagnosis of NSTEMI between 2016-2020 (N= 407,570; OR: 1.43, [1.12-1.66], p=0.05). Obesity with complicated diabetes was associated with 35.22% higher odds of stent thrombosis among patient receiving PCI without history of prior PCI before index admission and admitted with primary hospital diagnosis of STEMI (N= 253,090; OR: 1.35, [1.00- 1.83], p=0.05); 45.69% higher odds of in-stent restenosis among patient receiving PCI with history of prior PCI before index admission and admitted with primary hospital diagnosis of STEMI (N= 36,874.997; OR: 1.46, [1.07-1.98], p=0.02); 58.95% higher odds of in-stent restenosis among patients receiving PCI without history of PCI presenting with primary diagnosis of STEMI between 2016-2020 (N= 253,090; OR: 1.59, [1.25 - 2.02], p≤0.001); 31.63% higher odds of in- stent restenosis among patients receiving PCI with history of PCI presenting with primary diagnosis of NSTEMI (N= 164,435; OR: 1.32, [1.18-1.47], p≤0.001); and 80.33% higher odds of in-stent restenosis among patients receiving PCI without history of PCI presenting with primary diagnosis of NSTEMI (N=609,260; OR: 1.80, [1.66-1.96], p≤0.001) between 2016-2020. [0147] Again, the importance of the presenting factor and the relationship between the inciting event and the subsequent effects of cannabis use are relevant; as well as the temporal trends in coding variation within the sample dataset, and when the sample is stratified: 1) On multivariable logistic regression utilizing 2016-2020, among CAD patient encounters presenting with primary NSTEMI or STEMI diagnosis with history of graft or stent and receiving index PCI, cannabis use was associated with higher odds of all-cause in-stent restenosis and all- cause stent failure compared to others (and controlling for the interaction between complicated diabetes and cannabis use) (aOR: 2.33, [1.34, 4.07], p=0.003; aOR: 2.02, [1.18, 3.48], p=0.011). 2) Among CAD patients presenting with primary diagnosis of STEMI without history of prior graft or PCI and receiving index percutaneous coronary intervention, from January 2017 to December 2020, the incidence of stent thrombosis was significantly higher for CUD-A compared to others (CUD-A(N=140/5,750) 2.43% vs Others (N=4,105/261,960) 1.57%, p=0.02, respectively). 3 Again demonstrating that the ICD-10 CM coding changes over time and increased reporting were associated with increased incidence of the events within the dataset. 3.1) Among CAD patients presenting with primary diagnosis of STEMI without history of prior graft or stent and receiving index percutaneous coronary intervention between January 2018 to December 2020, the odds of stent thrombosis were significantly higher for CUD-A compared to others (aOR: 1.81, [1.06, 3.11], p=0.03, N=139,765; CUD-A(N=3,475) 2.45% vs Others (N=144,945) 1.21%, p=0.003, respectively). Within this model the interaction term for obesity with complicated diabetes was associated with higher odds of stent thrombosis compared to others (aOR: 1.97, [1.12-3.48], p=0.019). 3.2) In a more extensive model of the above logistic regression model, CAD patients presenting with primary diagnosis of STEMI without history of prior stent (i.e., excluding aortocoronary graft) and receiving index percutaneous coronary intervention between January 2018 to December 2020, the odds of stent thrombosis were significantly higher for CUD-A compared to others (aOR: 1.76, [1.03, 3.02], p=0.039, N= 142,660). Within this model the interaction term for obesity with complicated diabetes was associated with compared to others (aOR: 1.99, [1.14-3.48], p=0.016). 4) Notably, from 2018-2020 among primary STEMI-CAD patients without history of graft or stent and receiving PCI during index admission, diagnosis of CUD-A or obesity with complicated diabetes represented 7.48% of the total population of patients admitted (13,010/173,890) but represented 11.77% (N=345/2,930) of those with stent thrombosis during this period (p≤0.001). Among CAD patients presenting with primary diagnosis of STEMI without history of prior graft or stent and receiving index percutaneous coronary intervention, from January 2017 to December 2020, the odds of stent thrombosis were significantly higher for obesity with complicated diabetes compared to others (aOR: 1.68, [1.03-2.73], p=0.038; N= 190,165). [0148] Active Cannabis Use is Associated with Stent Failure on Matched Analysis [0149] Finally, from 2016-2020, on propensity-score matched analysis among CAD encounters with history of graft or stent presenting with primary NSTEMI or STEMI and receiving index PCI (Matched Observations=49,625), the all-cause stent failure adverse event rate was 9.75% higher for active cannabis use compared to others (ATE: .0975, [0.0523, 0.1427], p≤0.001); and the all-cause stenosis rate (Matched Observations= 49,625) was 12.75% greater for CUD-A compared to others (ATE: 0.1275, 0.0830, 0.1719], p≤0.001). However, when limited to the primary STEMI population (Matched Observations= 8,425), the all-cause stent failure event rate was 6.62% lower than others (ATE: -0.0662, [-0.1318, -0.0007], p=0.048), indicative of new STEMI unrelated to prior procedural location. [0150] On chi-square analysis between 2019-2020 CUD-A was significantly associated with stent thrombosis compared to others (2.31% (N=55/2,380) vs 1.16% (N=1,130/97,155), p=0.023. Between 2019-2020, on matched analysis (Matched Observations=18,613) among primary STEMI-CAD patient encounters without history of graft or stent and receiving PCI during index hospitalization, active cannabis use was associated with significantly higher risk of stent thrombosis compared to others (ATE:0.04545, [0.00404-0.0869], p=0.031). [0151] To further ensure accurate modeling of treatment and outcome and the associated prediction of treatment effect, an inverse-probability weighted (IPW) match and an augmented inverse propensity weight (AIPW) match was performed on the population utilizing 2017-2020 to correspond with the final changes made to the ICD-10 CM coding for stent thrombosis. To limit confounding, patients with AIDS/HIV, lymphoma, metastatic cancer, or solid tumor without metastasis were excluded from the analysis. Among primary STEMI-CAD patients without history of subsequent AMI (NSTEMI or STEMI) within the last 4 weeks without history of prior PCI and receiving PCI during index admission, the IPW analysis demonstrated an ATE event rate for CUD- A was 2.90% greater than that of others (ATE: 0.0280517, [0.0007033-0.0554002], p=0.044; N= 37,285); and the mean rate of stent thrombosis associated with those without CUD-A was 1.28% (Mean: 0.0127667, [0.0116092-0.0139242], p=0.000). The AIPW analysis demonstrated 3.04% higher absolute risk difference for stent thrombosis for CUD-A compared than that of others (ATE: 0.0300332, [0.030385-0.0570278], p=0.029; N= 37,285); and the mean rate of stent thrombosis associated with those without CUD-A was 1.28% (Mean: 0.0127601, [0.0116034-0.0139168], p=0.000). [0152] Discussion: [0153] The Cannabinoid Receptor 1 Activation Increases Risk for Stent Failure and Subsequent Acute Myocardial Infarction: [0154] The study highlights the pathophysiological outcomes associated with cannabis use and highlights that the introduction of the exogenous CB1 agonists or excessive production of endogenous CB1 agonist in relation to peri-procedural intervention is associated with adverse outcomes including increased risk of stent thrombosis, in-stent restenosis, stent occlusion, and other associated outcomes. The cannabis use population is associated with an increased risk of acute and chronic all-cause stent failure and increased risk for subsequent acute myocardial infarction secondary to coronary microembolization during procedural intervention. These findings provide information to inform management of patients receiving PCI, and it engenders further research studies to improve risk stratification among patients with coronary artery disease and active cannabis use, its clinical corollary: obesity with complicated diabetes, and those with significant risk of AE or other complications who receive PCI during hospital admission. The power of large, clinical data repositories can bridge the gap in clinical understanding of the consequences of cannabis use and provide insights to guide clinical decision-making. As such, the utilization of a CB1 antagonist/inverse agonist/allosteric modulator or other method such as immunoglobulin-mediated treatment or binding to the CB1 receptor for the purpose of modulation of receptor activity in the treatment of a subject in need thereof may represent powerful modalities, individually or in combination with one another and/or other pharmaceutical preparations to address, ameliorate, and treat those adverse events related to procedural intervention as described above. Moreover, these findings implicate the CB1 receptor modulation in multiple other pathophysiological processes which are precipitated and/or exacerbated by procedural manipulation or intervention. [0155] The CB1 receptor (CB1R/CB1) has potent vascular endothelial effects in intracellular calcium-handling, immunomodulatory effects for mediating macrophage activity, and metabolic effects at the level of the adipocyte itself. CB1R activation disinhibits lipoprotein phospholipase (LPL) activity in the presence of insulin, and the pathophysiologic state characterizing CB1 receptor overaction is the clinical corollary obesity-related insulin resistance. The THC molecule is an agonist of the CB1 receptor, and the functional activity of the CB1R may explicate the increased risk for thrombosis and in-stent restenosis following PCI at significantly higher rates, younger age, and shorter intervals of time following primary PCI among the cannabis population. Acutely, these effects result in a higher risk of stent thrombosis within 4 weeks compared to non-cannabis users; and chronically, a significantly higher risk of in-stent restenosis compared to non-cannabis users; with similar outcomes for those with obesity with complicated diabetes and represent a treatment target suitable for modulation of disease. There is a significant gap in knowledge concerning clinical outcomes for patients with cannabis use despite a growing number of patients reporting use and increased trends in state legalization for recreational use. Moreover, obesity and diabetes represent salient modifiers of patient mortality and morbidity with significant and growing costs and healthcare expenditure. [0156] The cannabinoid receptors are plastic enough to modulate abnormal responses to inflammation through immune and non-immune mechanisms; as in the case with COVID-19 or acute myocardial infarct (STEMI or NSTEMI)/percutaneous coronary intervention (PCI)- mediated cardiovascular insult which acutely up regulates cannabinoid 1 receptors (CB1) or CB1- related pathways to induce response to inflammation; or chronically through mediation of cell death and healing, Th1 and Th2 responses, and transient receptor cation cannels regulating stretch through TRPA1/TRPV2, and fibrosis in cardiac transplant, among others. Moreover, it functionalizes the adipocyte and lipolysis as such as a mechanism of immune-activation and inflammation which relates to the outcomes noted in my study regarding stent thrombosis and in- stent restenosis and microembolization. However, the difference in capacity to induce these events compared to obese patients with complicated diabetes may relate to the pharmacodynamics and limited means of metabolism of THC in the human body and the functional capacity of THC to concentrate within adipocytes and selectively release from adipocytes into serum in the setting of stress, concentrating its effects in response to acute injury or catecholamine-induced lipolysis. These effects were also validated in a separate study among CAD patients hospitalized with primary diagnosis of STEMI or NSTEMI who received PCI during index hospitalization and irrespective of history of prior PCI, COVID-19 was associated with higher incidence of combined outcome: stent thrombosis or stenosis compared to others (8.92%(N=165/1,850) vs 6.03% (N=13,540/224,620, p=0.020, respectively), among CAD patients hospitalized with primary diagnosis of STEMI or NSTEMI who received PCI during index hospitalization, irrespective of history of prior PCI. In context, in a separate study among hospitalized patients in 2020, it was demonstrated that cannabis use was associated with lower risk of death, mechanical ventilation, and acute pulmonary embolism on matched analysis, presumably through antagonism of CB1 receptors in macrophages and adipocytes which are targets of COVID-19. Finally, the receptors themselves modulate the friability and neutrophilic content within adipocytes which relates to the increased free fat mobility associated with CB1 activation and the associated increased risk of coronary micro-embolization and secondary myocardial infarction among the obese patient population and the THC patient population. [0157] The Endocannabinoid System at the Heart of Immunometabolism and Cardiovascular Disease [0158] Prior studies indicate that an elevated leukocyte count is associated with poor clinical outcomes in both acute myocardial infarction and in the setting of heart failure. Energy and metabolism are heavily implicated in the acute and chronic changes within cardiovascular system and the significant number of insulin receptors within cardiac tissue and the immune cells therein implicate these changes in the efficiency of energy production, metabolic rate, mitochondrial respiration, and cellular changes–pathological or adaptive—in response to the intracellular and extracellular interaction. [0159] What is more, the modulation of innate and adaptive immunity within acute and chronic dysfunction effectuates significant changes in the immune-metabolic state, modulating cytokine production and inflammatory response along divergent cellular and metabolic pathways. These changes in the immune-metabolic ecosystem are central to cardiovascular response and resolution to injury, so much so that these changes within the environment themselves effectuate a shift in the localized ecosystem. Moreover, local inflammatory response is amplified through the neuro-immune axis which increases local inflammatory mediators and cellular response to inflammation. These cellular changes are translated across metabolic pathways as oxidation of lipids and glycolysis by CD4 + helper T cells, B-cells, dendritic cells, and other immune cells modulate the response to inflammation. Moreover, hypoxia and hypoxia inducible factor, decreased availability of amino acids, and altered neuro-muscular interactions potentiate inflammation. [0160] Prior research has indicated that CD4+ T helper (Th) 1 cells are increased following myocardial infarction and the depletion of these cells following coronary ligation ameliorates pathological remodeling and ventricular dysfunction, with similar finds for CD8+ T cells in experimental models. The activation of these T-cell receptors promotes glycolytic metabolism through upregulation of Glut,1,7 and T cell differentiation; and support INF-gamma cytokine production and CD8+ T cell granzyme B expression. Moreover, the increased presence of Th17 cells following MI is mediated through mammalian target of rapamycin (mTOR)- dependent HIF-1^ activation which modulates metabolic activity to increase glycolytic pathways. What is more, the functional role of IL-6 in the promotion of differentiation in naïve CD4+ T cells highlights the role of the CB1 receptor in linking innate and acquired immune response. The combination of IL-6 with transforming growth factor (TGF)-^ was previously shown to be indispensable for Th17 differentiation from naïve CD4+ T cells, while it functionally inhibits the Foxp3+ T cells (Tregs) differentiation. Notably, Treg function to in the attenuation of cardiac and ventricular remodeling and improve healing mechanisms after AMI, and their presence following MI may be dependent upon extracellular nutrients such as leucine, required for T-cell differentiation and the presence of which stimulates mTOR mediated reprogramming in favor of Th1 and Th17 development after uptake by T-cells in the setting of MI. [0161] Additionally, the recruitment and functional activation of B-cells following ischemic events leads to the increased production of cytokines such as CCL7 and increase recruitment of inflammatory monocytes and inflammatory macrophage activation; as well as the presentation of (self) antigens to B-cells and subsequent production of antibodies/immunoglobulins which target the cardiac tissue itself. The increased production of CCL7 is also mediated by transcriptional activation by the glycolysis regulator HIF-1^. What is more, the production of IL-10, enriched in the B-cells within the pericardial adipose tissue, is cardioprotective. The fatty acid oxidation of short-chain fatty acid butyrate enhances the production of IL-10 from B cells. Moreover, the stimulation of T-cell and B-cell differentiation into T-follicular helper-cells and Ab-producing plasma cells; and the production of IL-21 which regulates immunoglobulin synthesis and IgG4 production, specifically, are mediated through IL- 6. The result of these imbalanced processes precipitates hypergammaglobulinemia and autoantibody production. This shift in phenotypic immunoglobulin expression or production and shift to fatty acid oxidation induced by CB1 modulation may counteract the adverse outcomes associated with B-cell anticardiac or other IgG antibody production and favor regulatory function, and it may explain the role of butyrate in autoimmune disease presentation noted my prior study examining autoimmune disease among metabolic and bariatric patients. Moreover, in antagonizing the CB1 receptor, the functional improvement of cardiac and non-cardiac metabolic pathways can be salvaged. These aberrant pathways are characterized by dysfunctional lipid accumulation, metabolism, and cardiac peroxisome proliferator-activated receptor (PPAR)^ and PPAR^ signaling which may contribute to the development of heart failure (See Additional Notes below for more information). [0162] C. Cannabinoid Receptor 1 Modulation for Therapeutic Benefit: [0163] Taken together, these findings indicate that the modulation of the CB1 receptor is associated with increased risk of stent failure categorically among those presenting with primary diagnosis of AMI with history of CAD with or without history of prior PCI, and highlights that among those presenting with STEMI, the modulation of the receptor is associated with new, subsequent STEMI location unrelated to site of prior intervention. Moreover, the upregulation of P-Selectin associated with the CB1 agonism and the associated effects noted in this study—in both noting A) increased associations between cannabis use and stent thrombosis; stent thrombosis and STEMI within 4 weeks; cannabis use and STEMI within 4 weeks, and B) demonstrating a fundamental link between CB1 modulation and COVID-19 and COVID-19 increased incidence of stent thrombosis among the COVID-19 population (likely mediated by P-selectin upregulation)-- -indicate that the CB1 receptor has a key functional role in regulation of inflammation and inflammation as such. Complicated diabetes mellitus induces a state which represents an extreme example of vascular endothelial remodeling, and is associated with more extensive atherosclerosis, a greater propensity for forming longer lesions encapsulated by a higher density necrotic core, a smaller lumen area, and larger calcium content. However, the ability to concentrate these effects and subsequently engender vascular tone across the transposed area indicates and confirms an underlying connection within the vasculature such that one area can affect others, but it also indicates that the adipocyte itself is able to effectuate these changes, rapidly precipitating in-stent restenosis, thrombosis, NSTEMI, or STEMI as in the cannabis use population or the obese with complicated diabetes population. These changes as well as other risk factors associated with AMI influence outcomes of adverse events among those undergoing PCI and even the subsequent type of AMI. The modulating effects of the CB1 receptor precipitate accelerated symptomatic disease of greater severity, in so far as presenting diagnosis is more likely to be STEMI/a transmural infarct instead of non-transmural infarct, decrease the time to adverse event, and increase the precipitation of procedurally related adverse outcomes. As indicated by the STRADIVARIUS clinical trial total atheroma volume may be modulated through CB1 antagonism which may provide utility in prevention of microvascular disease secondary to coronary microembolization. [0164] This research reveals a fundamental relationship between CB1 activation, and the incidence of adverse event (AE) defined as in-stent thrombosis and/or stenosis, noting comparable incidence of AE among those with increased CB1 tone which is associated with pathological inhibition of insulin function on LPL function, adipocyte growth, and inflammation. The latest guidelines recommend the use of dual anti-platelet therapy (DAPT) with PY12 and antiplatelet therapy (i.e., clopidogrel and aspirin) for the secondary prevention of adverse cardiovascular complications following PCI or CABG. Antiplatelet therapy is also recommended among those with ischemic cardiomyopathy. However, no guideline or medical therapies have been approved for use that target mechanisms associated with modulation of disease secondary to microembolization seen with difficult procedural manipulation and angioplasty, or risk modification for cannabis users generally or with CAD specifically, and while utilization of drug eluting stent (DES) has decreased PCI complications, coronary artery in-stent restenosis (ISR), stent thrombosis, stent occlusion, etc. are still significant complications intrinsic to the procedure itself and associated with subsequent derangements in the activation of the CB1 receptor in response to injury. Perioperative utilization of CB1 receptor antagonist/inverse agonist/allosteric modulators/signaling specific inhibitor/cannabinoformins may ameliorate disease conditions and complications associated with PCI and CABG surgery. Similarly, CB1 antagonism/inverse agonism for patients with history of cannabis use, and, more generally, for those with history of PCI, to decrease risk of subsequent acute myocardial infarct or other complications associated with DES, metal stent, or other intravascular stent placement represents a viable therapeutic option. These proposed therapies and the various clinical utility at different stages of the treatment and therapeutic process of management of ischemic and micro- or macrovascular cardiomyopathy can have far reaching effects for many diverse patient groups. As such, the benefits and the outcomes of this research may extend beyond those with cannabis use as evidenced by my prior studies noting similar pathology to patients with concomitant DM and obesity, and to provide support for further clinical testing to examine the potential role of risk stratification, treatment, and therapeutic options involving CB1 receptor antagonism/inverse agonism in the modulation of disease trajectories. For example, because the atherosclerotic lesions are more friable due to CB1 agonism, the associated cannabis use micro-emboli in relative number and/or especially size (both number of stents vs angioplasty and number of arteries were significantly associated with subsequent stent thrombosis/restenosis on primary analysis) -- and subsequent AMI is more likely to be STEMI— i.e. a transmural infarct—not NSTEMI. [0165] THC modulates CB1 receptor activation in the vasculature and vascular adipose tissue. Additionally, animal models report that the CB1 receptor plays a role in activation and migration of cardiac myofibroblasts, the modulation of which by CB1-antagonists may decrease myofibroblast migration without preventing reendothelialization following vascular insult. Notably CXCL12 was noted to be correlated with CB1 receptor mRNA concentrations in lymphoma cell populations intimating a CB1-mediated-CXCL12 and CB2-2-AG migratory mechanism associated with chemokine production. TRPA1 has an inhibitory role in TGF-β1- driven Fibroblast-to-Myofibroblast Differentiation; myofibroblast Gαs signaling as a mediator of fibroblast proliferation; and function of the CB1 receptor in GRK2 mediated signaling indicate a coordinated mechanism existent between cannabinoid receptors and beta-2 adrenergic receptor signaling. While neointimal hyperplasia plays an important role in stent failure, other factors contribute to its precipitation, and, in addition to neointimal hyperplasia, other vascular-related, patient-related, and stent-related factors such as delayed hypersensitivity reaction, neo- atherosclerosis, bifurcating and ostial stenting, penetration of a necrotic core, stent malposition, drug-drug interactions, and coagulopathy are important factors involved in stent and CABG failure. [0166] Unfortunately, animal models do not completely account for human-specific atherosclerotic and vascular cholesterol build-up, differences in CB1 receptor ligand affinities between species, and utilization of non-specific peripheral antagonism in other models limits the evaluation as to whether centrally mediated mechanisms played a role in immunomodulatory effects. Moreover, the incidence of these conditions within the population characterizes rare events and the outcomes of this analysis represent real world evidence regarding the clinical outcomes associated with endocannabinoid system modulation. The use of prospective studies may not accurately characterize risk due to the large changes in treatment effect determinations associated with loss to follow up and the need for large samples size of patients to determine treatment effect; and ethical concerns related to administration of substances known to increase risk of adverse events may preclude additional testing methodology. [0167] Finally, in separate analysis, among those with CAD and diagnosed in-stent restenosis, hospitalized from 2016-2020 and excluding those with subsequent STEMI within 4 weeks, CUD-A was associated 24.84% greater odds for those with prior PCI compared to others on univariate regression (OR: 1.25, [1.00-1.57], p=0.05, N=90,765; 44.37%(N=690/1,555) vs 38.99%(N=34,780/89,210, p=0.05, respectively). As such, these findings indicate the activation of the CB1 receptor is a predictive factor for in-stent restenosis and stent thrombosis and further implicate the CB1 receptor in disease presentation and a therapeutic benefit associated with the modulation thereof in context with procedural intervention or PCI. [0168] Conclusion: CB1 antagonist/inverse agonist/allosteric modulation can improve PCI-related and procedural outcomes among patients with cannabis use disorder and others in need of modulation of effects related to CB1 receptor activation. [0169] Supplement [0170] Data Source: [0171] The study cohort was sampled from the National Inpatient Sample (NIS) 2020 database. The NIS is the largest publicly available all-payer, inpatient healthcare database designed to produce United States (U.S.) regional and national estimates of inpatient utilization, access, charges, quality, and outcomes. In 2012, the sampling design was reconstructed as a 20% national patient-level sample, with non-representative sampling across hospitals. These changes were associated with corresponding changes to sampling weights for patient encounters to estimate national outcomes. The NIS is sponsored by the Agency of Healthcare Research and Quality (AHRQ) and developed by the Healthcare Cost and Utilizations Project (HCUP). [0172] The Diagnosis Related Groups (DRGs) are a patient classification scheme and provides a means of relating the type of patients a hospital treats (i.e., its case mix) to the costs incurred by the hospital. Three major versions of DRG are currently in use: basic DRGs, All Patient DRGs, and All Patient Refined DRGs. The Centers for Medicare and Medicaid Services (CMS) uses the basic DRGs for hospital payment for Medicare beneficiaries. To provide more representative data of non-Medicare populations, the All Patient DRGs (AP-DRGs) are an expansion of the basic DRGs. The All Patient Refined DRGs (APR-DRG) incorporate severity of illness subclasses into the AP-DRGs. Moreover, the term case-mix complexity has been used to refer to an interrelated but distinct set of patient attributes which include severity of illness, risk of dying, prognosis, treatment difficulty, need for intervention, and resource intensity. The APDRG Severity of Illness Subclass (APDRG-S) refers to the extent of physiologic decompensation or organ system loss of function; and it and the Elixhauser comorbidity index have been noted in prior studies to model risk of mortality. [0173] Study Population, Outcomes, and Causality: A Quasi- Experiment [0174] Importantly, according to John Stuart Mill’s classical formulation (Shadish, Cook, & Campbell, 2002), in order to establish a causal relationship requires three criteria: (a) temporal precedence (i.e., the cause precedes the effect), (b) covariance (i.e., the cause and effect are related), and (c) disqualification of alternative explanations (i.e., no third variable accounts for the observed relationship). In demonstrating increased risk for outcomes among those without history of prior PCI the cause: cannabis (within the adipose tissue and catecholamine induced lipolysis) necessarily precedes the effects. As I have demonstrated the two conditions are related. The study controls for multiple variables and was derived from the AHQR for accurate outcome analysis within inpatient admissions. In preventing the development of medical uses of cannabis, the regulatory framework of therapeutic uses of cannabis has created a temporal relationship between cannabis use and subsequent outcomes—cause and effect. Moreover, the incidence of these conditions within the population characterizes rare events and the outcomes of this analysis real world evidence. The use of prospective studies may not accurately characterize risk due to the large changes in treatment effect determinations associated with loss to follow up and the need for large samples size of patients to determine treatment effect; and ethical concerns related to testing populations with known risk modifying exposures may preclude further testing methods. [0175] Notably, among those with CUD-A from 2016-2020 with no history of prior PCI presenting with primary STEMI, there was a significant association with stent thrombosis (0.64%(N=175/27,455) vs 0.45% (N=7,320/1,639,035, p=0.036). Among those with CUD-A from 2017-2020 with no history of prior graft or stent presenting with primary STEMI, significant association with stent thrombosis (0.72% (N=90/20,920) vs 0.47% (N=5,495/1,157,795, p=0.024); and among those with coronary artery disease, 1.36% (N=150/10,990) vs 0.74% (N=4,570/ 618,215, p≤0.001)). Analysis was also adjusted for multiple comorbid conditions and other factors. As such, these results and analysis should be interpreted with the understanding of cause and effect. [0176] Type of PCI Procedure Definition: [0177] Type of PCI procedure following primary catheterization procedure: no catheterization, angioplasty, stent, angioplasty and stent, were identified using coding variables for procedure day incorporated into the NIS dataset; and number of arteries with drug eluting stent and number of drug eluting stents (DES) or metal stents placed in one coronary artery using a percutaneous approach and identified as the primary inpatient procedure were encoded using ICD10 procedure codes (02703) and was used to further stratify and analyze outcomes of interest. [0178] All-cause Stenosis: [0179] The code includes categorical variable for all-cause stenosis. The variable identifies Coronary Artery Bypass Graft (CABG) stenosis, CABG thrombosis, in-stent restenosis, and stent thrombosis. [0180] All-cause Stent Failure: [0181] The code includes categorical variable for all-cause stent failure. The variable identifies CABG stenosis, CABG thrombosis, CABG occlusion: atherosclerosis of CABG Artery, atherosclerosis of CABG Vein; in-stent restenosis, and stent thrombosis, stent occlusion: atherosclerosis of coronary stent. [0182] Selection of Variables and Demographic Characteristics: Variables were selected based upon stratification from Elixhauser classifications, and/or known clinical or confounding factors associated with conditions of interest. The variables selected controlled for hospital-level characteristics (hospital region, hospital location and teaching status, hospital bed size), admission-level differences such as admission on the weekend; patient level characteristics such as income, age, insurance payor, race, gender, and sex; and comorbid conditions which may each represent potential confounders of the described analysis. Please note prior art for additional information. [0183] Elixhauser mean score for CAD patients with primary AMI irrespective of history of PCI and receiving PCI during index admission was significantly different between CUD-A and others 4.18% vs 3.53%, p≤0.001; and with STEMI-P (4.05% vs 3.25%, p≤0.001); and for NSTEMI (4.23% vs 3.63%, p≤0.001). The elixhauser median score (ELIX Median) was 3 [IQR: 2-5] within the AMI irrespective of history of PCI and receiving PCI during index admission; and with STEMI-P (3 [2-4]) ; and for NSTEMI (3 [IQR: 2-5]). , p≤0.001). There was a 0.17 difference in mean ELIX Median for CUD-A compared to others (p≤0.001). [0184] Moreover, excluding obesity with complicated diabetes (Ob-DM), among those with CUD-A in the sample population without history of prior PCI and irrespective of procedural PCI during index admission, 78.50% (N= 6625/8440) of those presenting with primary STEMI diagnosis had concomitant coronary artery disease (CAD). In contrast, 69.69% (N=22,060/31,655) of those presenting with primary NSTEMI had concomitant CAD. [0185] Among patients younger than 50 years old (y.o.) between 2016-2020 and excluding those with obesity and complicated diabetes, CUD-A was associated with significantly increased risk for premature AMI (defined as AMI at age <50 y.o.) with significantly greater incidence of NSTEMI compared to others (78.92%(N=18,845/23,880) vs 77.23% (N=245,985/318,505), p≤0.007); but lower incidence of STEMI compared to others (21.19%(N=5,060/23,880) vs 22.89% (N=72,910/318,505), p≤0.007). [0186] Among CAD patients younger than 50 years old (y.o.) between 2016-2020 who received PCI during index admission and NOT excluding those with obesity and complicated diabetes, CUD-A was associated with significantly increased risk for premature AMI (defined as AMI at age <50 y.o.) with significantly greater incidence of primary STEMI OR any STEMI (any position of the medical claim) compared to primary STEMI or any STEMI among other patient populations (38.53%(N=2,855/7,410) vs 35.53%(N=41,150/115,815), p=0.020; 38.43%(N=3,065/7,975) vs 35.64%(N=44,325/124,385), p=0.024). [0187] Among CAD patient encounters with STEMI-P no history of PCI and receiving PCI during index admission, the incidence of stent thrombosis among the CUD-A population increased over time from 2.47% vs 1.55%, p=0.013 for 2016-2020, to 2.66% vs 1.51%, p≤0.005, in 2018-2020. When stratified the incidence increased from 1.07% vs 1.80%, p=0.013 in 2016, to 3.61% vs 1.69%, p≤0.005, in 2018. [0188] Primary vs Secondary STEMI or NSTEMI Diagnosis: Cannabis Use Disorder (CUD) vs Non-Cannabis Use Disorder (N-CUD): [0189] Primary STEMI or NSTEMI vs Secondary STEMI or NSTEMI was defined to stratify outcomes in the analysis. Primary diagnosis on a medical claim during hospitalization was utilized in differentiating primary admitting diagnosis of AMI compared to patients diagnosed with AMI following admission, corresponding to AMI diagnosis in secondary or other positions besides 1 on a medical claim. [0190] Secondary STEMI or NSTEMI was identified using diagnosis code of STEMI/NSTEMI in the secondary position or any other position on a medical claim except for primary position, inclusive of inpatient hospital encounters. This code was utilized to identify patients with subsequent myocardial infarction during index admission. Notably, the ICD-10 code for acute myocardial infarction type 3-5 (ICD-10 CM: I21A9) which includes peri-procedural complications and myocardial infarction was released for use in 2018. However, due to coding variation over time, the utilization of the code may not accurately reflect the incidence of peri- procedural adverse events during index admission. As can be noted with other diagnoses such as in-stent restenosis and stent thrombosis and cannabis use, the utilization and incidence from 2016- 2020 increased. This may reflect the coding variation over time as new codes are introduced to specify specific diagnosis, an increase incidence of these events over time, and/or increased use over time, especially as it pertains to cannabis use, which is increasing nationally over time among various demographic populations and age groups but may still be underreported. [0191] There were 460 CAD patient encounters among the primary AMI group who received PCI diagnosed with MI Type 3-5; 47.83% of these patients were diagnosed with one of those diagnoses identified in all-cause stent failure. However, relative to all patients within the all- cause stent failure population, those with peri-procedural complication diagnosis represent 0.25% of all patients within the all-cause stent failure population (N=220/88,675; p≤0.001). In contrast, subsequent acute myocardial infarction was able to identify 0.88% of those among the all-cause stent failure population, representative of 7.24% of the total subsequent AMI population (780/10,780). [0192] COVID-19 Disease: [0193] Utilization of COVID-19 U.071 and B97.29 Disease Coding over Time: [0194] The CDC (Centers for Disease Control) officially activated ICD10-CM U.071 in April 2020. However, the World Health Organization (WHO) released information concerning the creation of International Classification of Disease version 10 (ICD-10) coding for COVID-19 disease in March 2020. I chose to utilize January instead of April in defining the COVID-19 characterization because: [0195] 1) The CDC reports that the first laboratory confirmed case of the 2019 Novel Coronavirus (COVID-19) in the U.S. was on January 18 in Washington state; 5 and within the NIS dataset 42,315 hospitalizations nationally, before April 2020 were associated with B97.29 (January: 3,495 hospitalizations; February: 2,575 hospitalizations; March: 32,150 hospitalizations) [0196] 2) The WHO (World Health Organization) Emergency Activation of ICD-10 U07.1 occurred in March 2020. There was a significant difference in utilization of U.071 for inpatient hospitalizations in the month of March compared to January or February (p≤0.001; p≤0.001); and 59.71% (47,760/79,795) of the COVID-19 inpatient population in March 2020 contained ICD-10-CM coding indicating U07.1. The mortality associated with this patient population was 24.88% compared to that of all-cause hospitalizations 2.86%, (p≤0.001); and compared to that of the mortality associated with COVID-19 vs all-cause hospitalizations in April 2020, 20.54% vs 2.48% (p≤0.001). The mortality associated with COVID-19 U.071 in January of 2020 was 18.75% vs 2.51%, and 21.95% vs 2.44% in February. Mortality rate within the COVID- 19 population was not significantly different between January and February; but for each month thereafter, the mortality rate associated with COVID-19 was significantly greater than either January or February (p≤0.05). However, these hospitalizations represent a negligible 0.017% of the total COVID-19 related hospitalizations reported within the dataset (290/1,698,560). It is unclear if these patients represent COVID-19 positive patients as the means of testing for the SARS-CoV2 infection were not well developed at that time. Nor is it clear if ICD coding records may be backlogged using updated coding information guidance from the CDC/CMS for those hospitals sampled within the NIS. [0197] 3) Guidance from the CDC recommended utilization of COVID-19 infections to B97.29 and following activation of the ICD-10-CM U07.1, to indicate associated complications for patients for whom COVID-19 pneumonia was not the primary indication for admission, but ancillary to primary inpatient admission indication. [0198] COVID-19 disease U07.1 as primary diagnosis on a medical claim during hospitalization was utilized in differentiating primary admitting diagnosis of COVID-19 compared to patients diagnosed with COVID-19 following admission, corresponding to COVID-19 diagnosis in secondary or other positions besides 1 on a medical claim. [0199] Notably in 2020, among patients with STEMI-P and NSTEMI-P who received index PCI with history of graft or prior PCI, the incidence of AE among the COVID-19 subpopulation was significantly higher than that of others (25.33% (90/375) vs 13.93% (6,605/47,425), p=0.005, respectively). [0200] Supplementary Outcomes and Results: [0201] Primary NSTEMI with Procedural Percutaneous Coronary Intervention vs No Percutaneous Coronary Intervention: [0202] Notably, excluding those with obesity with complicated diabetes (Ob-DM) and limiting to the NSTEMI-P CAD sample population with history of prior PCI, irrespective of PCI during index admission and excluding those with AMI within 4 weeks of prior AMI , CUD-A was significantly associated with in-stent restenosis (8.71% (N=495/5,680) vs 6.44% (N=23,190/360,130), p=0.002; OR: 1.39, [1.13, 1.71], p=0.002, N=365,809); and similarly, when stratified to those who did not receive percutaneous intervention (N= 217,570, OR: 1.78, [1.31, 2.41], p≤0.001; 6.62% (N=225/3,400) vs 3.83% (N=8,210/ 214,170), p≤0.001, respectively). [0203] Cannabis Use Disorder Associated with Increased incidence of Non-Fatal AMI: [0204] Notably, between 2016-2020 among primary NSTEMI or NSTEMI-CAD patients irrespective of prior graft or stent and receiving PCI during index admission, CUD-A was associated with significantly lower incidence of death compared to others (1.10% (N=225/20,530) vs 2.81% (N=29,335/1,042,550), p≤0.001). [0205] Between 2017-2020 among primary NSTEMI or NSTEMI-CAD patients without history of prior graft or stent and receiving PCI during index admission, CUD-A was associated with significantly lower incidence of death compared to others ( 1.19% (N=160/13,475) vs 3.03% (N=18,950/625,755), p≤0.001); and among those with history of prior stent or graft (0.47% (N=15/3225) vs 2.36% (N=4885/206,990), p=0.002). [0206] Additionally, from 2016-2020, among CAD patients with history of graft or stent, irrespective of primary diagnosis of AMI, CUD-A was associated with significantly higher incidence of subsequent AMI within 4 weeks compared to others (0.48% (60/12,515) vs 0.23% (2190/962,040)). Moreover, among those with history of graft or stent who received angioplasty- only during index admission, the odds of subsequent myocardial infarction within 4 weeks of prior AMI were 5.63 times higher for CUD-A than that among others (OR: 5.63, [1.97-16.09], p≤0.001). [0207] Stroke: [0208] Additionally, among those diagnosed with all-cause stent failure (and CAD patients with primary AMI receiving index PCI), the incidence of acute hemorrhagic stroke was significantly higher for CUD-A compared to that among others (0.77% (10/1300) vs 0.21% (180/87,375). However, cumulative stroke risk (defined as acute hemorrhagic stroke, acute ischemic stroke, cardioembolic stroke) among all patients admitted with AMI (in any position of the medical claim) from 2016-2020 was significantly lower for CBD-A compared to others (3.18% (N=2,265/71,325) vs 3.52% (N=145,080/4,123,225), p=0.027, respectively). [0209] Percutaneous Intervention Target Population: High Risk Groups [0210] The market opportunity entailed by this finding and invention includes all patients at risk for adverse events associated with PCI. Those presenting with primary STEMI or NSTEMI and those without primary AMI with and without history of prior percutaneous coronary artery intervention and those at risk for complications related to the procedure such as coronary microembolization each represent high risk groups. [0211] This population of patients is described in the NIS: [0212] Nationally, those with history of graft or stent represent 25.78% of those presenting with AMI (STEMI, N=51,615/269,345; NSTEMI, N=256,700/618,135 from 2016- 2020; p≤0.001). Between 2016-2020 among patients receiving coronary catheterization with history of coronary artery disease, there were 60,895 encounters related to an AE-- 37.74% of whom were patients with history of prior PCI; and 62.26% of whom were patients without history of PCI (p≤0.001). Notably, this only represents 11.42% of patients presenting with history of prior stent(p≤0.001); and 10.57% or those with prior graft or stent (N= 263,845) admitted with AMI (p≤0.001). [0213] Among those receiving PCI and excluding those with diagnosis of adverse event, it should be noted that a proportionally higher percent of patients with history of graft or stent have secondary AMI during index admission (HxGraftStent: N=276,455; No Subsequent AMI: 84.84% vs Subsequent AMI: 15.16%; compared to those Without HxGraftStent: N= No Subsequent AMI: 89.44% vs Subsequent AMI: 10.56%, p≤0.001). [0214] However, among all patients with secondary AMI during index admission(N=131,480) those without history of graft or stent represent 68.13% of encounters diagnosed with subsequent AMI during index admission. As such, the representative sample of patients in need of the medical therapy is 1) Not only the 848,360 CAD patients without history of graft or stent and without diagnosis of STS or ISR who received procedural PCI during index admission. 2) Nor the 276,455 with history of graft or stent without diagnosis of STS or ISR who received procedural PCI during index admission. 3) Nor the 70,980 hospital encounters associated with AE (diagnosed with AE) among CAD patient encounters receiving index PCI 2016-2020, 44.89%(N=31,860/70,980) of whom had history of graft or stent, 4,080(12.81%, N=4,080/31,860) of whom were diagnosed with secondary AMI; and 55.11% of whom did not have history of graft or stent (N=39,120/70,980), and 16.76% (N=6,555/39,120) of were diagnosed with secondary AMI--indicating that subsequent AMI among those without history of prior PCI represented/was associated with 9.23% of all patients diagnosed with AE, and subsequent AMI generally/regardless of history of graft or stent represented/was associated with 14.98%(N=10,635/70,980) of the patient encounters among CAD encounters diagnosed with AE receiving index PCI. [0215] It is the 308,315 with history of graft or stent and the 887,480 without history of graft or stent, and the 1,195,795 patients from 2016 to 2020 with CAD, among whom 11.88%(N=142,115/1,195,795) experienced subsequent AMI during index admission, as well as those at risk for the development of the disease who may benefit from therapy. [0216] Secondary Acute Myocardial Infarction Outcomes: [0217] Notably, CUD-A was associated with significant increased incidence of secondary AMI among CAD patient encounters without history of PCI and primary diagnosis of STEMI or NSTEMI, and receiving index PCI (CUD-A, N=10,565 vs N-CUD-A, N=503,055; 1.42% vs 0.83%, p=0.004). However, among all AMI (inclusive of STEMI or NSTEMI in any position of the medical claim) patients with Ob-DM were significantly associated with secondary AMI (Ob- DM, N=45,860 vs N-Ob-DM, N=525,120; 14.70% vs 10.45%, p≤0.001). In contrast, the subpopulation of STEMI-P and NSTEMI-P Ob-DM patients were associated with proportional percentages in the opposite direction (Ob-DM, N=39,335 vs N-Ob-DM, N=474,285, 0.56% vs 0.87%, p=0.004). [0218] What is more, controlling for other factors and utilizing an interaction term between CUD-A and number of DES in one artery primary PCI procedure (subsequent AMI during index admission, subsequent procedural intervention, and IVUS use), among CAD patients receiving PCI with history of prior PCI and with NSTEMI (in any position of the medical claim), CUD-A individually was associated with significantly higher odds of stent thrombosis compared to others (aOR: 3.90, [1.00, 15.22], p=0.05; N=129,685). [0219] Angioplasty vs DES Stent vs Metal Stent: [0220] Angioplasty was associated with significantly higher incidence of stent thrombosis among CAD patients receiving PCI during index admission compared to those who received no angioplasty with significantly higher incidence among those who received 2 DES with angioplasty compared to those who did not receive angioplasty (Mean Difference: 3.40%, p≤0.001); and among those who received angioplasty compared to those who received 1 metal stent (Mean Difference: 3.74%, p≤0.001; 2.87%, p≤0.001). [0221] Angioplasty alone was associated with significantly higher incidence of stent thrombosis compared to one DES stent, two DES stent, three DES stent, or four DES stent; or one metal stent or two metal stent (Mean difference DES: 2.33%, 2.23%, 2.10%, 2.15%, p≤0.001 for each, respectively; Mean difference one or two Metal stent: 1.97%, 1.50%, p≤0.001 for each, respectively ; Mean difference three metal stent: 1.94%, p=0.009, respectively). [0222] Late Stent Thrombosis: [0223] Notably, from 2016-2020 among those with primary diagnosis of STEMI and stent thrombosis and obesity with complicated diabetes, on chi-square analysis among group A) primary STEMI-CAD patients diagnosed with secondary AMI during index admission receiving PCI during index admission and B) among patients with primary STEMI diagnosis without secondary diagnosis of AMI during index admission with history of stent, those in group A were significantly associated with group B compared to non-group-A patient encounters (69.23%(N=225/260) vs 30.77%(N=100/260)). Notably, the latter group represents patient with history of prior PCI, and among this population of patients (non-group A) group B was significantly associated with identification of 57.14% of those with stent thrombosis and obesity with complicated diabetes (57.14% (100/175) vs 42.86% (75/175), p≤0.001). The latter comparison represents "late stent thrombosis" and indicate that modulation of the CB1 receptor is associated with significant incidence of late stent thrombosis among obese with complicated diabetes. [0224] On logistic regression from 2015-2020 within the NIS, irrespective of primary or secondary AMI diagnosis or history of CAD; and controlling for the effects of group A and B or presence of prior PCI/stent, obesity with complicated diabetes was associated with significantly higher odds of stent thrombosis compared to others (aOR: 1.18, [1.04-1.35], p=0.012). [0225] Subsequent Acute Myocardial Infarction within 4 weeks of prior AMI: [0226] Among CAD patients, subsequent STEMI or NSTEMI within 4 weeks of prior AMI was significantly associated with CUD-A when limited to years 2019-2020 (0.91% (N=70/ 7720) vs 0.52% (N=2,240/434,140), p=0.035, respectively). [0227] Atrial Fibrillation: [0228] From 2016-2020 among primary STEMI- or NSTEMI-CAD patients irrespective of prior history of PCI and receiving PCI during index admission, the incidence of new-onset atrial fibrillation was significantly lower for CUD-A vs others (3.41% (N=700/20,535) vs 7.29% (N=76,050/1,043,090), p≤0.001). On multivariable logistic regression, CUD-A was associated with significantly lower odds of new-onset atrial fibrillation compared to others (aOR: 0.7979, [0.6638-0.9592], p=0.016, N=996,025); while Ob-DM was associated with significantly higher odds of atrial fibrillation compared to others (aOR: 1.171085, [1.067762-1.284407], p^ 0.001). [0229] From 2017-2020, limited to those without history of stent, on matched analysis, CUD-A was associated with a significantly lower general atrial fibrillation event rate compared to others ((ATE: -.0456, [-.0798719, -0.0113], p=0.009, N=160,233); aOR:0.7400, [0.6197- 0.8836], p≤0.001, N=108,555). [0230] Ventricular Fibrillation and Ventricular Flutter: Agonist Dose-Response [0231] From 2016-2020 among primary STEMI- or NSTEMI-CAD patients irrespective of prior history of PCI and receiving PCI during index admission, the incidence of ventricular fibrillation or ventricular flutter was significant higher for CUD-A compared to others (11.52% (N=2,705/23,465) vs 9.56% (N=116,260/1,186,770), p≤0.001). On multivariable logistic regression, CUD-A was associated with significantly lower odds of ventricular fibrillation/ventricular flutter compared to others (aOR: 0.7799, [0.6992-0.8699], p≤0.001, N=997,530); while Ob-DM was associated with significantly higher odds of ventricular fibrillation compared to others (aOR: 1.2952, [1.1841-1.4167], p^ 0.001). [0232] From 2017-2020, limited to those without history of graft or stent, on matched analysis, CUD-A was associated with a significantly lower ventricular fibrillation/ventricular flutter event rate compared to others (ATE: -0.03394; aOR: 0.6840, [0.6009-0.7786], p≤0.001, N=110,718) [0233] Notably, among all patients admitted with NSTEMI or STEMI from 2015-2020, CUD-A was associated with significantly higher incidence of long-QT syndrome compared to others (3.08% (745/24,180) vs 1.59% (834,65/5,258,750), p≤0.001). Moreover, among primary STEMI- or NSTEMI-CAD patients without history of prior PCI and receiving PCI during index admission, CUD-A was associated with significantly higher incidence of long-QT syndrome compared to others (3.28% (100/3,050) vs 1.98% (17,055/859,270), p=0.022); and significantly higher incidence irrespective of prior history of PCI compared to others (3.11% (120/3,860) vs 1.93% (20,415/1,059,765), p=0.017). Acutely and chronically, it modulates the potency of the arrhythmic triggers and indirectly increases the potency and heterogeneity of the sympathetic response; and increases risk for R-on-T ventricular arrhythmia or other ventricular arrythmia. [0234] Moreover, from 2016-2020 among all AMI patient encounters, irrespective of primary diagnosis, with history of CAD and without prior history of stent, active cannabis dependence was associated with significantly higher incidence of long QT syndrome compared to active cannabis abuse (2.15% (N=25/1,140) vs 0.81% (N=300/37,100), p=0.029, respectively). Additionally, from 2016-2020 among all AMI patient encounters, irrespective of primary AMI diagnosis or PCI status or inpatient procedural PCI status, the incidence of paroxysmal atrial fibrillation was not significantly different between those with active cannabis abuse vs active cannabis dependence (4.91% (N=3,395/69,155) vs 3.46% (N=75/2,170), p=0.166, respectively). However, the incidence of ventricular fibrillation/tachycardia was significantly lower for those with active cannabis dependence compared to active cannabis abuse (6.68% (N=145/2,170) vs 9.66% (N=6,680/69,155), p=0.038, respectively). [0235] Finally, from 2016-2020 among CAD patient encounters without history of stent and receiving PCI during index admission (and excluding active cannabis dependence encounters), the incidence of ventricular fibrillation/tachycardia was significantly higher for those with active cannabis abuse compared to others (12.55% (N=2,300/18,325) vs 10.56% (N=99,425/941,760), p≤0.001, respectively). In contrast, from 2016-2020 among CAD patient encounters without history of stent and receiving PCI during index admission (and excluding active cannabis abuse encounters), the incidence of ventricular fibrillation/tachycardia was not significantly different for those with active cannabis dependence compared to others (13.00% (N=65/500) vs 10.56% (N=99,425/941,760), p=0.427, respectively); and the same was true when the sample was not limited to those who received inpatient PCI, with active cannabis abuse associated with significantly higher incidence of ventricular fibrillation/tachycardia compared to others (11.00% (N=4,115/37,395) vs 8.84% (N=199,415/2,255,810), p≤0.001, respectively); and active cannabis dependence associated with a non-significant higher incidence of ventricular fibrillation/tachycardia compared to others (10.33% (N=125/1,210) vs 8.84%(N=199,415/2,255,810), p=0.414, respectively). However, from 2016-2020 among CAD patient encounters without history of stent and irrespective of PCI during index admission, these differences were attenuated on multivariable logistic regression, with non-significant lower odds of ventricular fibrillation/tachycardia for active cannabis dependence compared to active cannabis abuse encounters (aOR: 0.9838833, [0.6323732-1.530783], p=0.943). [0236] In context with the above prior described mechanism associated with pause- dependent paroxysmal AVB, the inactivation of a salient number of cardiac myocytes within the ventricle inhibits the subsequent depolarization such that an increased proportional inactivation prevents even subsequent depolarization within the ventricle from reaching the threshold potential needed to induce an R-on-T event. Alternatively, the preservation of GRK2 signaling cascades within the epicardial boarder zone through acutely increased serum concentration may function to maintain GRK2 signaling during periods of acute ischemia, thereby antagonizing the electrochemical disturbances and/or loss of receptor kinase activity needed to form a substrate for ventricular arrythmia; and/or antagonizing activation and increased responsiveness of the heart to B-adrenergic stimulation of during the critical window of susceptibility following acute MI and procedural intervention. [0237] These modulatory acute effects are efficacious at both the atria and ventricle, and the chronic effects are more potent (i.e. at a lower dose) at the atria compared to the ventricle due to chronic desensitization; differences in autonomic signaling and arrhythmogenic triggers between the atria and ventricle; and temporospatial, distribution differences of autonomic signaling inputs between the atria and ventricle, with significant differences dependent upon the degree of desensitization from chronic stimulation such that increased stimulation produces increased desensitization at both atria and ventricle, as noted above. As such, the utility of the medical therapy for prevention of arrythmia in preventing the prolongation of QT-- for example, with an antagonist/allosteric modulation with signaling specific inhibitor; or shortening of the QT- - for example with, an antagonist/ or antagonist/inverse agonist; or desensitization of atrial or ventricular arrythmia-inducing receptors; or alternative method of use for the purposes of modulation of arrythmia represent viable mechanisms of prevention or treatment of arrythmia; and administered, for example, from the time of hospital admission: hour 0 to time of hospital discharge: hour 168hr or during the perioperative period prior to procedural intervention or prior to arrival at the hospital through administration from bystanders or medical professionals en-route to the hospital during an acute ischemic event or in association with such an event, or among those at risk of arrythmia prior to such an event or during the 120 minutes prior to procedural intervention and/or thereafter for a brief period of time or for life, or generally among those with arrythmia or ventricular arrythmia irrespective of ischemic event as needed for the treatment or prevention of subsequent adverse events based upon the medical judgement of the practitioner. The former may represent suitable therapy acutely or chronically for prevention or treatment of atrial arrythmia and/or ventricular arrythmia, while the latter may represent suitable therapy during acute hospitalization for prevention or treatment of ventricular arrythmia. However, these treatment modalities are viable options for treatment and/or prevention of atrial or ventricular arrythmia by potentiating desensitization and decreasing heterogeneity of responses within the respective target tissue or in a subject in need of treatment thereof at appropriate dose. Acutely and chronically, the utilization of the medication has utility for treatment or modulation of atrial or ventricular arrythmia. [0238] Microvascular Disease, Depression, and Endocannabinoids: Takotsubo Cardiomyopathy [0239] Importantly, from 2016-2020 among CAD patients without history of prior PCI, irrespective of primary AMI diagnosis or index procedural PCI, CUD-A was associated with significantly higher incidence of Takotsubo Cardiomyopathy compared to others (1.36% (N=520/38,265) vs 1.05% (N=23,740/2,256,160), p=0.009); and among primary STEMI- or NSTEMI-CAD and subsequent NSTEMI diagnosis without history of prior PCI, irrespective of index procedural PCI, CUD-A was associated with significantly higher incidence of Takotsubo Cardiomyopathy compared to others (1.31% (N=310/23,685) vs 1.01% (N=13,510/1,339,000), p=0.041; OR:1.30, [1.009896-1.676432], p=0.042). Moreover, from 2016-2020 primary NSTEMI- STEMI-CAD patients without history of PCI and receiving PCI during index admission, vitamin D deficiency or depression was significantly associated with Takotsubo Cardiomyopathy (0.57% (N=60/10,555) vs 0.32% (N=2,755/851,765), p=0.050, respectively; (0.64% (N=465/72,695) vs 0.30% (N=2350/789,625), p≤0.001). Notably, depression was significantly associated with vitamin D deficiency among primary NSTEMI- STEMI-CAD patients without history of PCI and receiving PCI during index admission from 2016-2020 (2.39% (N=1,735/72,695) vs 1.12% (N=8,820/789,625), p≤0.001, respectively). On multivariable regression analysis among CAD patients without history of stent, irrespective of primary AMI diagnosis, who received PCI during index admission, CUD-A was associated with a non- significant increase in Takotsubo Cardiomyopathy compared to others (aOR:1.43504, [0.7705776- 2.672476], p=0.255). However, in the same model depression was significantly associated with Takotsubo Cardiomyopathy compared to others and controlling for other factors (aOR:1.48539, [ 1.199226-1.839844], p≤0.001; N= 1,271,955). Finally, because Takotsubo Cardiomyopathy may not necessitate PCI for diagnosis, when the sample was not limited to those who received PCI during index admission: on multivariable regression analysis from 2016-2020 among CAD patients without history of prior stent, irrespective of primary AMI diagnosis, who received PCI during index admission, CUD-A was associated with a non-significant increase in Takotsubo Cardiomyopathy compared to others (aOR:1.696267, [1.358516-2.117988], p≤0.001); and depression was significantly associated with Takotsubo Cardiomyopathy compared to others and controlling for other factors (aOR:1.423479,[ 1.314688-1.541272], p≤0.001; N=2,153,935). Additionally, in the latter model, weight loss was associated with significantly higher odds of Takotsubo Cardiomyopathy (aOR: 1.491361, [1.334408-1.666775], p≤0.001; N=1,271,955); and this association becomes more significant among those who received PCI as seen in the former model (aOR: 2.0453, [1.559567-2.682317], p≤0.001; N= 1,271,955). Percutaneous Coronary Intervention and the associated increased risk of microembolization may explain this finding. [0240] Prior reports have posited that Takotsubo Cardiomyopathy may represent a manifestation of microvascular disease; and I previously reported adverse inpatient outcomes associated with Takotsubo Syndrome. Considering the known significant association between serotonin function, endocannabinoid signaling, B2-Adrenergic signaling, vitamin D, and depression, these findings support this theory; and indicate that these factors combined as well as serotonin modulation and signaling pathways are significantly associated with microvascular disease presentation, if not only in part. [0241] Valvular Disease: [0242] Of note, among all patients from 2016-2020 admitted with either STEMI or NSTEMI at any location within the encounter medical claims, the incidence of non-rheumatic valvular disease was significantly higher for CUD-A patients compared to others, specifically among those Age 30-Age 65 compared to others in the respective age group (Age Group 30- 54:3.73% vs 3.00%, p≤0.001, Age Group 55-64: 4.86% vs 4.01%, p=0.003, respectively). [0243] These results were more significant within the valvular heart disease subpopulation (38.74% (N=3,130/8,080) vs 28.87% (N=195,920/678,550), p≤0.001, respectively); and among those with CHF between Age Group 30-64:6.82% (N=1,645/24,135) vs 6.10% (N=36,985/606,715), p=0.041, respectively); and the congestive heart failure with valvular disease subpopulation (40.31% (N=2,185/5,420) vs 30.45% (N=142,730/468,810), p≤0.001, respectively). Among those with or without chronic pulmonary disease, CUD-A was significantly associated with valvular disease (13.32% (N=840/6,305) vs 9.75% (N=9,695/99,425), p≤0.001; 8.09% (N=2,180/26,945) vs 7.01% (N=35,290/503,705), p=0.002 respectively). [0244] Chronic Total Occlusion of Coronary Artery (CTO): [0245] Among AMI-CAD patients receiving PCI, CUD-A was significantly associated with chronic total occlusion of coronary artery (CTO) compared to others (6.95% (N=1,300/18,715) vs 6.15% (N=57,890/941,875), p=0.04, respectively). Moreover, among primary STEMI- or NSTEMI-CAD patients receiving PCI, CUD-A was significantly associated with chronic total occlusion of coronary artery (CTO) compared to others (6.88% (N= 1,180/ 17,155) vs 6.08% (N= 51,425/ 845,165), p=0.05, respectively) and higher odds compared to others, controlling for other factors (aOR: 1.150554, [1.004759-1.317504], p=0.042); as well as obesity with complicated diabetes (1.134194, [1.024482-1.255657], p=0.015). [0246] Additionally, among CAD patients receiving PCI, CTO was significantly associated with right heart STEMI compared to others (10.68% (N=470/4400) vs 6.20% (N=73,915/1,191,395), p≤0.001, respectively). Furthermore, among primary STEMI- or NSTEMI-CAD patients receiving index PCI, CTO was significantly associated with right heart STEMI compared to others (11.50% (N= 395/3435) vs 6.16% (N= 65,275/ 1,060,190), p≤0.001, respectively). [0247] Importantly, among all patients admitted form 2016-2020 with AMI in any position of the medical claim, CUD-A was significantly associated with right heart STEMI compared to others (2.38% (N=195/8,200) vs 1.70% (N=71,110/4,185,845), p=0.03, respectively). What is more, among primary STEMI- or NSTEMI-CAD patients receiving PCI during index admission and without history of PCI, CUD-A was significantly associated with chronic total occlusion of coronary artery (CTO) compared to others when controlling for other factors, including right heart STEMI (aOR: 1.149587, [1.003927-1.316381], p=0.044); and obesity with complicated diabetes (1.133702, [1.024021-1.25513], p=0.016); and in the model, right heart STEMI was associated with significantly higher odds of CTO compared to others (aOR: 1.647669, [1.286368-2.110449], p≤0.001). [0248] A. Mental Illness and Acute ISR and Thrombosis: National Trends and Outcomes Using the National Inpatient Sample [0249] Results: [0250] A total number of 840,789 patients met the inclusion criteria: 69,779 patients had depression (DP) (8.30%) with a mean age 64 ± 0.11 years and predominance of males 36,260 (51.96%). Among those without history of depression patients (N-DP); 520,871 (67.56%) were male, with a mean age 64±0.04 years. Adverse event incidence among DP (5.14%) was significantly higher than patients without depression (3.90%, p≤0.001). Between 2016 and 2019, there was a statistically significant positive temporal relationship between AE and depression over time (Beta-Coefficient: 0.007, [0.002-0.01], p≤0.009). Controlling for other factors, among those with primary NSTEMI without prior history of stent or graft and receiving PCI during index admission, single, nonrecurrent major depressive disorder (MDD) was associated with a significant positive temporal trend in AE over time (Beta-Coefficient: 0.0096669, [0.0035796- 0.0157543], p=0.002). Controlling for AMI and other factors, depression was associated with 23.08% higher odds of AE compared to N-DP (aOR:1.230758, [1.083932-1.397473], p=0.001; N=437,360); MDD with 19.68% higher odds of AE compared to those without MDD (aOR:1.19677, [1.046175-1.369044] , p=0.009; N=437,255). On PSM analysis among those with primary NSTEMI without prior history of stent or graft and receiving PCI during index admission, depression (Matched Observations: 59,155) was associated with 1.22% higher AE rate compared to N-DP (Average Treatment Effect (ATE): 0.0121545, Confidence Interval (CI): 0.0040102- 0.0202989], p=0.003); and single, nonrecurrent major depressive disorder (MDD) (Matched Observations: 59,155) was associated with 1.01% higher AE rate compared to those without MDD (ATE: .0101428, [.0026-0.0177], p=0.008).

Claims

WHAT IS CLAIMED IS: 1. A method for prevention and treatment of diseases associated with cardiovascular therapy in a patient through peri-procedural administration of a pharmaceutical composition for inhibiting or modulating cannabinoid receptor 1, comprising: administering a first dose of the pharmaceutical composition to the patient within a first time period before or substantially concurrently with performing the cardiovascular therapy on the patient, wherein the pharmaceutical composition comprises a therapeutically effective amount of an inhibitor or modulator of cannabinoid receptor 1 and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, stabilizer, or mixture thereof; administering one or more subsequent doses of the pharmaceutical composition to the patient within subsequent time periods after performing the cardiovascular therapy on the patient. 2. The method of claim 1, wherein the patient has a history of cannabis use. 3. The method of claim 1, wherein the cardiovascular therapy comprises percutaneous coronary intervention, coronary artery bypass surgery or stent placement. 4. The method of claim 1, wherein the diseases associated with cardiovascular therapy comprise coronary artery disease, coronary microembolization, atheromatous embolism, stent thrombosis, stent restenosis, stent occlusion, coronary artery bypass graft thrombosis, coronary artery bypass graft stenosis, coronary artery bypass graft occlusion, congestive heart failure, myocardial infarction, coronary artery disease, microvascular coronary dysfunction, cardiac arrhythmia, peripheral vascular disease, or combinations thereof. 5. The method of claim 1, wherein the pharmaceutical composition is administered by intravenous, intraperitoneal, intracranial, subcutaneous, intradermal, intramuscular, intrathecal, intranasal or epidural administration. 6. The method of claim 1, wherein the inhibitor or modulator of cannabinoid receptor 1 is 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1- piperidyl)pyrazole-3-carboxamide, (6aR.10aR)-3-(1-methanesulfonylamino-4-hexyn-6-yl)- 6a,7,10,10a-tetrahydro-6,6,9-trimethyl- 6H-dibenzob. dpyran, N-(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)-2-bu tanyl-2-methyl-2-5- (trifluoromethyl)-2-pyridinyl oxypropanamide, 5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-4- ethyl-N-(1- piperidinyl)-1H-pyrazole-3-carboxamide, 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-(4- chlorophe nyl)-sulfonyl-4-phenyl-4,5-dihydro-1H-pyrazole-1- carboxamidine, (+)-N-1-bis(4- chlorophenyl)methyl-3-azetidinyl-N- (3,5-difluorophenyl)-methanesulfonamide, 1-8-(2- chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6- yl)-4-(ethylamino)piperidine-4-carboxamide, and (+)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(1-piperidinyl)-4,5-dihydro-1H-pyrazole-3- carboxamide or a pharmaceutically acceptable salt thereof. 7. The method of claim 1, wherein the first dose is 0.01 to 40 mg per kg of patient body weight, and wherein the first time period is within one month before performing the cardiovascular therapy on the patient. 8. The method of claim 1, wherein the subsequent doses are 0.01 to 40 mg per kg of patient body weight, and wherein each subsequent dose is administered once every one to four hours for twenty-four hours after performing the cardiovascular therapy on the patient. 9. The method of claim 1, wherein the subsequent doses are 0.01 to 40 mg per kg of patient body weight, and wherein each subsequent dose is administered once a day for seven days after performing the cardiovascular therapy on the patient. 10. The method of claim 1, wherein the subsequent doses are 0.01 to 40 mg per kg of patient body weight, and wherein each subsequent dose is administered once a week for three to six months after performing the cardiovascular therapy on the patient. 11. A method for prevention and treatment of diseases associated with cardiovascular therapy in a patient through acute administration of a pharmaceutical composition for inhibiting or modulating cannabinoid receptor 1, comprising: administering a single dose of the pharmaceutical composition to the patient within a time period before or substantially concurrently with performing the cardiovascular therapy on the patient, wherein the pharmaceutical composition comprises a therapeutically effective amount of an inhibitor or modulator of cannabinoid receptor 1 and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, stabilizer, or mixture thereof. 12. The method of claim 11, wherein the patient has a history of cannabis use. 13. The method of claim 11, wherein the cardiovascular therapy comprises percutaneous coronary intervention, coronary artery bypass surgery or stent placement. 14. The method of claim 11, wherein the diseases associated with cardiovascular therapy comprise coronary artery disease, coronary microembolization, atheromatous embolism, stent thrombosis, stent restenosis, stent occlusion, coronary artery bypass graft thrombosis, coronary artery bypass graft stenosis, coronary artery bypass graft occlusion, congestive heart failure, myocardial infarction, coronary artery disease, microvascular coronary dysfunction, cardiac arrhythmia, peripheral vascular disease, or combinations thereof. 15. The method of claim 11, wherein the pharmaceutical composition is administered by intravenous, intraperitoneal, intracranial, subcutaneous, intradermal, intramuscular, intrathecal, intranasal or epidural administration. 16. The method of claim 11, wherein the inhibitor or modulator of cannabinoid receptor 1 is 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1- piperidyl)pyrazole-3- carboxamide, (6aR.10aR)-3-(1-methanesulfonylamino-4-hexyn-6-yl)- 6a,7,10,10a-tetrahydro- 6,6,9-trimethyl-6H-dibenzob. dpyran, N-(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)-2-bu tanyl-2-methyl-2-5-(trifluoromethyl)-2-pyridinyl oxypropanamide, 5-(4-bromophenyl)-1-(2,4- dichlorophenyl)-4-ethyl-N-(1- piperidinyl)-1H-pyrazole-3-carboxamide, 4S-(-)-3-(4- chlorophenyl)-N-methyl-N'-(4-chlorophe nyl)-sulfonyl-4-phenyl-4,5-dihydro-1H-pyrazole-1- carboxamidine, (+)-N-1-bis(4-chlorophenyl)methyl-3-azetidinyl-N- (3,5-difluorophenyl)- methanesulfonamide, 1-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6- yl)-4- (ethylamino)piperidine-4-carboxamide, and (+)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(1- piperidinyl)-4,5-dihydro-1H-pyrazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 17. A method for prevention and treatment of diseases associated with activation or overactivation of cannabinoid receptor 1 through administration of a pharmaceutical composition for inhibiting or modulating cannabinoid receptor 1, comprising: administering one or more doses of the pharmaceutical composition to the patient, wherein the pharmaceutical composition comprises a therapeutically effective amount of an inhibitor or modulator of cannabinoid receptor 1 and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer, stabilizer, or mixture thereof, and wherein any doses of the pharmaceutical composition administered to the patient after a first dose are administered within subsequent time periods after administering the first dose to the patient. 18. The method of claim 17, wherein the patient has a history of cannabis use. 19. The method of claim 17, wherein the diseases associated with activation or overactivation of cannabinoid receptor 1 comprise COVID-19, obesity, diabetes, stroke, fibrosis, or keloid formation. 20. The method of claim 17, wherein the pharmaceutical composition is administered by intravenous, intraperitoneal, intracranial, subcutaneous, intradermal, intramuscular, intrathecal, intranasal or epidural administration. 21. The method of claim 17, wherein the inhibitor or modulator of cannabinoid receptor 1 is 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1- piperidyl)pyrazole-3- carboxamide, (6aR.10aR)-3-(1-methanesulfonylamino-4-hexyn-6-yl)- 6a,7,10,10a-tetrahydro- 6,6,9-trimethyl-6H-dibenzob. dpyran, N-(2S,3S)-4-(4-chlorophenyl)-3-(3-cyanophenyl)-2-bu tanyl-2-methyl-2-5-(trifluoromethyl)-2-pyridinyl oxypropanamide, 5-(4-bromophenyl)-1-(2,4- dichlorophenyl)-4-ethyl-N-(1- piperidinyl)-1H-pyrazole-3-carboxamide, 4S-(-)-3-(4- chlorophenyl)-N-methyl-N'-(4-chlorophe nyl)-sulfonyl-4-phenyl-4,5-dihydro-1H-pyrazole-1- carboxamidine, (+)-N-1-bis(4-chlorophenyl)methyl-3-azetidinyl-N- (3,5-difluorophenyl)- methanesulfonamide, 1-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6- yl)-4- (ethylamino)piperidine-4-carboxamide, and (+)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N-(1- piperidinyl)-4,5-dihydro-1H-pyrazole-3-carboxamide or a pharmaceutically acceptable salt thereof. 22. The method of claim 17, wherein the one or more doses are 0.01 to 40 mg per kg of patient body weight. 23. The method of claim 17, wherein more than one dose is administered to the patient, and wherein each subsequent dose is administered once every one to four hours for twenty-four hours after administering the first dose to the patient. 24. The method of claim 17, wherein more than one dose is administered to the patient, and wherein each subsequent dose is administered once a week for one to six months after administering the first dose to the patient. 25. The method of claim 17, wherein more than one dose is administered to the patient, and wherein each subsequent dose is administered once a day for seven days to three years after administering the first dose to the patient. 26. A biocompatible device for prevention and treatment of diseases associated with cardiovascular therapy in a patient, comprising: a device for deployment into the patient’s vascular system in connection with cardiovascular therapy; and a pharmaceutical composition attached to or contained within the device, wherein the pharmaceutical composition comprises a therapeutically effective amount of an inhibitor or modulator of cannabinoid receptor 1. 27. The biocompatible device of claim 26, wherein the device is a radially expandable wire, radially expandable stent, radially expandable balloon, perforated tube, catheter, intravascular needle, bioresorbable scaffold, bioresorbable polymer, ostial stent, or ostial balloon. 28. The biocompatible device of claim 26, wherein the inhibitor or modulator of cannabinoid receptor 1 is 1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-(1- piperidyl)pyrazole-3-carboxamide, (6aR.10aR)-3-(1-methanesulfonylamino-4-hexyn-6-yl)- 6a,7,10,10a-tetrahydro-6,6,9-trimethyl-6H-dibenzob. dpyran, N-(2S,3S)-4-(4-chlorophenyl)-3-(3- cyanophenyl)-2-butanyl-2-methyl-2-5-(trifluoromethyl)-2-pyridinyl oxypropanamide, 5-(4- bromophenyl)-1-(2,4-dichlorophenyl)-4-ethyl-N-(1- piperidinyl)-1H-pyrazole-3-carboxamide, 4S-(-)-3-(4-chlorophenyl)-N-methyl-N'-(4-chlorophe nyl)-sulfonyl-4-phenyl-4,5-dihydro-1H- pyrazole-1- carboxamidine, (+)-N-1-bis(4-chlorophenyl)methyl-3-azetidinyl-N- (3,5- difluorophenyl)-methanesulfonamide, 1-8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6- yl)- 4-(ethylamino)piperidine-4-carboxamide, and (+)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-N- (1-piperidinyl)-4,5-dihydro-1H-pyrazole-3-carboxamide or a pharmaceutically acceptable salt thereof.