AU2017260873B2

AU2017260873B2 - Cannabidiol for reducing a steroid dose and treating inflammatory and autoimmune diseases

Info

Publication number: AU2017260873B2
Application number: AU2017260873A
Authority: AU
Inventors: Sari Prutchi SAGIV; Moshe YESHURUN
Original assignee: Stero Biotechs Ltd
Current assignee: Stero Biotechs Ltd
Priority date: 2016-05-02
Filing date: 2017-05-01
Publication date: 2023-03-02
Anticipated expiration: 2037-05-01
Also published as: EP3452046A4; IL262713B1; CN109414443A; KR20190016952A; IL262713A; IL262713B2; WO2017191630A1; AU2017260873A1; CA3022900A1; CN117017998A; EP3452046A1; KR102537990B1

Abstract

The invention provides methods for preventing, ameliorating and treating the steroid side effects, steroid refractory conditions, autoimmune diseases and liver inflammation by using Cannabidiol and a steroid composition.

Description

CANNABIDIOL FOR REDUCING A STEROID DOSE AND TREATING INFLAMMATORY AND AUTOIMMUNE DISEASES

[001] This application claims the benefit of priority from U.S. Patent Application No.

15/143,694, filed on May 2, 2016. The content of the above document is incorporated by

reference in its entirety as if fully set forth herein.

FIELD OF INVENTION

[002] The present invention relates to methods and uses of Cannabidiol compositions in

reducing a steroid dose and treating inflammatory and autoimmune diseases and

conditions.

BACKGROUND OF THE INVENTION

[003] Steroids such as corticosteroids are useful in the management of many inflammatory

diseases such as asthma for more than 50 years. Regardless of the route used, it is advisable

to limit the use of these agents to patients who clearly require them and to take all precautions

to minimize side effects.

[004] There is ample evidence that the HPA axis function is suppressed by exogenous

corticosteroids.

[005] Several investigators have found that some patients receiving daily doses >5 mg

prednisone (or of other corticosteroids in equivalent pharmacologic doses) for months to years

have evidence of suppression of HPA function. This inhibition of adrenal function in the

presence of stress, e.g., surgery, severe trauma, or a serious illness, may cause circulatory

collapse and death if not promptly treated with supplemental hydrocortisone. As in status

asthmaticus, the precise amount of hydrocortisone has not been clearly delineated and various

regimens have been proposed.

[006] Intravenous supra-pharmacological doses of corticosteroids are used in various

inflammatory and autoimmune conditions because they are cumulatively less toxic than

sustained steroid treatment at lower quantitative dosage. Their action is supposed to be

mediated through non-genomic actions within the cell. Common indications for use in

children include steroid resistant and steroid dependent nephrotic syndrome, rapidly

progressive glomerulonephritis, systemic vasculitis, systemic lupus erythematosus, acute

renal allograft rejection, juvenile rheumatoid arthritis, juvenile dermatomyositis, pemphigus,

optic neuritis, multiple sclerosis and acute disseminated encephalomyelitis.

Methylprednisolone and dexamethasone show similar efficacy in most conditions. Therapy

is associated with significant side effects including worsening of hypertension, infections,

dyselectrolytemia and behavioral effects. Adequate monitoring is essential during usage.

[007] Glucocorticoids exert a variety of immunosuppressive, anti-inflammatory and anti

allergic effects on primary and secondary immune cells and tissues. Studies have shown that

the cellular effects of glucocorticoids are mediated by genomic and various nongenomic

mechanisms.

[008] Within the cell, glucocorticoids form complexes with specific cytosolic

glucocorticoid receptors (cGCR) which is a multiprotein complex containing several heat

shock proteins (hsp70 and hsp90), and has a zincfinger motif needed for transcription

function. The cGCR also interacts with immunophilins, cochaperones such as p23 and src,

and several kinases of the mitogen-activated protein kinase (MAPK) signaling system. The

activated glucocorticoid receptor complex moves to the nucleus, binds as a homodimer to a

specific DNA sequences in the promoters of the genes that it will affect (glucocorticoid

responsive elements, GRE), and activates transcription factors, thus causing inhibition or

induction of transcription, translation and finally the synthesis of specific regulator proteins.

[009] Induction of transcription via positive GRE is termed "transactivation". Inhibition of

transcription can occur via direct interaction between the GCR and negative GRE, or,

transcription factors can be displaced from the positive GRE through direct protein-protein

interaction between transcription factors and the GCR. These direct positive and negative

gene modulations affect proteins like cytokines, chemokines, inflammatory enzymes and

adhesion molecules, resulting in modification of inflammation and immune response

mechanisms.

[010] In another genomic mechanism termed "transrepression", monomers of the

glucocorticoid/GCR complex directly or indirectly interact with transcription factors. One

example is the induction of synthesis of IkB, which decreases the amount of the pro

inflammatory transcription factor NF-KB that could translocate to the nucleus and activate

transcription of genes for IL-1, IL- 6, and TNF-a.

[011] At high concentrations, glucocorticoid molecules intercalate into cell membrane,

which alters cellular functions by influencing cation transport via the plasma membrane and

by increasing the proton leak of the mitochondria. These result in reduced calcium and sodium

cycling across plasma membranes of immune cells, which is thought to contribute to rapid

immunosuppression and a subsequent reduction of the inflammatory process. Glucocorticoid

receptors have been found to be expressed on cell membranes of human cells (mGCR);

mGCR-mediated mechanism may be involved in the rapid induction of apoptosis, and

induction of lipomodulin, which inhibits production of prostaglandins and leukotrienes.

[012] The immunosuppressive clinical effects observed when high dose glucocorticoids

are administered intravenously occur too rapidly to be explained by the classic (genomic)

mechanism of action alone. Evidence suggests that high in vivo levels of steroids obtained by

pulse corticosteroid therapy have qualitatively different pharmacologic effects than those

produced at lower doses. High doses of glucocorticoids have been shown to inhibit NFkappaB action (transrepression) only at concentrations within the cell obtainable by the highest oral or intravenous doses.30 Buttgereit et al have postulated 3 "modules" of glucocorticoid effect on cells resulting from different concentrations: (i) low concentrations mediate effects via genomic events; (ii) medium concentrations bind as well to cell surface receptors, which activate cross membrane signal transmission for genomic and nongenomic intracellular events; and (iii) at very large concentrations steroids dissolve in the cell membrane resulting in greater membrane stability and reduced non-genomic cell function generally.

[013] A single glucocorticoid application at a high dose has a strong effect due to 100%

saturation of cytosolic receptors; however, the effect would last only for a short period

because receptor occupation rapidly reverts to the original value unless a new dose is given.

Therefore, a single high dose is unlikely to have sustained effect. Overall, the effects of

corticosteroid pulses appear to include downregulation of activation of immune cells and

proinflammatory cytokine production, leading to reduced expression of adhesion molecules

and reduced movement of neutrophils into sites of inflammation. These effects are

qualitatively like those seen with anti-TNF-alpha therapy.

SUMMARY OF THE INVENTION

[014] In one embodiment, provided a method for treating a subject afflicted with an

autoimmune disease or liver inflammation, comprising administering to the subject a

therapeutically effective amount of a composition comprising a cannabidiol (CBD) or a

functional derivative thereof, thereby treating a subject afflicted with an autoimmune disease

or liver inflammation. In one embodiment, autoimmune hepatitis is treated by the present

methods. In some embodiments, a method for treating a subject afflicted with an autoimmune

disease or liver inflammation may further comprise the step of administering to the subject a

therapeutically effective amount of a composition comprising a steroid.

[015] According to the present invention, a composition comprising a CBD or a functional

derivative thereof can be substantially devoid of Tetrahydrocannabinol (THC).

[016] The invention further provides, in some embodiments, a method for enhancing the

therapeutic effect of a steroid in a subject afflicted with an autoimmune disease or liver

inflammation, comprising administering to the subject: (1) a steroid and (2) a cannabidiol

(CBD) or a functional derivative thereof, thereby enhancing the therapeutic effect of a steroid

in a subject afflicted with an autoimmune disease or liver inflammation. According to some

embodiments, enhancing the therapeutic effect of a steroid is rendering a refractory steroid

dose of a steroid a therapeutic effective dose of the steroid. According to some embodiments,

enhancing the therapeutic effect of a steroid is reducing the effective dose of the steroid.

According to some embodiments, enhancing the therapeutic effect of a steroid is reducing

side effects associated with the steroid.

[017] The invention further provides, in some embodiments, a method for reducing the

dose of a steroid in a subject afflicted with an autoimmune disease or liver inflammation,

comprising administering to the subject: (1) a steroid and (2) a cannabidiol (CBD) or a

functional derivative thereof, thereby reducing the dose of a steroid in a subject afflicted with

an autoimmune disease or liver inflammation.

DETAILED DESCRIPTION OF THE INVENTION

[018] In one embodiment, provided herein methods for preventing, ameliorating and

treating a steroid side effect, a steroid refractory condition, an autoimmune disease and/or

a liver inflammation by administering Cannabidiol. In one embodiment, provided herein

methods for preventing, ameliorating and treating a steroid side effect, a steroid refractory

condition, an autoimmune disease and/or a liver inflammation by administering

Cannabidiol and a steroid composition. In one embodiment, treating a steroid side effect

is administering CBD or a functional derivative thereof to a subject treated with a steroid and suffering from a steroid side-effect. In one embodiment, treating a steroid side effect is administering CBD or a functional derivative thereof to a subject chronically treated with a steroid and suffering from a steroid side-effect. In one embodiment, treating a steroid side effect is reducing the required therapeutically effective amount/daily-dose of the steroid by at least 20%, 30%, 40%, 50%, or 60%.

[019] In one embodiment, provided herein a method for treating a subject afflicted with

an immunological disease or disorder (such as an autoimmune disease) or inflammation,

comprising administering to the subject a therapeutically effective amount of a

composition comprising a cannabidiol (CBD) or a functional derivative thereof, thereby

treating a subject afflicted with an autoimmune disease or liver inflammation.

[020] In one embodiment, inflammation is an inflammatory disease. In one

embodiment, inflammation is chronic inflammation or a chronic inflammatory disease. In

one embodiment, inflammation is a liver inflammatory disease.

[021] In one embodiment, provided herein a method for treating a subject afflicted with

an autoimmune disease or a liver inflammation, comprising administering to the subject a

therapeutically effective amount of: (1) a composition comprising a cannabidiol (CBD) or

a functional derivative thereof; and (2) a therapeutically effective amount of a composition

comprising a steroid, thereby treating a subject afflicted with an autoimmune disease or

liver inflammation. In one embodiment, provided herein a method for treating a subject

afflicted with an autoimmune disease or a liver inflammation, comprising administering to

the subject a therapeutically effective amount of single composition or at least 2

compositions comprising: a cannabidiol (CBD) or a functional derivative thereof and a

steroid, thereby treating a subject afflicted with an autoimmune disease or liver

inflammation.

[022] In one embodiment, provided herein a method for treating an immune disease or

an inflammatory disease comprising the steps of (A): assessing the required steroid dose,

wherein a required dose beyond the recommended dose (recommended steroid dose range

for a given disease is provided within the product insert of the steroid, the Merck Index,

the Merck manual, the MSD manual, or the PDR) or within the upper 20%, 30% or 40%

of the recommended dose range, further requires: (B) administering: (a) the required

steroid dose or a steroid dose lower by 20 to 80% from the required steroid dose; and (b)

CBD or a functional derivative thereof.

[023] In one embodiment, provided herein a method for chronically treating a chronic

immune disease or a chronic inflammatory disease comprising the steps of (A): assessing

the required steroid dose, wherein a required dose beyond the recommended dose

(recommended steroid dose range or required steroid dose for a given disease is within the

product insert of the steroid, the Merck Index, the Merck manual, the MSD manual, or the

PDR) or within the upper 20%, 30%, 40%, 50%, or 60% of the recommended dose range,

further requires: (B) administering: (a) the required steroid dose or a steroid dose lower by

20 to 80% from the required steroid dose; and (b) CBD or a functional derivative thereof.

In one embodiment, a chronic immune disease or a chronic inflammatory disease is a

disease requiring a steroid treatment lasting for more than 45 days, 60 days, 90 days, 6

months, 9 months, or a year.

[024] In one embodiment, provided herein a method for chronically treating a chronic

immune disease or a chronic inflammatory disease comprising the steps of (A): diagnosing

a subject at risk of being afflicted with an immune or an inflammatory condition or disease

for having a chronic immune or chronic inflammatory condition or disease, wherein a

diagnosis of a chronic immune or chronic inflammatory condition or disease, requires: (B) administering: (a) a required steroid dose or a steroid dose lower by 20 to 70% from the required steroid dose; and (b) CBD or a functional derivative thereof.

[025] In one embodiment, provided herein CBD or a functional derivative thereof for

lowering a steroid dose in a subject in need thereof. In one embodiment, provided herein

CBD or a functional derivative thereof for reducing and/or lowering by at least 20%, 30%,

40%, 50%, 60% or 70% a steroid dose in a subject in need thereof. In one embodiment,

provided herein CBD or a functional derivative thereof for inhibiting or decreasing a side

effect associated with a steroid. In one embodiment, provided herein CBD or a functional

derivative thereof for treating a chronic inflammatory disease and/or a chronic immune

disease. In one embodiment, provided herein: (a) a steroid and (b) CBD or a functional

derivative thereof for treating a chronic inflammatory disease and/or chronic immune

disease. In one embodiment, "a subject in needed thereof" is a subject afflicted with any

one or more of the diseases and conditions as described herein. In one embodiment, a

chronic immune disease is a chronic autoimmune disease.

[026] In one embodiment, provided herein CBD or a functional derivative thereof for

decreasing the daily amount and/or daily dose of a steroid in a subject in need thereof. In

one embodiment, provided herein CBD or a functional derivative thereof for decreasing

the daily amount and/or daily dose of a steroid in a subject afflicted with autoimmune

hepatitis. In one embodiment, provided herein CBD or a functional derivative thereof for

rendering a refractory daily amount and/or daily dose of a steroid in a subject afflicted with

a disease as described herein - a therapeutically effective dose.

[027] In one embodiment, provided herein CBD or a functional derivative thereof for

reducing, inhibiting and/or eliminating a steroid side effect in a subject treated with steroid

therapy. In one embodiment, provided herein CBD or a functional derivative thereof for

reducing, inhibiting and/or eliminating a steroid side effect in a subject chronically treated with a steroid therapy. In one embodiment, provided herein CBD or a functional derivative thereof for decreasing the daily amount and/or daily dose of a steroid in a subject chronically treated with a steroid therapy.

[028] a refractory daily amount and/or daily dose of a steroid in a subject afflicted with

a disease as described herein - a therapeutically effective dose.

[029] In one embodiment, "reducing" or "lowering" a steroid dose is "reducing" or

"lowering" a required steroid dose which is beyond the recommended steroid dose. In one

embodiment, recommended steroid dose range or required steroid dose for a given disease

and/or a given steroid is provided within the product insert of the steroid, the Merck Index,

the Merck manual, the MSD manual, or the PDR.

[030] In one embodiment, "reducing" or "lowering" a steroid dose is "reducing" or

"lowering" a required steroid dose within the upper 20%, 30%, 40%, 50%, or 60% of the

recommended dose range (the recommended dose range as provided within the product

insert of the steroid, the Merck Index, the Merck manual, the MSD manual, or the PDR).

In one embodiment, "reducing" or "lowering" a steroid dose is rendering a previously

refractory daily dose - a therapeutically effective daily dose.

[031] In one embodiment, provided herein a method for reducing the amount of a steroid

in the treatment of a subject afflicted with an autoimmune disease or an inflammation,

comprising administering to the subject a therapeutically effective amount of a

composition comprising a cannabidiol (CBD) or a functional derivative thereof and a

therapeutically effective amount of a composition comprising a steroid.

[032] In one embodiment, provided herein a method for reducing the amount of a steroid

comprising administering to the subject a therapeutically effective amount of a composition comprising a cannabidiol (CBD) or a functional derivative thereof and a reduced amount of a composition comprising a steroid.

[033] In one embodiment, combination therapy of cannabidiol (CBD) or a functional

derivative thereof with a steroid enables reduction in the therapeutic effective amount or

dose of the steroid. In one embodiment, combining CBD or a functional derivative thereof

with a steroid enables reduction in the necessary amount of the steroid to be administered.

In one embodiment, combining CBD or a functional derivative thereof with a steroid

enables reduction in the dose of a steroid (referring to the dose of a monotherapy) while

maintaining or increasing the therapeutic effect. In one embodiment, combining CBD or a

functional derivative thereof with a steroid enables reduction in the dose of a steroid

(referring to the dose of a monotherapy) while decreasing steroid side effects. In one

embodiment, combining CBD or a functional derivative thereof with a steroid enables

reduction in the dose of a steroid (referring to the dose of a monotherapy) while

maintaining or increasing the therapeutic effect and decreasing steroid side effects.

[034] In one embodiment, combining CBD or a functional derivative thereof with a

steroid is administering each of CBD or a functional derivative thereof and the steroid,

separately and/or in separate compositions. In one embodiment, combining CBD or a

functional derivative thereof with a steroid is daily administering each of CBD or a

functional derivative thereof and the steroid, separately or together. In one embodiment,

separately is in two distinct compositions. In one embodiment, separately is in distinct time

points during the day. In one embodiment, together is within a single composition. In one

embodiment, together is at the same time.

[035] In one embodiment, "reduction" refers to reducing the steroid monotherapy dose.

In one embodiment, "reduction" refers to reducing a steroid side effect. In one

embodiment, reduction is at least 10% reduction in the daily or weekly steroid dose. In one embodiment, reduction is at least 20% reduction in the daily or weekly steroid dose. In one embodiment, reduction is at least 30% reduction in the daily or weekly steroid dose. In one embodiment, reduction is at least 40% reduction in the daily or weekly steroid dose. In one embodiment, reduction is at least 50% reduction in the daily or weekly steroid dose. In one embodiment, reduction is at least 60% reduction in the daily or weekly steroid dose. In one embodiment, reduction is at least 70% reduction in the daily or weekly steroid dose.

[036] In one embodiment, provided herein a method for enhancing the therapeutic effect

of a steroid in a subject treated with a steroid, comprising administering to the subject a

steroid and a cannabidiol (CBD) or a functional derivative thereof, thereby enhancing the

therapeutic effect of a steroid in a subject treated with a steroid. In one embodiment, a

method for enhancing the therapeutic effect of a steroid in a subject treated with a steroid,

further comprises evaluation of the steroid's side-effect and/or steroid treatment efficacy

within the subject. In one embodiment, a subject as described herein is first evaluated as a

subject at risk of a given steroid dose (side effects etc.). In one embodiment, a subject as

described herein is suffering from a steroid side effect. In one embodiment, a subject as

described herein is treated with a steroid in an amount within the upper 10%, 20%, 30%,

40%, or 50% of the daily recommended dose range of a steroid. In one embodiment, a

subject as described herein is in need of a chronic steroid treatment.

[037] In one embodiment, provided herein a method for reducing the weekly or daily

dose of a steroid in a subject treated with a steroid, comprising administering to the subject

a steroid and a cannabidiol (CBD) or a functional derivative thereof, thereby reducing the

weekly or daily dose of a steroid in a subject treated with a steroid.

[038] In one embodiment, provided herein a method for enhancing the therapeutic effect

of a steroid in a subject afflicted with an autoimmune disease or liver inflammation,

comprising administering to the subject a steroid and a cannabidiol (CBD) or a functional derivative thereof, thereby enhancing the therapeutic effect of a steroid in a subject afflicted with an autoimmune disease or liver inflammation.

[039] In one embodiment, provided herein a "chronic treatment" to a chronic

inflammatory disease and/or a chronic immune disease as described herein. In one

embodiment, "chronic treatment" is a medical treatment that continuously lasts for more

than 2, 4, 6, 10, 12, 15, 18, or 24 months. In one embodiment, "chronic treatment" is a

medicinal daily treatment that continuously lasts for more than 6 months. In one

embodiment, "chronic treatment" is a medicinal daily treatment that continuously lasts for

more than 12 months. In one embodiment, "chronic treatment" is a medicinal daily

treatment that continuously lasts for more than 18 months. In one embodiment, "chronic

treatment" is a medicinal daily treatment that continuously lasts for more than 24 months.

[040] In one embodiment, inflammation or an inflammatory disease treatable by the

methods and composition as described herein is a chronic inflammation. In one

embodiment, inflammation or an inflammatory disease treatable by the methods and

composition as described herein is: rheumatoid arthritis, atherosclerosis, heart disease,

Alzheimer, asthma, acquired immunodeficiency disorder(AIDS), cancer, congestive heart

failure (CHF), multiple sclerosis (MS), diabetes, infections (bacteria, fungi, parasites),

gout, IBD-inflammatory bowel disease, aging and any other neurodegenerative CNS

disease.

[041] In one embodiment, provided herein a method for using a steroid in a "chronic

treatment" or chronically administering a steroid. In one embodiment, provided herein a

method for chronically administering a steroid to a subject in need thereof, comprising

administering to the subject a cannabidiol (CBD) or a functional derivative thereof, daily,

for at least 2, 3, 6, 10, 12, 18, 24, or 30 months, thereby chronically administering a steroid

to a subject in need thereof. In one embodiment, provided herein a method for chronically administering a steroid to a subject in need thereof, comprising administering to the subject a steroid and a cannabidiol (CBD) or a functional derivative thereof, daily, for at least 2,

3, 6, 10, 12, 18, 24, or 30 months, thereby chronically administering a steroid to a subject

in need thereof.

[042] In one embodiment, chronically administering or chronical administration is a

daily administration for a period of at least 2, 3, 6, 10, 12, 18, 24, or 30 months. In one

embodiment, chronically administering or chronical administration is weekly

administration for a period of at least 2, 3, 6, 10, 12, 18, 24, or 30 months. In one

embodiment, chronically administering or chronical administration is bi-weekly

administration for a period of at least 2, 3, 6, 10, 12, 18, 24, or 30 months.

[043] In one embodiment, provided herein a method that substantially reduces risks and

side effect associated with using steroids chronically and daily (for a period of more than

6 months, 12 months, 18 months, 24 months, or 30 months). In one embodiment, provided

herein a method for reducing the therapeutic effective amount of a steroid in a chronic

steroid treatment. In one embodiment, provided herein a method for reducing the dose and

the therapeutic effective daily amount of a steroid in a subject consuming a steroid in an

amount within the upper 30% of the daily recommended dose range of a steroid. In one

embodiment, provided herein a method for reducing the dose and the therapeutic effective

daily amount of a steroid in a subject consuming a steroid in an amount beyond the daily

recommended dose range of a steroid.

[044] In one embodiment, a steroid side effect comprises: indigestion or heartburn,

increased appetite, sleeping difficulties, changes in mood and behavior, increased risk of

infections, pain, high blood sugar or diabetes, Cushing's syndrome, thin skin, glaucoma or

cataract, a sore mouth or throat, a cough, oral thrush, nosebleeds, folliculitis, contact dermatitis, acne, changes in skin colour, excessive hair growth, depression, or any combination thereof.

[045] In one embodiment, provided herein a method for treating a disease such as an

inflammatory disease or an immune disease by administering to a patient a reduced

therapeutic effective amount of a steroid and 50 to 500 mg of CBD. In one embodiment,

the combination or dual therapy as described herein permits daily, prolonged and effective

utilization of a steroid while minimizing the harmful side-effects associated with a steroid.

[046] In one embodiment, a steroid or corticosteroid side effect that is reduced or

inhibited by the current methods is a: cosmetic change, facial rounding, dorsal hump

formation, striae, weight gain, acne, alopecia, facial hirsutism, osteopenia with vertebral

compression, brittle diabetes, psychosis, pancreatitis, opportunistic infection, labile,

hypertension, infection, heart-rate disturbances, and malignancy. In one embodiment,

CBD provides means for substantially reducing an initial high dose of steroid. In one

embodiment, CBD provides means for masking the adverse effect of a given dose of a

steroid.

[047] In one embodiment, a composition as described herein comprises at least 50% v/v

and/or w/w CBD. In one embodiment, a composition as described herein comprises at least

60% v/v and/or w/w CBD. In one embodiment, a composition as described herein

comprises at least 70% v/v and/or w/w CBD. In one embodiment, a composition as

described herein comprises at least 80% v/v and/or w/w CBD. In one embodiment, a

composition as described herein comprises at least 90% v/v and/or w/w CBD.

[048] In one embodiment, a composition as described herein is devoid of THC. In one

embodiment, a composition as described herein is substantially devoid of THC. In one

embodiment, a composition as described herein comprises less than 20% v/v and/or w/w

THC. In one embodiment, a composition as described herein comprises less than 15% v/v and/or w/w THC. In one embodiment, a composition as described herein comprises less than 10% v/v and/or w/w THC. In one embodiment, a composition as described herein comprises less than 7.5% v/v and/or w/w THC. In one embodiment, a composition as described herein comprises less than 5% v/v and/or w/w THC. In one embodiment, a composition as described herein comprises less than 2% v/v and/or w/w THC. In one embodiment, a composition as described herein comprises less than 1% v/v and/or w/w

THC. In one embodiment, a composition as described herein comprises less than 0.5% v/v

and/or w/w THC. In one embodiment, a composition as described herein comprises less

than 0.1% v/v and/or w/w THC.

[049] In another embodiment, a CBD derivative is a synthetic isomer of CBD. In another

embodiment a CBD derivative is (+)CBD. In another embodiment, a CBD derivative is (

) and/or (+) CBD-DMH. In another embodiment, a CBD derivative is (+) 70H-CBD. In

another embodiment, a CBD derivative is (-)and/or (+) 70H-CBD-DMH. In another

embodiment, a CBD derivative is (-) and/or (+)COOH-CBD. In another embodiment, a

CBD derivative is and (-) and/or (+) COOH-CBD-DMH. In another embodiment, a CBD

derivative is a (+) and/or a (-)CBD analogue such as disclosed in Bisogno et al., Br. J.

Pharm. 2001;134:845-852 which is hereby incorporated by reference in its entirety. In

another embodiment, a derivative is a functional derivative.

[050] In one embodiment, the autoimmune disease is: Addison's disease,

Agammaglobulinemia, Alopecia areata, Amyloidosis, Ankylosing spondylitis, Anti

GBM/Anti-TBM nephritis, Antiphospholipid syndrome, Autoimmune hepatitis,

Autoimmune inner ear disease, Axonal & neuronal neuropathy, Behcet's disease, Bullous

pemphigoid, Castleman disease, Celiac disease, Chagas disease, Chronic inflammatory

demyelinating polyneuropathy, Chronic recurrent multifocal osteomyelitis, Cicatricial

pemphigoid/benign mucosal pemphigoid, Churg-Strauss, Cogan's syndrome, Cold agglutinin disease, Congenital heart block, Coxsackie myocarditis, CREST syndrome,

Crohn's disease, Dermatitis herpetiformis, Dermatomyositis, Devic's disease, Discoid

lupus, Dressler's syndrome, Endometriosis, Eosinophilic esophagitis, Eosinophilic

fasciitis, Erythema nodosum, Essential mixed cryoglobulinemia, Evans syndrome,

Fibromyalgia, Fibrosing alveolitis, Giant cell arteritis, Giant cell myocarditis,

Glomerulonephritis, Goodpasture's syndrome, Granulomatosis with Polyangiitis, Graves'

disease, Guillain-Barre syndrome, Hashimoto's thyroiditis, Hemolytic anemia, Henoch

Schonlein purpura, Herpes gestationis or pemphigoid gestationis,

Hypogammalglobulinemia, IgA Nephropathy, IgG4-related sclerosing disease, Inclusion

body myositis, Interstitial cystitis, Juvenile arthritis, Juvenile diabetes, Juvenile myositis,

Kawasaki disease, Lambert-Eaton syndrome, Leukocytoclastic vasculitis, Lichen planus,

Lichen sclerosus, Ligneous conjunctivitis, Linear IgA disease, Lupus, chronic Lyme

disease, Meniere's disease, Microscopic polyangiitis, Mixed connective tissue disease,

Mooren's ulcer, Mucha-Habermann disease, Multiple sclerosis, Myasthenia gravis,

Myositis, Narcolepsy, Neuromyelitis optica, Neutropenia, Ocular cicatricial pemphigoid,

Optic neuritis, Palindromic rheumatism, PANDAS, Paraneoplastic cerebellar

degeneration, Paroxysmal nocturnal hemoglobinuria, Parry Romberg syndrome, Pars

planitis, Parsonnage-Turner syndrome, Pemphigus, Peripheral neuropathy, Perivenous

encephalomyelitis, Pernicious anemia, POEMS syndrome, Polyarteritis nodosa,

Polymyalgia rheumatic, Postmyocardial infarction syndrome, Postpericardiotomy

syndrome, Polymyositis, Primary biliary cirrhosis, Primary sclerosing cholangitis,

Progesterone dermatitis, Psoriasis, Psoriatic arthritis, Pure red cell aplasia, Pyoderma

gangrenosum, Raynaud's phenomenon, Reactive Arthritis, Reflex sympathetic dystrophy,

Reiter's syndrome, Relapsing polychondritis, Restless legs syndrome, Retroperitoneal

fibrosis, Rheumatic fever, Rheumatoid arthritis, Sarcoidosis, Schmidt syndrome, Scleritis,

Scleroderma, Sjogren's syndrome, Sperm & testicular autoimmunity, Stiff person syndrome, Subacute bacterial endocarditis, Susac's syndrome, Sympathetic ophthalmia,

Takayasu's arteritis, Temporal arteritis/Giant cell arteritis, Thrombocytopenic purpura,

Tolosa-Hunt syndrome, Transverse myelitis, Type 1 diabetes, Ulcerative colitis,

Undifferentiated connective tissue disease, Uveitis, Vasculitis, Vitiligo, and/or Wegener's

granulomatosis. In one embodiment, the autoimmune disease is autoimmune hepatitis.

[051] In one embodiment, liver inflammation is Cirrhosis. In one embodiment, liver

inflammation is hepatitis. In one embodiment, liver inflammation is hepatitis resulting

from a viral infection. In one embodiment, a method as described herein provides treating

a subject in need of a steroid or a corticosteroid treatment with: (a) steroid or a

corticosteroid; and (b) CBD or a derivative thereof. In one embodiment, the steroid is

methylprednisolone (MP). In one embodiment, treating a subject in need of a steroid or a

corticosteroid treatment is treating a subject in need of a daily steroid or a corticosteroid

treatment. In one embodiment, the steroid is any corticosteroid such as but not limited to:

Betamethasone, Budesonide, Cortisone Dexamethasone, Hydrocortisone,

Methylprednisolone, Prednisolone, and/or Prednisone.

[052] In one embodiment, the steroid is administered at steroid doses of 0.2 to 10 mg/kg

body weight of the subject. In one embodiment, the steroid is administered at steroid doses

of 0.5 to 10 mg/kg body weight of the subject. In one embodiment, the steroid is

administered at steroid doses of 0.5 to 8 mg/kg body weight of the subject. In one

embodiment, the steroid is administered at steroid doses of 0.5 to 5 mg/kg body weight of

the subject. In one embodiment, the steroid is administered at steroid doses of 1 to 8 mg/kg

of 1 to 5 mg/kg body weight of the subject. In one embodiment, the steroid is administered

at steroid doses of 2 to 6 mg/kg body weight of the subject. In one embodiment, the steroid

is administered at steroid doses of 1 to 2 mg/kg body weight of the subject.

[053] In one embodiment, a subject as described herein does not respond to a steroid or

a corticosteroid treatment. In one embodiment, steroid or corticosteroid treatment is

ineffective and/or required in high dose in a subject as described herein. In one

embodiment, steroid or corticosteroid treatment causes undesired side effects in a subject

as described herein. In one embodiment, a subject as described herein requires a steroid

or a corticosteroid treatment for at least a month. In one embodiment, a subject as

described herein needs a steroid or corticosteroid treatment for at least two months. In one

embodiment, a subject as described herein needs a steroid or corticosteroid treatment for

at least three months. In one embodiment, a subject as described herein needs a steroid or

corticosteroid treatment for at least six months. In one embodiment, a subject as described

herein is afflicted with a chronic disease or condition which requires a steroid or a

corticosteroid treatment of at least a month. In one embodiment, a subject as described

corticosteroid treatment of at least two months. In one embodiment, a subject as described

corticosteroid treatment of at least three months. In one embodiment, a subject as described

corticosteroid treatment of at least a month every year, for at least 3 years. In one

embodiment, a subject as described herein is afflicted with a chronic disease or condition

which requires a steroid or a corticosteroid treatment of at least two months every year, for

at least 3 years.

[054] In one embodiment, a subject suffering a disease such as described herein is a

subject requiring a steroid or a corticosteroid therapy. In one embodiment, a subject

suffering a disease such as described herein will not respond to a steroid treatment of 0.5

to 25 mg/kg per day for at least 2 to 30 days. In one embodiment, steroid therapy in a subject suffering a disease such as described herein results in unwanted steroidal side effects. In one embodiment, steroid therapy in a subject suffering a disease such as described herein does not inhibit at least on side effect associated with the disease. In one embodiment, steroid therapy is 0.2 to 80 mg/kg steroid per day for at least 2 to 30 days. In one embodiment, steroid therapy is 0.2 to 50 mg/kg steroid per day for at least 2 to 50 days.

In one embodiment, steroid therapy is 0.2 to 30 mg/kg steroid per day for at least 2 to 50

days. In one embodiment, steroid therapy is 0.2 to 30 mg/kg steroid per day for at least 2

to 50 days. In one embodiment, steroid therapy is 0.2 to 20 mg/kg steroid per day for at

least 2 to 50 days. In one embodiment, steroid therapy is 0.2 to 15 mg/kg steroid per day

for at least 2 to 50 days.

[055] In one embodiment, a subject nonresponsive (or refractoriness) to a steroid or a

corticosteroid treatment, to be treated per the methods as described herein, does not exhibit

clinical progression after 3 days of steroid treatment. In one embodiment, a subject

nonresponsive (or refractoriness) to a steroid or a corticosteroid treatment, to be treated per

the methods as described herein, does not exhibit clinical progression after 5 days of steroid

treatment. In one embodiment, a subject nonresponsive (or refractoriness) to a steroid or a

clinical progression after 7 days of steroid treatment. In one embodiment, a subject

nonresponsive (or refractoriness) to a steroid or a corticosteroid treatment, to be treated

according to the methods as described herein, does not exhibit clinical progression after 10

days of steroid treatment.

[056] In one embodiment, a subject to be treated according to the methods as described

herein does not show any clinical improvement after 2 days of a steroid or a corticosteroid

treatment. In one embodiment, a subject to be treated according to the methods as described

herein does not show any clinical improvement after 5 days of a steroid or a corticosteroid treatment. In one embodiment, a subject to be treated according to the methods as described herein does not show any clinical improvement after 3 days of a steroid or a corticosteroid treatment. In one embodiment, a subject to be treated according to the methods as described herein does not show any clinical improvement after 7 days of a steroid or a corticosteroid treatment. In one embodiment, a subject to be treated according to the methods as described herein does not show any clinical improvement after 9 days of a steroid or a corticosteroid treatment.

[057] In one embodiment, "clinical improvement" comprises incomplete response to a

steroid or a corticosteroid treatment as defined in acceptable medical literature. In one

embodiment, "clinical improvement" comprises incomplete response to a steroid or a

corticosteroid treatment as defined by one of skill in the art. In one embodiment, a subject

per the invention is a subject in need of a steroid or a corticosteroid treatment. In one

embodiment, a subject per the invention is a subject treated with a steroid or a

corticosteroid.

[058] In one embodiment, a subject per the invention is a subject treated with a steroid

or a corticosteroid for at least a week. In one embodiment, a subject per the invention is a

subject treated with a steroid or a corticosteroid for at least two weeks. In one embodiment,

a subject per the invention is a subject treated with a steroid or a corticosteroid for at least

a month. In one embodiment, a subject per the invention is a subject treated with a steroid

or a corticosteroid for at least 3 months. In one embodiment, a subject per the invention is

a subject treated with a steroid or a corticosteroid for at least 6 months.

[059] In one embodiment, a subject per the invention is a subject treated with a steroid

or a corticosteroid showing a deterioration in at least one symptom or a condition

associated with an autoimmune disease/autoimmune hepatitis/liver inflammation, after 3

days of a steroid treatment. In one embodiment, a subject per the invention is a subject treated with a steroid or a corticosteroid showing a deterioration in at least one symptom or a condition associated with an autoimmune disease/autoimmune hepatitis/liver inflammation, after 5 days of a steroid treatment. In one embodiment, a subject per the invention is a subject treated with a steroid or a corticosteroid showing a deterioration in at least one symptom or a condition associated with an autoimmune disease/autoimmune hepatitis/liver inflammation, after 7 days of a steroid treatment. In one embodiment, a subject per the invention is a subject treated with a steroid or a corticosteroid showing a deterioration in at least one symptom or a condition associated with an autoimmune disease/autoimmune hepatitis/liver inflammation, after 14 days of a steroid treatment. In one embodiment, a subject per the invention is a subject treated with a steroid or a corticosteroid showing a deterioration in at least one symptom or a condition associated with an autoimmune disease/autoimmune hepatitis/liver inflammation, after 30 days of a steroid treatment.

[060] The compositions described herein, comprise Cannabidiol (CBD), or any

functional derivative thereof (i.e. a CBD derivative possessing similar, equivalent, or

increased efficacy). In some embodiments, the described compositions optionally further

comprise at least one pharmaceutically acceptable carrier, diluent, excipient and/or

additive.

[061] The phrase "CBD or any functional derivative thereof", according to some

embodiments, refers to compounds and/or compositions that are substantially and/or

essentially devoid of THC. In one embodiment, a composition comprising CBD or any

functional derivative thereof, as described herein is substantially and/or essentially devoid

of THC.

[062] The phrase "CBD or any functional derivative thereof", according to some

embodiments, refers to compounds and/or compositions that comprise at least 80% CBD or any functional derivative thereof. The phrase "CBD or any functional derivative thereof", according to some embodiments, refers to compounds and/or compositions that comprise at least 90% CBD or any functional derivative thereof. The phrase "CBD or any functional derivative thereof", according to some embodiments, refers to compounds and/or compositions that comprise at least 92% CBD or any functional derivative thereof.

The phrase "CBD or any functional derivative thereof", according to some embodiments,

refers to compounds and/or compositions that comprise at least 95% CBD or any

functional derivative thereof. The phrase "CBD or any functional derivative thereof",

according to some embodiments, refers to compounds and/or compositions that comprise

at least 97% CBD or any functional derivative thereof. The phrase "CBD or any functional

derivative thereof", according to some embodiments, refers to compounds and/or

compositions that comprise at least 99% CBD or any functional derivative thereof.

[063] Cannabidiol is insoluble in water but soluble in organic solvents, such as oil. In

one embodiment, a composition of the invention comprises a vehicle such as an organic

solvent or oil. Accordingly, CBD can be formulated for use in the described methods

through use of any organic solvent known to the pharmaceutical arts, including, but not

limited to edible oils. When formulated for oral administration, any edible oil can be used

in the CBD formulation, including olive oil.

[064] In one embodiment, substantially and/or essentially devoid of THC is less than

15% by weight or weight/weight THC. In one embodiment, substantially and/or essentially

devoid of THC is less than 10% by weight or weight/weight THC. In one embodiment,

substantially and/or essentially devoid of THC is less than 7% by weight or weight/weight

THC. In one embodiment, substantially and/or essentially devoid of THC is less than 5%

by weight or weight/weight THC. In one embodiment, substantially and/or essentially

devoid of THC is less than 3% by weight or weight/weight THC. In one embodiment, substantially and/or essentially devoid of THC is less than 1% by weight or weight/weight

THC. In one embodiment, substantially and/or essentially devoid of THC is less than 0.5%

devoid of THC is less than 0.3% by weight or weight/weight THC. In one embodiment,

substantially and/or essentially devoid of THC is less than 0.1% by weight or

weight/weight THC. In one embodiment, substantially and/or essentially devoid of THC

is less than 0.05% by weight or weight/weight THC. In one embodiment, substantially

and/or essentially devoid of THC is less than 0.01% by weight or weight/weight THC.

[065] In one embodiment, a composition comprising CBD is a composition essentially

devoid of THC and consisting: (1) CBD or any functional derivative thereof; and (2) a

pharmaceutically acceptable excipient such as but not limited to: a CBD carrier, an

emulsifier, a preservative, a buffer or any combination thereof. In one embodiment, a

composition comprising CBD is a composition essentially devoid of THC and consisting:

(1) CBD or any functional derivative thereof; (2) a pharmaceutically acceptable excipient

such as but not limited to: a CBD carrier, an emulsifier, a preservative, a buffer or any

combination thereof; and (3) less than 1% by weight or weight/weight THC. In one

embodiment, a composition comprising CBD is a composition essentially devoid of THC

and consisting: (1) CBD or any functional derivative thereof; (2) a pharmaceutically

acceptable excipient such as but not limited to: a CBD carrier, an emulsifier, a preservative,

a buffer or any combination thereof; and (3) less than 0.5% by weight or weight/weight

THC. In one embodiment, a composition comprising CBD is a composition essentially

devoid of THC and consisting: (1) CBD or any functional derivative thereof; (2) a

emulsifier, a preservative, a buffer or any combination thereof; and (3) less than 0.1% by

weight or weight/weight THC. In one embodiment, a composition comprising CBD is a composition essentially devoid of THC and consisting: (1) CBD or any functional derivative thereof; (2) a pharmaceutically acceptable excipient such as but not limited to: a CBD carrier, an emulsifier, a preservative, a buffer or any combination thereof; and (3) less than 0.05% by weight or weight/weight THC. In one embodiment, a composition comprising CBD is a composition essentially devoid of THC and consisting: (1) CBD or any functional derivative thereof; (2) a pharmaceutically acceptable excipient such as but not limited to: a CBD carrier, an emulsifier, a preservative, a buffer or any combination thereof; and (3) less than 0.01% by weight or weight/weight THC.

[066] In one embodiment, "% by weight or weight/weight" is from the entire weight of

the composition. In one embodiment, "% by weight or weight/weight" is from the weight

of CBD or any functional derivative thereof within the composition. In one embodiment,

"% by weight or weight/weight" is from the weight of THC and CBD or any functional

derivative thereof within the composition.

[067] In the methods described herein, cannabidiol, or a functional variant thereof, free

or substantially free of THC, is administered to a subject treated with a steroid or a

corticosteroid. In the methods described herein, purified or substantially purified (greater

than 80% w/w, 85% w/w, 90%, w/w 95% w/w or 97% w/w) cannabidiol, or a functional

variant thereof, is administered to a subject suffering from a disease such as described

herein. Cannabidiol constitutes up to 40% of Cannabis sativa extracts, and is recognized

as a major non-psychoactive cannabinoid, with a remarkable lack of any cognitive and

psychoactive actions. CBD, also termed 2-[(6R)-3-Methyl-6-prop-1-en-2-yl-1cyclohex-2

envyl]-5pentylbenzene-1,3-diol, has the molecular formula of C 2 1H 30 0 2 . The chemical

structure of CBD is shown in Formula I:

.1H OH

H HO

[068] A CBD derivative, is in some embodiments, a metabolite of CBD such as but not

limited to: (-)-7-hydroxy-CBD and (-)-CBD-7-oic acid and their dimethylheptyl (DMH)

homologs, as well as of the corresponding compounds in the enantiomeric (+)-CBD series.

A CBD derivative is characterized, in some embodiments, by a structure wherein at least

one of the hydroxyl substituent groups is converted to a stable form thereof. In one

embodiment, a CBD derivative is cannabinol comprising a quinone ring. In one

embodiment, a CBD derivative is an endocannabinoid derivative. In some embodiments,

a CBD derivative is described in Frank D King; G Lawton; A W Oxford Progress in

medicinal chemistry. Vol. 44. Pages 207-331, Elsevier Science, 2006 ISBN: 0080462103

9780080462103 which is hereby incorporated by reference in its entirety.

[069] In some embodiment, the dose, dosage, or daily dose or daily dosage of

Cannbidiol or a functional derivative thereof is 50 to 2500 mg. In some embodiment, the

dose, dosage, or daily dose or daily dosage of Cannbidiol or a functional derivative thereof

is 150 to 1500 mg. In some embodiment, the dose, dosage, or daily dose or daily dosage

of Cannbidiol or a functional derivative thereof is 100 to 1000 mg. In some embodiment,

the dose, dosage, or daily dose or dosage of Cannbidiol or a functional derivative thereof

is 200 to 1000 mg. In some embodiment, the dose, dosage, or daily dose or daily dosage

of Cannbidiol or a functional derivative thereof is the therapeutically effective dose.

[070] The methods of the present invention provide long desired therapy for

autoimmune disease/autoimmune hepatitis/liver inflammation by inhibiting the destructive

inflammatory/immunologic process, alleviate symptoms associated with autoimmune

disease/autoimmune hepatitis/liver inflammation and/or steroidal therapy, and prevent

disease progression. The methods for treating autoimmune disease/autoimmune

hepatitis/liver inflammation of the present invention provide, in some embodiments,

treatment with Cannbidiol or a functional derivative thereof combined with systemic

treatment of a steroid or a corticosteroid, optionally combined with additional medications.

In some embodiments, Cannbidiol or a functional derivative thereof inhibit and/or decrease

side-effects of a steroid. In some embodiments, CBD as described herein alleviates

symptoms associated with autoimmune disease/autoimmune hepatitis/liver inflammation.

[071] The present invention now demonstrates the beneficial effects of treatment with

Cannbidiol or a functional derivative thereof for the treatment of autoimmune

disease/autoimmune hepatitis/liver inflammation. More specifically, the present invention

demonstrates that treatment with the Cannabidiol or a functional derivative thereof

compositions of the invention significantly reduces the severity, as well as other

complications associated with autoimmune disease/autoimmune hepatitis/liver

inflammation.

In some embodiments, CBD enhances the therapeutic effect of a steroid or a corticosteroid.

In some embodiments, CBD reduces a side effect associated with the steroid or the

corticosteroid. In some embodiments, CBD combined with a steroid or a corticosteroid

provides a synergistic steroidal treatment. In some embodiments, CBD combined with a

steroid or a corticosteroid provides a synergistic anti-inflammatory treatment to a subject

as described herein. In some embodiments, CBD combined with a steroid or a

corticosteroid provides a synergistic immune-modulating treatment to a subject as described herein. In some embodiments, CBD renders a refractory steroid dose an effective therapeutic dose. In some embodiments, CBD enables the reduction of a steroid or a corticosteroid dose without compromising its therapeutic benefit, thereby reducing undesired side effects associated with a steroid or a corticosteroid. In one embodiment, autoimmune disease/autoimmune hepatitis/liver inflammation is steroid-refractory autoimmune disease/autoimmune hepatitis/liver inflammation.

In one embodiment, a steroid is a corticosteroid and/or glucocorticoid or a combination of

glucocorticoids and/or corticosteroids. In one embodiment, a steroid is a synthetic steroid.

In one embodiment, a corticosteroid and/or glucocorticoid is a synthetic corticosteroid

and/or synthetic glucocorticoid. In one embodiment, the steroid is methylprednisolone,

prednisolone, Prednisone, hydrocortisone, dexamethasone, beclomethasone, budesonide,

clobetasol, triamcinolone, fluticasone, mometasone, Diflorasone Desoximetasone,

aclometasone, fluocinonide, halobetasol, flurandrenolide, betamethasone, cortisone,

prednisone or any equivalents thereof and/or a combination thereof.

[072] In one embodiment, steroid daily dose is a single dose per day. In one

embodiment, steroid daily dose is divided to 2 to 8 portions/doses per day. In one

embodiment, steroid treatment includes 0.2 to 25 mg/kg (body weight) per day steroid, for

2 to 30 days. In one embodiment, administering to the subject a therapeutically effective

amount of a composition comprising the CBD or a functional derivative thereof is daily

administering 5 to 1000 mg CBD. In one embodiment, administering to the subject a

therapeutically effective amount of a composition comprising said CBD or a functional

derivative thereof is daily administering 20 to 500 mg CBD. In one embodiment, mg/kg is

mg per body weight in kg. In one embodiment, administering CBD or a functional

derivative thereof is administering a composition comprising a therapeutically effective

amount of CBD or a functional derivative thereof.

[073] In one embodiment, a therapeutically effective amount of CBD or a functional

derivative thereof according to the invention is capable of reducing the daily therapeutic

effective dose of a steroid by at least 20%. In one embodiment, a therapeutically effective

amount of CBD or a functional derivative thereof according to the invention is capable of

reducing the daily therapeutic effective dose of a steroid by at least 30%. In one

embodiment, a therapeutically effective amount of CBD or a functional derivative thereof

according to the invention is capable of reducing the daily therapeutic effective dose of a

steroid by at least 40%. In one embodiment, a therapeutically effective amount of CBD or

a functional derivative thereof according to the invention is capable of reducing the daily

therapeutic effective dose of a steroid by at least 50%. In one embodiment, a

therapeutically effective amount of CBD or a functional derivative thereof according to

the invention is capable of reducing and/or eliminating a steroid side effect.

[074] In one embodiment, a method as described herein requires a step of determining

that the given steroid dose is refractory. In one embodiment, a method as described herein

further requires a step of gradually reducing the daily/weekly dose of a steroid by at least

10% per week up to 40% total dose reduction (the reduction in the weekly/daily dose is

calculated from the initial steroid monotherapy daily/weekly dose). In one embodiment, a

method as described herein further requires a step of gradually reducing the daily/weekly

dose of a steroid by at least 20% per week up to 50% total dose reduction (the reduction in

the weekly/daily dose is calculated from the initial steroid monotherapy daily/weekly

dose). In one embodiment, a method as described herein further requires a step of

gradually reducing the daily/weekly dose of a steroid by 10% to 50% per week up to 80%

total dose reduction (the reduction in the weekly/daily dose is calculated from the initial

steroid monotherapy daily/weekly dose).

[075] In one embodiment, a method as described herein requires a step of evaluating the

required dose of a steroid, wherein a required dose beyond the recommended therapeutic

effective and safe range of a steroid dose requires the dual or combined therapy as

described herein. In one embodiment, a method as described herein requires a step of

evaluating the required dose of a steroid, wherein a required dose of a steroid beyond the

recommended therapeutic effective and safe range of a steroid dose requires obtaining an

equivalent steroid therapeutic effect but with at least 20%, 30%, 40, or 50% lower steroid

dose. In one embodiment, obtaining "an equivalent steroid therapeutic effect" but with a

lower steroid dose as described herein required administering CBD or a derivative thereof

together with the steroid therapy.

[076] In one embodiment, the combined or dual therapy includes a single composition

comprising a steroid and CBD or a derivative thereof. In one embodiment, the combined

or dual therapy includes a single composition comprising CBD or a functional derivative

thereof. In one embodiment, the combined or dual therapy includes two separate

compositions: the first composition comprising CBD or a functional derivative thereof and

the second composition comprising a steroid. In one embodiment, provided herein is a kit

comprising two separate compositions: the first composition comprising CBD or a

functional derivative thereof and the second composition comprising a steroid. In one

embodiment, provided herein is a kit comprising two separate compositions: the first

composition comprising 50 to 500 mg CBD or a functional derivative thereof and the

second composition comprising a steroid in a dose or an amount equal to or less than the

required steroid dose/amount without treatment with CBD or a functional derivative

thereof.

[077] In one embodiment, a functional derivative of CBD is a compound disclosed in

Mechoulam R. and Lumi'r H. Cannabidiol: an overview of some chemical and pharmacological aspects. Part I: chemical aspects. Chemistry and Physics of Lipids 121

(2002) 35/43 which is hereby incorporated by reference in its entirety. In one embodiment,

a functional derivative of CBD is a compound disclosed in Handbook of Cannabis and

Related Pathologies 1st Edition. Biology, Pharmacology, Diagnosis, and Treatment.

Editors: Victor Preedy. eBook ISBN: 9780128008270. Hardcover ISBN: 9780128007563.

Academic Press.

[078] In one embodiment, a functional derivative of CBD is a compound which reduces

psychotic symptoms. In one embodiment, a functional derivative of CBD is a compound

which relieves convulsions and/or nausea. In one embodiment, a functional derivative of

CBD is a compound which decreases anxiety. In one embodiment, a functional derivative

of CBD is a compound which decreases inflammation. In one embodiment, a functional

derivative of CBD is a compound which reduces depressive symptoms.

[079] In one embodiment, reducing a steroid effective dose is reducing a steroid

monotherapy effective dose. In one embodiment, rendering an ineffective or refractory

dose of a steroid - an effective dose, is providing a CBD-steroid combined therapy. In one

embodiment, the ineffective or refractory dose of a steroid is a steroid dose provided in a

monotherapy. In one embodiment, lowering a steroid dose is lowering the required steroid

monotherapy dose.

[080] In one embodiment, the terms "monotherapy" or "single therapy" as used herein

refer to treatment with steroid and without CBD. In one embodiment, the terms

"monotherapy" or "single therapy" as used herein refer to treatment with steroid only. In

one embodiment, the terms "monotherapy" or "single therapy" as used herein refer to

treatment with steroid and any other composition which is devoid of CBD.

[081] In one embodiment, a subject as described herein is a human. In one embodiment,

a subject as described cannot benefit from steroid treatment. In one embodiment, a steroid

treatment is refractory to a subject such as described herein.

[082] Treating, according to some embodiments, includes inhibiting the progression or

deterioration of autoimmune disease/autoimmune hepatitis/liver inflammation.

[083] In one embodiment, a therapeutically effective amount of a composition

comprising a CBD or a functional derivative thereof comprises 0.5 mg to 1 g of a CBD or

a functional derivative thereof. In one embodiment, a therapeutically effective daily dose

of a CBD or a functional derivative thereof comprises 0.5 mg to 1 g of a CBD or a

functional derivative thereof. In one embodiment, a therapeutically effective amount of a

composition comprising a CBD or a functional derivative thereof comprises 5 mg to 750

mg of a CBD or a functional derivative thereof. In one embodiment, a therapeutically

effective daily dose of a CBD or a functional derivative thereof comprises 5 mg to 750 mg

of a CBD or a functional derivative thereof. In one embodiment, a therapeutically effective

amount of a composition comprising a CBD or a functional derivative thereof comprises

5 mg to 600 mg of a CBD or a functional derivative thereof. In one embodiment, a

therapeutically effective daily dose of a CBD or a functional derivative thereof comprises

therapeutically effective amount of a composition comprising a CBD or a functional

derivative thereof comprises 50 mg to 500 mg of a CBD or a functional derivative thereof.

In one embodiment, a therapeutically effective daily dose of a CBD or a functional

In one embodiment, a therapeutically effective amount of a composition comprising a CBD

or a functional derivative thereof comprises 80 mg to 400 mg of a CBD or a functional

derivative thereof. In one embodiment, a therapeutically effective daily dose of a CBD or a functional derivative thereof comprises 80 mg to 400 mg of a CBD or a functional derivative thereof. In one embodiment, a therapeutically effective daily dose of a CBD or a functional derivative thereof comprises 80 mg to 600 mg of a CBD or a functional derivative thereof. In one embodiment, a single therapeutically effective dosage of CBD or a functional derivative thereof comprises 30 mg to 400 mg of a CBD or a functional derivative thereof. In one embodiment, a single therapeutically effective dosage of CBD or a functional derivative thereof comprises 50 mg to 500 mg of a CBD or a functional derivative thereof. In one embodiment, a single therapeutically effective dosage of CBD or a functional derivative thereof comprises 80 mg to 300 mg of a CBD or a functional derivative thereof. In one embodiment, a single therapeutically effective dosage of CBD or a functional derivative thereof comprises 100 mg to 200 mg of a CBD or a functional derivative thereof.

[084] In one embodiment, a composition as described herein is a topical composition.

In one embodiment, a composition as described herein is an oral composition. In one

embodiment, a composition as described herein is a systemic composition. In one

embodiment, a subject as described herein is treated with a combination of steroid

compositions selected from: a topical composition, a systemic composition, and an oral

composition.

[085] In one embodiment, provided a method for enhancing the therapeutic effect of a

steroid in a subject in need of a steroid therapy, comprising administering to the subject

the steroid and a cannabidiol (CBD) or a functional derivative thereof, thereby enhancing

the therapeutic effect of a steroid in a subject in need of a steroid therapy. In one

embodiment, provided a method for enhancing the therapeutic effect of a steroid dose or

dosage in a subject in need of a steroid therapy, comprising administering to the subject

the steroid dose or dosage and a cannabidiol (CBD) or a functional derivative thereof, thereby enhancing the therapeutic effect of a steroid dose or dosage in a subject in need of a steroid therapy. In one embodiment, enhancing the therapeutic effect of a steroid is maintaining a fixed dose and combining it with a cannabidiol (CBD) or a functional derivative thereof. In one embodiment, enhancing the therapeutic effect of a steroid is rendering a refractory steroid dose and/or dosage, therapeutically effective. In one embodiment, enhancing the therapeutic effect of a steroid is rendering a sub-efficient steroid dose and/or dosage, therapeutically effective. In one embodiment, enhancing the therapeutic effect of a steroid is avoiding increase in steroid dose and/or dosage. In one embodiment, enhancing the therapeutic effect of a steroid is avoiding increase in steroid dose and/or dosage due to insufficient and/or poor clinical effect. In one embodiment, enhancing the therapeutic effect of a steroid is decreasing side-effects directly associated with a steroid treatment. In one embodiment, enhancing the therapeutic effect of a steroid is reducing the duration of steroid treatment. In one embodiment, a steroid is glucocorticosteroid, corticosteroid or any steroid known to one of skill in the art or described herein.

[086] In one embodiment, provided a pharmaceutical composition comprising a

cannabidiol (CBD) or a functional derivative thereof for use in enhancing the therapeutic

effect of a steroid. In one embodiment, provided a pharmaceutical composition comprising

a cannabidiol (CBD) or a functional derivative thereof for use in reducing a dose or a

dosage of a steroid. In one embodiment, provided a pharmaceutical composition

comprising a cannabidiol (CBD) or a functional derivative thereof for use in reducing a

dose or a dosage of a steroid while maintaining or enhancing the steroid's therapeutic

effect. In one embodiment, provided a pharmaceutical composition comprising a

cannabidiol (CBD) or a functional derivative thereof for use in maintaining or enhancing

the therapeutic effect of a steroid therapy. In one embodiment, maintaining or enhancing the therapeutic effect of a steroid therapy, according to the methods of the invention, include reducing the dosage or dose of a steroid in a subject treated with a cannabidiol

(CBD) or a functional derivative thereof.

[087] In one embodiment, provided a pharmaceutical composition comprising a

cannabidiol (CBD) or a functional derivative thereof for reducing the effective dose of a

steroid. In one embodiment, provided a pharmaceutical composition comprising a

cannabidiol (CBD) or a functional derivative thereof for reducing a side effect associated

with steroid treatment. In one embodiment, provided a pharmaceutical composition

comprising a cannabidiol (CBD) or a functional derivative thereof for reducing the

effective dose of a steroid and thereby reducing a side effect associated with steroid

treatment.

[088] In one embodiment, provided a pharmaceutical composition comprising a

steroid in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver

inflammation. In one embodiment, provided a pharmaceutical composition comprising a

with steroid treatment in a subject afflicted with autoimmune disease/autoimmune

hepatitis/liver inflammation. In one embodiment, provided a pharmaceutical composition

treatment in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver

inflammation.

[089] In one embodiment, provided a pharmaceutical composition comprising a

steroid in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation. In one embodiment, "effective dose" is the "therapeutically effective dose for a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation.

In one embodiment, a pharmaceutical composition comprising a cannabidiol (CBD) or a

functional derivative thereof reduces the effective dose of steroid by at least 10% and/or

10% w/w. In one embodiment, a pharmaceutical composition comprising a cannabidiol

(CBD) or a functional derivative thereof reduces the effective dose of steroid by at least

20% and/or 20% w/w. In one embodiment, a pharmaceutical composition comprising a

cannabidiol (CBD) or a functional derivative thereof reduces the effective dose of steroid

by at least 30% and/or 30% w/w. In one embodiment, a pharmaceutical composition

comprising a cannabidiol (CBD) or a functional derivative thereof reduces the effective

dose of steroid by at least 50% and/or 50% w/w. In one embodiment, a pharmaceutical

composition comprising a cannabidiol (CBD) or a functional derivative thereof reduces

the effective dose of steroid by at least 75% and/or 75% w/w.

[090] In one embodiment, a pharmaceutical composition comprising a cannabidiol

(CBD) or a functional derivative thereof reduces the effective dose of steroid by 10% to

70% w/w. In one embodiment, a pharmaceutical composition comprising a cannabidiol

30% w/w. In one embodiment, a pharmaceutical composition comprising a cannabidiol

40% w/w. In one embodiment, a pharmaceutical composition comprising a cannabidiol

50% w/w. In one embodiment, a pharmaceutical composition comprising a cannabidiol

60% w/w.

[091] In one embodiment, %w/w reflects the total amount of a steroid in a composition

or a medicament administered to a given subject afflicted with a disease as described

herein.

[092] In one embodiment, provided a method for enhancing the therapeutic effect of a

inflammation, comprising administering to the subject the steroid and a cannabidiol (CBD)

or a functional derivative thereof, thereby enhancing the therapeutic effect of a steroid.

[093] In one embodiment, provided a method for reducing a side effect associated with

a steroid in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver

inflammation and treated with a steroid, comprising administering to the subject the steroid

and a cannabidiol (CBD) or a functional derivative thereof. In one embodiment, provided

a method for reducing a side effect associated with a steroid in a subject afflicted with

autoimmune disease/autoimmune hepatitis/liver inflammation and treated with a steroid,

comprising administering to the subject the steroid and a cannabidiol (CBD) or a functional

derivative thereof. In one embodiment, provided a method for reducing the effective dose

of a steroid in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver

inflammation and treated with a steroid, comprising administering to the subject a reduced

steroid dose and a cannabidiol (CBD) or a functional derivative thereof.

[094] In one embodiment, a steroid is an anabolic steroid. In one embodiment, a steroid

is a corticosteroid. In one embodiment, a subject in need of a steroid therapy is afflicted

with inflammation. In one embodiment, a subject in need of a steroid therapy is in need of

reducing and/or inhibiting an immune response.

[095] In some embodiments, a reduced dose includes at least 15% (by weight) less

steroid. In some embodiments, a reduced dose includes at least 20% (by weight) less

steroid. In some embodiments, a reduced dose includes at least 25% (by weight) less steroid. In some embodiments, a reduced dose includes at least 30% (by weight) less steroid. In some embodiments, a reduced dose includes at least 40% (by weight) less steroid. In some embodiments, a reduced dose includes at least 50% (by weight) less steroid.

[096] In some embodiments, the phrase "effective dose" is the dose effective for treating

or ameliorating autoimmune disease/autoimmune hepatitis/liver inflammation as

described herein. In some embodiments, the phrase "effective dose" is synonymous with

the phrase "daily effective dose" as described herein. In some embodiments, the phrase

"effective dose" is the dose effective for reducing bilirubin level in the blood of a subject

afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation. In some

embodiments, the phrase "effective dose" is the dose effective for reducing and/or

inhibiting a pathology and/or risk associated with autoimmune disease/autoimmune

hepatitis/liver inflammation. In some embodiments, reducing the effective dose of a steroid

results in minimizing or reducing at least one side effect associated with steroid treatment.

[097] In one embodiment, provided a method for enhancing the therapeutic autoimmune

disease/autoimmune hepatitis/liver inflammation effect of a given steroid dose in a subject

afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation and treated

with a steroid, comprising administering to the subject the given steroid dose and a

cannabidiol (CBD) or a functional derivative thereof.

[098] In some embodiments, enhancing the therapeutic effect of a steroid enables the

reduction of the steroid dose administered and/or the reduction of dosing. In some

dose a therapeutic effective dose. In some embodiments, a refractory steroid dose is any

steroid dose found to be refractory in a subject afflicted with autoimmune

disease/autoimmune hepatitis/liver inflammation. In one embodiment, a refractory steroid dose is a daily steroid dose of 0.2 to 20 mg/kg (body weight) per day found to be refractory in terms of therapeutic effect in a subject afflicted with autoimmune disease/autoimmune hepatitis/liver inflammation. In one embodiment, provided a method for treating a subject afflicted with steroid-refractory autoimmune disease/autoimmune hepatitis/liver inflammation, comprising administering to the subject: (a) a steroid; and (b) a cannabidiol

(CBD) or a functional derivative thereof.

[099] In some embodiments, enhancing the therapeutic effect of a steroid is enhancing

the therapeutic effect of a given or a fixed dose of a steroid. In some embodiments,

enhancing the therapeutic effect of a steroid is enhancing steroid therapy which is reducing

or gradually reducing (within a period of 3 days to 6 months) the administered dosage or

dose of a steroid while maintain and/or improving/enhancing/maintaining: (a) the

therapeutic effect of the reduced dose of a steroid; or (b) the efficacy of the steroid therapy.

In some embodiments, enhancing the therapeutic effect of a steroid is rendering a

refractory steroid therapy (treatment with a given steroid dose) - therapeutically effective

and optionally further reducing or gradually reducing (within a period of 3 days to 6

months) the administered dosage or dose of a steroid (the dose or dosage found previously

to be refractory) while continuously maintaining and/or improving/enhancing: (a) the

[0100] In some embodiments, enhancing the therapeutic effect of a given dose of asteroid

or reducing the given dose of a steroid by maintain or improving the steroid's therapeutic

effect can be a process wherein the steroid dose administered with CBD is gradually

decreased over time. In some embodiments, enhancing the therapeutic effect of a given

dose of a steroid or reducing the given dose of a steroid by maintain or improving the

steroid's therapeutic effect can be a process wherein the steroid dose administered with

CBD is gradually decreased over a period of 3 days to 6 months. In some embodiments, enhancing the therapeutic effect of a given dose of a steroid or reducing the given dose of a steroid by maintain or improving the steroid's therapeutic effect can be a process wherein the steroid dose administered with CBD is gradually decreased over a period of 3 weeks to 3 months, over a period of 3 weeks to 2 months.

[0101] In some embodiments, the Cannabidiol or any functional derivative thereof

according to the present invention is a natural product extracted and/or purified from

Cannabis sativa. In other embodiments, the CBD or functional derivative thereof is a

synthetic product. In still further embodiments, the CDB-containing composition is the

Cannabis plant itself. Whenever reference is made herein to "Cannabis sativa" the same

applies also to other Cannabis plants producing Cannabidiol, including Cannabisindica

and Cannabis ruderalis. Cannabis sativa is referred to herein specifically, for the sake of

brevity.

[0102] In some embodiments, the CBD, or a functional derivative thereof, is administered

following onset of symptoms of inflammation, autoimmune disease/autoimmune

hepatitis/liver inflammation as described herein. In other embodiments, the CBD, or a

functional derivative thereof, is administered after a diagnosis is made of the form of

autoimmune disease/autoimmune hepatitis/liver inflammation. In other embodiments, the

CBD, or a functional derivative thereof, is administered with a steroid. In other

embodiments, the CBD or a functional derivative thereof, is administered before and/or

after a steroid. In one embodiment, inflammation is chronic inflammation and/or a chronic

inflammatory disease. In one embodiment, a chronic inflammatory disease according to

the invention, required steroidal treatment for at least a month. In one embodiment, a

chronic inflammatory disease according to the invention, required steroidal treatment for

at least 3 months. In one embodiment, a chronic inflammatory disease according to the

invention, required steroidal treatment for at least 6 months.

[0103] Administration of the Cannabidiol or a functional derivative thereof compositions

to a subject as described herein lasts for at least 20 days. Administration of the Cannabidiol

or a functional derivative thereof compositions to a subject as described herein lasts for at

least 30 days. Administration of the Cannabidiol or a functional derivative thereof

compositions to a subject as described herein lasts for at least 40 days. Administration of

the Cannabidiol or a functional derivative thereof compositions to a subject as described

herein lasts for at least 50 days. Administration of the Cannabidiol or a functional

derivative thereof compositions to a subject as described herein lasts for at least 60 days.

Administration of the Cannabidiol or a functional derivative thereof compositions to a

subject as described herein lasts for at least 70 days. Administration of the Cannabidiol or

a functional derivative thereof compositions to a subject as described herein lasts for at

least 80 days. Administration of the Cannabidiol or a functional derivative thereof

compositions to a subject as described herein lasts for at least 90 days. Administration of

herein lasts for at least 100 days.

[0104] In some embodiments, the method of the invention may optionally further

comprise the step of administering at least one additional therapeutic agent, including

currently used drugs given to autoimmune disease/autoimmune hepatitis/liver

inflammation patients. These additional therapeutic agents, specifically, any

immunomodulatory agent or known medicament, may be either combined with

Cannabidiol or may be administered separately in an additional separate step having an

optional different mode of administration.

[0105] The pharmaceutical compositions containing Cannabidiol according to the present

invention can be administered for prophylactic and/or therapeutic treatments. In

therapeutic application, compositions are administered to a patient already suffering from autoimmune disease/autoimmune hepatitis/liver inflammation in an amount sufficient to cure or at least partially arrest the condition and its complications. An amount adequate to accomplish this is defined as a "therapeutically effective dose." In prophylactic applications, compositions containing Cannabidiol are administered to a patient who is at risk of developing autoimmune disease/autoimmune hepatitis/liver inflammation. Such an amount is defined to be a "prophylactically effective dose". Amounts effective for both prophylactic and therapeutic purposes will depend upon the risk to develop autoimmune disease/autoimmune hepatitis/liver inflammation, the severity of autoimmune disease/autoimmune hepatitis/liver inflammation condition and the general state of the patient, but generally range from about 0.01 to about 10 mg/Kg body weight, specifically, about 0.5 to about 10 mg/Kg of Cannabidiol per day. Single or multiple administrations on a daily schedule can be carried out with dose levels being selected by the treating physician.

It should be noted that doses of Cannabidiol can be elevated every day during the treatment

period according to the clinical response of the patient, provided no significant drug related

side effects present.

[0106] Additionally, the administration of Cannabidiol according to the invention, or

pharmaceutical compositions comprising Cannabidiol, may be periodic, for example, the

periodic administration may be effected twice daily, three times daily, or at least once daily

for 2 days to 180 days, 90 to 180 days and 2 days to 12 months (or longer as needed) for

the treatment of autoimmune disease/autoimmune hepatitis/liver inflammation following

onset of symptoms or diagnosis.

[0107] In some embodiments, CBD is provided to a patient in once, twice, thrice or more

doses per day. Specific embodiments of the invention relate to the use of typically two

doses per day, each containing at least 10 mg Cannabidiol, but usually not more than a daily dose of 600 mg. In one embodiment, a daily dose comprises 150 to 400 mg CBD administered in one or two dosages.

[0108] In some embodiments, the Cannabidiol compositions according to the present

invention can be prepared in any type of oil, such as canola oil, olive oil, sunflower oil,

soybean oil, corn oil, or paraffin oil.

[0109] In some embodiments, the administration of pharmaceutical compositions

comprising Cannabidiol or any derivative thereof according to the invention for the

prevention, treatment, amelioration of autoimmune disease/autoimmune hepatitis/liver

inflammation, may be any one of oral, sublingual, buccal, rectal, vaginal, topical,

parenteral, intravenous, intramuscular, subcutaneous, intra-peritoneal or via oral or nasal

inhalation, such as in the form of purified vapors or by smoking of Cannabis.

[0110] Compositions and formulations for oral administration include powders or

granules, suspensions or solutions in water or non-aqueous media, capsules, sachets,

lozenges (including liquid-filled), chews, multi- and nano-particulates, gels, solid solution,

liposome, films, ovules, sprays or tablets. Thickeners, flavoring agents, diluents,

emulsifiers, dispersing aids or binders may be desirable.

[0111] Pharmaceutical compositions used to treat subjects in need thereof according to

the invention, which may conveniently be presented in unit dosage form, may be prepared

according to conventional techniques well known in the pharmaceutical industry. Such

techniques include the step of bringing into association the active ingredients with the

pharmaceutical carrier(s) or excipient(s). The compositions may be formulated into any of

many possible dosage forms such as, but not limited to, tablets, capsules, liquid syrups,

soft gels, suppositories, and enemas. The compositions of the present invention may also

be formulated as suspensions in aqueous, non-aqueous or mixed media. The suspension may also contain stabilizers. The pharmaceutical compositions of the present invention also include, but are not limited to, emulsions and liposome-containing formulations.

[0112] Addition to the ingredients particularly mentioned above, the formulations may

also include other agents conventional in the art having regard to the type of formulation

in question, for example those suitable for oral administration may include flavoring

agents. Pharmaceutical formulations adapted for rectal administration may be presented as

suppositories or enemas. Pharmaceutical formulations adapted for vaginal administration

may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations.

[0113] According to certain embodiments, pharmaceutical compositions comprising

Cannabidiol, or any derivative thereof according to the present invention are also useful

for parenteral administration, i.e., subcutaneously (s.c.), intramuscularly (i.m.), and

intravenously (i.v.). The compositions for parenteral administration commonly comprise a

solution of Cannabidiol dissolved in an acceptable carrier.

[0114] In one embodiment, the compositions of the invention are suitable for oral

administration. The Cannabidiol compositions can be administered from one or more times

per day to one or more times per week, including once every other day. Dosing is

dependent on the severity of the symptoms and on the responsiveness of the subject to the

treatment. The skilled artisan will appreciate that certain factors may influence the dosage

and timing required to effectively treat a subject, including but not limited to the severity

of the disease, previous treatments, the general health and/or age of the subject, and other

diseases present.

[0115] The present invention relates to the treatment of subjects, or patients, in need

thereof By "patient" or "subject in need" it is meant any mammal for which administration

of the composition of the invention is desired, in order to prevent, overcome or slow down

a medical condition. As described herein, the medical condition for treatment includes autoimmune disease/autoimmune hepatitis/liver inflammation, or any of the conditions described herein that are associated with autoimmune disease/autoimmune hepatitis/liver inflammation.

[0116] The terms "treatment", "prevention" and "prophylaxis" refer to the complete

range of therapeutically positive effects of administrating to a subject including inhibition,

reduction of, alleviation of, and relief from, autoimmune disease/autoimmune

hepatitis/liver inflammation. More specifically, treatment or prevention includes the

prevention or postponement of development of the disease, prevention or postponement of

development of symptoms and/or a reduction in the severity of such symptoms that will or

are expected to develop. These further include ameliorating existing symptoms, preventing

additional symptoms and ameliorating or preventing the underlying causes of symptoms.

[0117] To provide a "preventive treatment" or "prophylactic treatment" is acting in a

protective manner, to defend against or prevent something, especially a condition or

disease.

[0118] As used herein, "disease", "disorder", "condition" and the like, as they relate to a

subject's health, are used interchangeably and have meanings ascribed to each and all of

such terms.

[0119] The term "pharmaceutical composition" refers to an active compound in any form

suitable for effective administration to a subject, e.g., a mixture of the compound and at

least one pharmaceutically acceptable carrier.

[0120] The term "therapeutically effective amount" is intended to mean that amount of a

drug or pharmaceutical agent that will elicit the biological or medical response of a tissue

or human that is being sought by a researcher, medical doctor, or other clinician, or by the

subject himself.

[0121] As used herein, a "pharmaceutically acceptable carrier" means a carrier or diluent

that does not cause significant irritation to a subject and does not abrogate the biological

activity and properties of the administered compound.

[0122] A "pharmaceutically acceptable excipient" means an inert substance added to a

pharmaceutical composition to further facilitate administration of the compound.

Examples, without limitation, of excipients include calcium carbonate, calcium phosphate,

various sugars and types of starch, cellulose derivatives, gelatin, vegetable oils and

polyethylene glycols.

[0123] In one embodiment, a composition as described herein is formulated to a suitable

route of administration, such as: topical, oral, rectal, transmucosal, transnasal, intestinal or

parenteral delivery, including intramuscular, subcutaneous and intramedullary injections

as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or

intraocular injections.

[0124] Oral administration of a composition as described herein, in one embodiment,

comprises a unit dosage form comprising tablets, capsules, lozenges, chewable tablets,

suspensions, emulsions and the like. Such unit dosage forms comprise a safe and effective

amount of the desired compound, or compounds, each of which is in one embodiment,

from about 0.7 mg to about 280 mg/70 kg, or in another embodiment, about 0.5 mg to

about 210 mg/70 kg.

[0125] The pharmaceutically-acceptable carriers suitable for the preparation of unit

dosage forms of a composition as described herein for peroral administration are well

known in the art. In some embodiments, tablets typically comprise conventional

pharmaceutically-compatible adjuvants as inert diluents, such as calcium carbonate,

sodium carbonate, mannitol, lactose and cellulose; binders such as starch, gelatin and

sucrose; disintegrants such as starch, alginic acid and croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. In one embodiment, glidants such as silicon dioxide can be used to improve flow characteristics of the powder-mixture. In one embodiment, coloring agents, such as the FD&C dyes, can be added for appearance.

Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and

fruit flavors, are useful adjuvants for chewable tablets. Capsules typically comprise one or

more solid diluents. In some embodiments, the selection of carrier components depends on

secondary considerations like taste, cost, and shelf stability, which are not critical for the

purposes of this invention, and can be readily made by a person skilled in the art.

[0126] In one embodiment, the oral dosage form comprises predefined release profile. In

one embodiment, the oral or topical dosage form of the present invention comprises a

dosage form (composition) or dosage forms having different release profile for the

compounds described herein.

[0127] Peroral compositions, in some embodiments, comprise liquid solutions,

emulsions, suspensions, and the like. In some embodiments, pharmaceutically-acceptable

carriers suitable for preparation of such compositions are well known in the art. In some

embodiments, liquid oral compositions comprise from about 0.012% to about 0.933% w/w

or w/v of the desired compound or compounds, or in another embodiment, from about

0.033% to about 0.7% w/v or w/w.

[0128] In some embodiments, compositions for use in the methods of this invention

comprise solutions or emulsions, which in some embodiments are aqueous solutions or

emulsions comprising a safe and effective amount of the compounds of the present

invention and optionally, other compounds, intended for topical intranasal administration.

In some embodiments, compositions comprise from about 0.01% to about 10.0% w/v or

w/w of a subject compound. In some embodiments, compositions comprise from about

0.1% to about 2.0 w/w or w/v, which is used for systemic delivery of the compounds by

the intranasal route.

[0129] In another embodiment, the pharmaceutical compositions are administered by

intravenous, intra-arterial, or intramuscular injection of a liquid preparation. In some

embodiments, liquid formulations include solutions, suspensions, dispersions, emulsions,

oils and the like. In one embodiment, the pharmaceutical compositions are administered

intravenously, and are thus formulated in a form suitable for intravenous administration.

In another embodiment, the pharmaceutical compositions are administered intra-arterially,

and are thus formulated in a form suitable for intra-arterial administration. In another

embodiment, the pharmaceutical compositions are administered intramuscularly, and are

thus formulated in a form suitable for intramuscular administration.

[0130] Further, in another embodiment, the pharmaceutical compositions are

administered topically to body surfaces, and are thus formulated in a form suitable for

topical administration. Suitable topical formulations include gels, ointments, creams,

lotions, drops and the like. For topical administration, the compounds of the present

invention are combined with an additional appropriate therapeutic agent or agents,

prepared and applied as solutions, suspensions, or emulsions in a physiologically

acceptable diluent with or without a pharmaceutical carrier.

[0131] In one embodiment, pharmaceutical compositions of the present invention are

manufactured by processes well known in the art, e.g., by means of conventional mixing,

dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping

or lyophilizing processes.

[0132] In some embodiments, the compounds/ingredients described hereinabove are

included in the pharmaceutical or cosmetic composition of the present invention at a

concentration suitable for achieving an anti-inflammatory effect or skin disease medication. In some embodiments, the pharmaceutical or cosmetic composition is buffered to a pH of 5.5-7.5 since. In another embodiment, a composition as described includes a dermatologically or topically acceptable carrier.

[0133] The phrase "dermatologically acceptable carrier", refers, in some embodiments,

to a carrier which is suitable for topical application onto the skin, i.e., keratinous tissue,

has good aesthetic properties, is compatible with the active agents of the present invention

and any other components, and is safe and non-toxic for use in mammals. An effective

amount of carrier is selected from a range of about 20% to about 99.99%, or from about

40% to about 99.9%, by weight, of the composition.

[0134] In another embodiment, a composition as described includes an emulsion carrier,

including, but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water, and oil-in

water-in-silicone emulsions, a cream, an ointment, an aqueous solution, a lotion or an

aerosol.

[0135] In some embodiments, emulsions according to the present invention comprise a

pharmaceutically effective amount of an agent disclosed herein and a lipid and/or an oil.

Lipids and oils may be derived from animals, plants, or petroleum and may be natural or

synthetic (i.e., man-made). In some embodiments, emulsions also comprise a humectant,

such as but not limited to glycerin. In some embodiments, emulsions of the invention

comprise from about 1% to about 10%, or from about 2% to about 5%, of an emulsifier,

based on the weight of the carrier. Emulsifiers may be nonionic, anionic or cationic.

Suitable emulsifiers are described in, for example, U.S. Pat. No. 3,755,560, issued to

Dickert, et al. Aug. 28, 1973; U.S. Pat. No. 4,421,769, issued to Dixon, et al., Dec. 20,

1983; and McCutcheon's Detergents and Emulsifiers, North American Edition, pages 317

324 (1986). The term "about", in some embodiments, refers to +/- 10% of the recited value.

[0136] In some embodiments, the composition of the invention is a foam. In another

embodiment, an emulsion comprises an anti-foaming agent to minimize foaming upon

application to the keratinous tissue. In some embodiments, the composition of the

invention comprises a water-in-silicone emulsion.

[0137] In some embodiments, a topical composition of the present invention comprises a

surfactant. In some embodiments, a topical composition of the present invention comprises

an anionic surfactant. In one embodiment, a composition as described herein comprises

from about 0.05% to about 10% or from about 1% to about 6% or from about 1% to about

3% of at least one hydrophilic surfactant which can disperse the hydrophobic materials in

the water phase (percentages by weight of the topical carrier). In some embodiments,

surfactants include any of a wide variety of known cationic, anionic, zwitterionic, and

amphoteric surfactants. See, McCutcheon's. Detergents and Emulsifiers, North American

Edition (1986), published by Allured Publishing Corporation; U.S. Pat. No. 5,011,681 to

Ciotti et al., issued Apr. 30, 1991; U.S. Pat. No. 4,421,769 to Dixon et al. issued to Dec.

20, 1983; and U.S. Pat. No. 3,755,560 all of which are hereby incorporated by reference

in their entireties.

[0138] In some embodiments, a topical composition of the present invention comprises a

cationic emulsifier such as but not limited to amino-amides. Nonlimiting examples of

cationic emulsifiers include: stearamidopropyl PG-dimonium chloride phosphate,

behenamidopropyl PG dimonium chloride, stearamidopropyl ethyldimonium ethosulfate,

stearamidopropyl dimethyl (myristyl acetate) ammonium chloride, stearamidopropyl

dimethyl cetearyl ammonium tosylate, stearamidopropyl dimethyl ammonium chloride,

stearamidopropyl dimethyl ammonium lactate, and mixtures thereof.

[0139] In some embodiments, a topical composition of the present invention comprises

from about 25% to about 98% or from about 65% to about 95% or from about 70% to about 90% water by weight of the topical carrier. A pharmaceutical or a cosmetic composition of the present invention can be formulated in any of a variety of forms utilized by the pharmaceutical or cosmetic industry for skin application including solutions, lotions, sprays, creams, ointments, salves, gels, etc.

[0140] In one embodiment, pharmaceutical compositions for use in accordance with the

present invention are formulated in conventional manner using one or more

physiologically acceptable carriers comprising excipients and auxiliaries, which facilitate

processing of the active ingredients into preparations which, can be used pharmaceutically.

In one embodiment, formulation is dependent upon the route of administration chosen.

[0141] In one embodiment, injectables, of the invention are formulated in aqueous

solutions. In one embodiment, injectables, of the invention are formulated in

physiologically compatible buffers such as Hank's solution, Ringer's solution, or

physiological salt buffer. In some embodiments, for transmucosal administration,

penetrants appropriate to the barrier to be permeated are used in the formulation. Such

penetrants are generally known in the art.

[0142] In one embodiment, the preparations described herein are formulated for

parenteral administration, e.g., by bolus injection or continuous infusion. In some

embodiments, formulations for injection are presented in unit dosage form, e.g., in

ampoules or in multidose containers with optionally, an added preservative. In some

embodiments, compositions are suspensions, solutions or emulsions in oily or aqueous

vehicles, and contain formulatory agents such as suspending, stabilizing and/or dispersing

agents.

[0143] The compositions also comprise, in some embodiments, preservatives, such as

benzalkonium chloride and thimerosal and the like; chelating agents, such as edetate

sodium and others; buffers such as phosphate, citrate and acetate; tonicity agents such as sodium chloride, potassium chloride, glycerin, mannitol and others; antioxidants such as ascorbic acid, acetylcystine, sodium metabisulfote and others; aromatic agents; viscosity adjustors, such as polymers, including cellulose and derivatives thereof; and polyvinyl alcohol and acid and bases to adjust the pH of these aqueous compositions as needed. The compositions also comprise, in some embodiments, local anesthetics or other actives. The compositions can be used as sprays, mists, drops, and the like.

[0144] In some embodiments, pharmaceutical compositions for parenteral administration

include aqueous solutions of the active preparation in water-soluble form. Additionally,

suspensions of the active ingredients, in some embodiments, are prepared as appropriate

oily or water based injection suspensions. Suitable lipophilic solvents or vehicles include,

in some embodiments, fatty oils such as sesame oil, or synthetic fatty acid esters such as

ethyl oleate, triglycerides or liposomes. Aqueous injection suspensions contain, in some

embodiments, substances, which increase the viscosity of the suspension, such as sodium

carboxymethyl cellulose, sorbitol or dextran. In another embodiment, the suspension also

contain suitable stabilizers or agents which increase the solubility of the active ingredients

to allow for the preparation of highly concentrated solutions.

[0145] In another embodiment, the active compounds can be delivered in a vesicle, in

particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al., in

Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler

(eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see

generally ibid).

[0146] In some embodiments, preparation of effective amount or dose can be estimated

initially from in vitro assays. In one embodiment, a dose can be formulated in animal

models and such information can be used to more accurately determine useful doses in

humans.

[0147] In one embodiment, toxicity and therapeutic efficacy of the active ingredients

described herein can be determined by standard pharmaceutical procedures in vitro, in cell

cultures or experimental animals. In one embodiment, the data obtained from these in vitro

and cell culture assays and animal studies can be used in formulating a range of dosage for

use in human. In one embodiment, the dosages vary depending upon the dosage form

employed and the route of administration utilized. In one embodiment, the exact

formulation, route of administration and dosage can be chosen by the individual physician

in view of the patient's condition. [See e.g., Fingl, et al., (1975) "The Pharmacological

Basis of Therapeutics", Ch. 1 p.1].

[0148] In one embodiment, depending on the severity and responsiveness of the condition

to be treated, dosing can be of a single or a plurality of administrations, with course of

treatment lasting from several days to several weeks or until cure is effected or diminution

of the disease state is achieved.

[0149] In one embodiment, compositions of the present invention are presented in a pack

or dispenser device, such as an FDA approved kit, which contain one or more unit dosage

forms containing the active ingredient. In one embodiment, the pack, for example,

comprise metal or plastic foil, such as a blister pack. In one embodiment, the pack or

dispenser device is accompanied by instructions for administration. In one embodiment,

the pack or dispenser is accommodated by a notice associated with the container in a form

prescribed by a governmental agency regulating the manufacture, use or sale of

pharmaceuticals, which notice is reflective of approval by the agency of the form of the

compositions or human or veterinary administration. Such notice, in one embodiment, is

labeling approved by the U.S. Food and Drug Administration for prescription drugs or of

an approved product insert.

EXAMPLES

Example 1: treating autoimmune Hepatitis with reduced steroid dose

[0150] Forty-one (41) patients over 18 years of age suffering from autoimmune Hepatitis

with no signs of remission are recruited. Patients having history of psychosis or asthma, or

consuming Cannabis during the last two months before the study are excluded from the

study. 15 of the patients had Jaundice.

[0151] All patients are receiving standard treatment consisting of prednisolone in a daily

dose of 40 to 60 mg/day.

[0152] On the first two weeks of trial all patients are receiving prednisolone

monotherapy.

[0153] On the third week of trial all patients are receiving CBD (STI Pharmaceuticals,

Brentwood, Essex, UK) dissolved in olive oil at a concentration of 2.5% and (oral) at a

dose of 75 mg CBD twice a day together with prednisolone at a dose reduced by 30%.

[0154] On the fourth week of trial all patients are receiving CBD (STI Pharmaceuticals,

dose of 100 mg CBD twice a day together with prednisolone at a dose reduced by 50%

from the initial dose of 40 to 60 mg/day.

[0155] On the fifth week of trial all patients are receiving CBD (STI Pharmaceuticals,

dose of 150 mg CBD twice a day together with prednisolone at a dose reduced by 65%

from the initial dose of 40 to 60 mg/day.

[0156] During the first two weeks 75% of the patients are suffering from at least one

prednisolone specific side effects.

[0157] During the third week 62% of the patients are suffering from at least one

prednisolone specific side effects. During the fourth and the fifth weeks there is a steady

decline in the number of patients suffering from at least one prednisolone specific side

effects to 53% and 36%, respectively.

[0158] Importantly, no side effects due to the use of CBD are reported. On the fifth week

sign of remission are appearing in 68% of the patients with normalization of

aminotransferases and immunoglobulin G. These signs of remission are attributed to the

steroids and not to CBD.

[0159] After total remission, the present dual CBD and low-dose steroid therapy is

continued as maintenance therapy for 18 to 30 months.

[0160] These results are indicating that administration of Cannabidiol reduces the

severity of steroids' side effects due to a substantial increase in the potency of a lower dose

of steroid once administered with Cannabidiol. Unlike dual therapy with Azathioprine,

CBD is not showing any side-effects within the current daily doses. This finding is utmost

important as CBD-steroid treatment unlike azathioprine-steroid treatment is free of side

effects such as: cholestatic hepatitis, pancreatitis, arthralgias, fever, vomiting, nausea,

emesis, rash, opportunistic infection bone marrow suppression and malignancy which are

attributed to the use of azathioprine.

[0161] Moreover, CBD unlike Azathioprine unexpectedly and dramatically reduces

steroidal side effects.

Example 2: Cannabidiol (CBD)/steroid for treatment of severe UC

[0162] A 42 years old male with severe relapse of Ulcerative colitis (UC) is refractory to

both high-dose of oral prednisone and intravenous hydrocortisone cyclosporine for 14

days.

[0163] The patient is immediately starting dual daily treatment of 70 mg prednisone and

250 mg oral CBD. After 6 days of dual CBD/prednisone therapy the patient is in complete

cessation of diarrhea, abdominal pain and fever.

Example 3: Cannabidiol (CBD/steroid for treatment of erythroderma)

[0164] A 35 years old female with is afflicted with severe erythroderma, confirmed by

skin biopsy. The patient is now 10 days refractory to twice daily Triamcinolone topical

treatment and complains of severe skin blistering and burning.

[0165] The patient is immediately starting dual daily treatment of once daily topical

Triamcinolone and 300 mg oral CBD. After 5 days of dual CBD/ Triamcinolone therapy

the patient is relieved of any steroidal side effects with dramatic remission in erythroderma.

Example 4: Cannabidiol (CBD) renders a refractory high dose of steroids and

tacrolimus -effective

[0166] 63 years old female with hepatitis developed jaundice with bilirubin level of 4.2

mg%. She started tacrolimus and high-dose steroids- prednisone, and had a partial response

for a short period of time. Two months later, while still given tacrolimus and steroids she

developed pancreatitis and had an upsurge in bilirubin to 8.5 mg%.

[0167] She started oral CBD 150 mg BID. Jaundice resolved gradually and bilirubin

dropped to normal levels. Steroids could be tapered off by 50% to a low dose of 7.5 mg

QD with no CBD and or steroidal side-effects.

Example 5: Cannabidiol (CBD) renders an ineffective dose of Dexamethasone

effective

[0168] 68 years old female with Rheumatoid Arthritis (RA) developed pericarditis with

sudden flares of joint pain. She is immediately treated for 14 days with Dexamethasone (4

mg orally every 12 hours) with only slight improvement of joint pain and developed

anemia.

[0169] She's is immediately prescribed with oral CBD 150 mg BID and the daily

dexamethasone dose is decreased to 3 mg orally every 12 hours. After 10 days from the

beginning of treatment the patient is relived of burning joint pain and no signs of anemia

are apparent, Dexamethasone is further reduced to 2 mg orally every 12 hours. After 14

days from the beginning of treatment the patient is still relived of burning joint pain and

walks more comfortably, Dexamethasone is further reduced to 1.5 mg orally every 12

hours.

Example 6: Cannabidiol (CBD) renders a refractory high dose of Prednisone

effective

[0170] A 58 years old male with refractory follicular lymphoma underwent an allogeneic

hematopoietic cell transplantation. One month later he was admitted with severe late onset

acute skin inflammation and upper (nausea and vomiting) plus lower gastrointestinal involvement (bloody diarrhea, crampy abdominal pain and severely inflamed and ulcerated mucosa).

[0171] He started high-dose steroids (Prednisone). Despite skin response, GIT

inflammation was refractory to prolonged systemic treatment of steroids.

[0172] He started oral CBD 150 mg BID, symptoms improved gradually and a very good

partial response (VGPR) was attained to the steroids. Prednisone was tapered off to 20 mg

QD (40%)- found to be therapeutically effective.

[0173] The present CBD treatments, unexpectedly, rendered a dangerously high dose or

a refractory dose of a steroid-therapeutically effective with minimal to no steroid side

effects.

Claims

CLAIMS What is claimed is:

1. A method of converting a sub-efficient monotherapy steroid dose and/or dosage to a

therapeutically effective dose and/or dosage in a subject in need thereof, the method comprising

administering to said subject said sub-efficient steroid dose and/or dosage and cannabidiol

(CBD), wherein said CBD is at a daily dose of 20 to 500 mg, thereby converting a sub-efficient

monotherapy steroid dose and/or dosage to an efficient dose.

2. The method of claim 1, wherein said subject is chronically treated with said steroid.

3. The method of claim 1 or 2, wherein said subject suffers from an autoimmune disease.

4. The method of any one of claims 1-3, wherein said CBD is substantially devoid of

Tetrahydrocannabinol (THC).

5. The method of claim 3, wherein said autoimmune disease is autoimmune hepatitis.

6. The method of any one of claims 1 to 5, wherein said sub-efficient monotherapy dose

and/or dosage is a refractory dose and/or dosage.

7. The method of any one of claims 1 to 6, wherein said subject suffers from a steroid

refractory disease.

8. A method of treating a subject suffers from a steroid refractory disease or autoimmune

disease, the method comprising administering to said subject a sub-efficient steroid dose and/or

dosage and cannabidiol (CBD), wherein said CBD is at a daily dose of 20 to 500 mg, thereby

treating said steroid refractory disease or autoimmune disease.

9. The method of claim 8, wherein said subject is chronically treated with said steroid.

10. The method of claim 8 or 9, wherein said subject suffers from an autoimmune disease.

11. The method of any one of claims 8 to 10, wherein said CBD is substantially devoid of

Tetrahydrocannabinol (THC).

12. The method of any one of claims 8 to 11, wherein said autoimmune disease is

autoimmune hepatitis.

13. The method of any one of claims 8 to 12, wherein said sub-efficient monotherapy dose

and/or dosage is a refractory dose and/or dosage.

14. The method of any one of claims 8 to 13, wherein said subject suffers from a steroid

refractory disease.

15. The use of a sub-efficient steroid dose and cannabidiol (CBD) at a daily dose of 20 to

500 mg for the manufacture of a medicament for the treatment of a steroid refractory disease

or autoimmune disease.

16. The use of claim 15, wherein said medicament is for use in the treatment of an

autoimmune disease.

17. The use of claim 15 or 16, wherein said autoimmune disease is autoimmune hepatitis.

18. The use of any one of claims 15 to 17, wherein said CBD is substantially devoid of

Tetrahydrocannabinol (THC).

19. The use of any one of claims 15 to 18, wherein said sub-efficient monotherapy dose is

a refractory dose.

20. The use of any one of claims 15 to 19, wherein said medicament is for use in the

treatment of a steroid refractory disease.