WO2006079999A2

WO2006079999A2 - Induction of a novel state of mind with a 5-ht2a agonist and a nmda antagonist

Info

Publication number: WO2006079999A2
Application number: PCT/IB2006/051080
Authority: WO
Inventors: Frederik H. Barth
Original assignee: Individual
Current assignee: Individual
Priority date: 2006-04-09
Filing date: 2006-04-09
Publication date: 2006-08-03
Anticipated expiration: 2008-10-09
Also published as: WO2006079999A3

Abstract

It has been discovered that the administration of a hallucinogenic 5-HT2A agonist in combination with a NMDA antagonist to a human being induces a novel and particular state of the human mind. This state of mind is non-psychotic and benign. The induction of this novel and particular state of the human mind can be used for therapeutic, recreational and other useful purposes.

Description

Description INDUCTION OF A NOVEL STATE OF MIND WITH A 5-HT2A

AGONIST AND A NMDA ANTAGONIST

Technical Field

[1] This invention concerns the human mind and ways to modify it.

Background Art

[2] The uniqueness of the human mind parts man from all other species. It is our mind that makes us human. The human mind is a miracle created by evolution, and the species Homo sapiens seems to mark the pinnacle of the evolution of species. It does not seem possible that a new species will evolve with a mind superior to the human mind. When the evolution of species had created Homo sapiens as its ultimate product, the evolution of mankind began. The uniqueness of the human mind enabled a continuous and collective process of learning, discovery and invention, which created the modern world that surrounds us.

[3] In spite of intense research, it is still a mystery how the substance matter of the human brain becomes conscious and emanates the human mind. However, scientific research has created much knowledge about the functioning of the human brain, and this knowledge enables us today to manipulate the human mind with pharmacological tools which affect the functioning of the substance matter of the brain. Such pharmacological tools, when administered to humans, are called drugs.

[4] Society, science and the law distinguish between legitimate and illegitimate uses of drugs which influence the human mind, based on the benefit their use creates for the individual and society.

[5] Currently, the only generally accepted and legitimate reason for the pharmacological manipulation of the functioning of the human brain is for the purpose to correct malfunctions. Such malfunctions of the human brain affect the mind and cause mental diseases and disorders. The treatment of such diseases and disorders is highly desirable and beneficial for the individual as well as for society. Much effort is undertaken to develop new drugs for this purpose.

[6] However, humans also seek the effects of mind altering drugs for reasons which are generally considered illegitimate. Such drugs have an effect on the human mind which the individual subjectively experiences as desirable. Objectively, however, these drugs are detrimental for the individual, because they impair the mind. Such drugs of abuse create immense problems for society and much suffering for mankind. Much effort is undertaken to prohibit and prevent such use of mind altering drugs, but the success of these efforts is unfortunately very limited. [7] The Applicant believes that there is an additional legitimate reason to manipulate the human brain with pharmacological tools. It is for the purpose of enhancing the human mind. Such an effect would be perceived as desirable by many individuals. Since such an effect would objectively not be detrimental for the individual, but might actually be beneficial for the individual, it would also be acceptable for society.

[8] It seems to be the general consensus in science that the healthy human mind can not be further enhanced significantly by pharmacological manipulation of the brain. Indeed, there is currently no method known in the art to pharmacologically manipulate the healthy human mind in an objectively beneficial or useful way. Research to find ways to enhance the human mind with pharmacological tools is practically nonexistent.

[9] It should be noted however that non-pharmacological methods to enhance the mind have a long tradition in human history. Mental and physical exercises such as meditation and yoga were developed as ways to enhance the mind and are widely practiced. It is therefore a clear and legitimate desire of man to enhance his mind. Disclosure of Invention

Technical Problem

[10] Since it is the human mind which both creates the world that surrounds us and manifests the world within us, it might be possible to improve both the world that surrounds us and the world within us, if we can enhance the human mind. It is also a clear and legitimate desire of man to enhance his mind. The Applicant has therefore sought novel ways to enhance the human mind.

Technical Solution

[11] A novel and useful way to influence the human mind by pharmacological manipulation of the brain using a 5-HT2A agonist and a NMDA antagonist has been discovered by the Applicant.

[12] A 5-HT2A agonist is any substance which exerts agonistic activity at the 5-HT2A receptor, but it may also have additional pharmacological activity. A NMDA antagonist is any substance which inhibits the agonistic activity of the excitatory amino acid derivative NMDA at its receptor, but it may also have additional pharmacological activity.

[13] Both NMDA antagonists and 5-HT2A agonists are psychosis-inducing drugs in human beings, see for example Pharmacopsychiatry 38(6):301-ll, 2005 (PMID: 16342002). These psychosis-inducing effects limit the usefulness of NMDA antagonists as drugs for the treatment of human beings, where they are being explored as neuroprotective treatments and for other therapeutic applications. Ketamine is a clinically employed NMDA antagonist used for its sedative, anesthetic and analgesic properties. It is usually administered together with other drugs, such as benzo- diazepines, to reduce its psychotomimetic side effects. There are no known therapeutic applications for 5-HT2A agonists except for the proposed local administration to the eye to lower the intraoccular pressure according to patent application WO 03053436. It is worthwhile to mention that both certain 5-HT2A agonists and certain NMDA antagonists constitute drugs of abuse. Their effect on the healthy human mind is clearly not beneficial.

[14] Due to the psychosis-inducing effects of either NMDA antagonists or 5-HT2A agonists in human beings, a combination of drugs of these two classes can only be expected to also have, and likely have even stronger, psychosis-inducing effects, precluding any therapeutic or other useful application.

[15] The only suggestion for a therapeutic use of a combination of these two drug classes can be found in patent US 5,902,815, which claims the combination of a NMDA antagonist with a non-hallucinogenic 5-HT2A agonist to reduce the neurotoxic effects of the NMDA antagonist. A combination of a 5-HT2A agonist and a NMDA antagonist is disclosed there to be non-neurotoxic. However, this patent only claims the use of non-hallucinogenic 5-HT2A agonists such as lisuride. It does not claim any useful effects caused by a combination of a hallucinogenic 5-HT2A agonist and a NMDA antagonist, but clearly states that hallucinogenic 5-HT2A agonists are generally unsuitable for therapeutic purposes due to their psychosis inducing properties. It does also not suggest in any way that the combined administration of a 5-HT2A agonist with a NMDA antagonist would have any special or particular or useful effects on the human mind.

[16] Data disclosed in Neuropsychopharmacology 22(6):618-25, 2000 (PMID:

10788761) suggest that certain 5-HT2A agonists can block the behavioral as well as the neurotoxic effects of NMDA antagonists in laboratory animals most likely through agonist actions at 5-HT2 receptors. This finding indicates that surprising effects may occur if the brain is concurrently exposed to a 5-HT2A agonist and a NMDA antagonist. However, no indication of any practical use of this finding is given, and no effects on the human mind are mentioned.

[17] The Applicant has now surprisingly discovered that the combined administration of a psychosis-inducing NMDA antagonist and a hallucinogenic, psychosis-inducing 5-HT2A agonist does not have a psychosis-inducing effect in a human being. Rather, this combination of drugs leads to a mutual reduction of the psychosis inducing effects of each drug type. The result of the concurrent administration of a hallucinogenic 5-HT2A agonist and a psychotomimetic NDMA antagonist to a human being is a novel, so far undescribed state of the human mind, which is significantly different from the psychotic state of mind induced by either type of drug alone. It does not resemble the psychotic state of mind induced by either type of drug alone, nor does it resemble the state of mind induced by any other drug or combination of drugs known in the art. This novel state of mind is non-psychotic and benign.

[18] This finding is surprising and non-obvious, because normally the effects of two drugs are additive. In this case, however, the effect of the administration of two psychosis inducing drugs is not additive, but inversive. Two psychosis-inducing drugs in combination induce a non-psychotic, benign and novel state of the human mind.

[19] This novel state of the human mind is characterized by mental clarity, elevated consciousness and absence of hallucinations. The subject experiences a peaceful and calm state of mind. Intelligence and creativity of a human being in which this novel state of mind is induced appear to be enhanced. The interest of the individual shifts away from simple desires such as food and towards higher, mental activities such as thoughtful consideration and ideation. Research conducted so far indicates that this novel state of the human mind is best described as an enhanced state or mode of the human mind, in which the highest mental functions are activated, enhanced or improved.

[20] This novel state of mind may well be described with the word metanoia. However, the Applicant sees the need to establish a new, unencumbered name for this novel phenomenon. The Applicant has therefore named this novel effect caused by the concurrent administration of a 5-HT2A agonist and a NMDA antagonist to a human being the eudynos effect, and the state or mode of mind which is induced by it has been named eudynoia. Further research is now needed to fully characterize and investigate the eudynos effect and the mental state of eudynoia.

[21] A neuropharmacological explanation for this phenomenon may be found in the effect a 5-HT2A agonist has on NMDA receptor mediated functions. Data disclosed by Arvanov et al. in Eur J Neurosci. 1999 Aug;ll(8):2917-34, 1999 (PMID: 10457188) and Eur J Neurosci. ll(9):3064-72, 1999 (PMID: 10510170) indicate that 5-HT2A agonists modulate the activity of glutamate gated ion channels via NMDA receptors. Arvanov et al. suggest that this modulation of NMDA receptor ionophores is responsible for the mind altering effects of hallucinogenic 5-HT2A agonists. And of course NMDA antagonists also have well known and powerful mind altering effects. Apparently, this ion channel is a centerpiece of the substance matter from which the mind emanates. The discovery of the unique effects on the human mind of a combination of a 5-HT2A agonist and a NMDA antagonist provides additional evidence for the pivotal role of NMDA receptor ionophores in the highest functions of the human brain. And it is a first indication that it might be possible to actually improve the functioning of the brain through pharmacological manipulations at this site.

[22] While this is pure speculation at this point in time, the Applicant considers the following scenario as a possible explanation of the known and newly discovered effects: both 5-HT2A agonists and NMDA antagonist modulate NMDA receptor ionophores out of balance, but in opposite directions. This would explain the similar yet distinct effects which 5-HT2A agonists and NMDA antagonist have on the human mind. However, when both a NMDA antagonist and a 5-HT2A agonist is present, NMDA receptor ionophores are not modulated out of balance, but are either stabilized in balance, or modulated in a third direction. If such a stabilization or modulation leads to an improvement in signal transmission, either by signal amplification, by an improvement of the signal-to-noise ratio, or by an improvement in the time domain, it could well lead to an enhancement of the mind. Further research needs to be conducted to elucidate what exactly happens when the substance matter of the brain concurrently encounters a NMDA antagonist and a 5-HT2A agonist.

[23] It is well known in the art that tolerance to the hallucinogenic effects of 5-HT2A agonists develops very quickly. Thus, if the same dose of a hallucinogenic 5-HT2A agonist is given to a human being on consecutive days, already on the second day the effects are reduced, and on the third or fourth day, the same dose is essentially without effect. A significant amount of time of abstinence is required to restore the initial sensitivity for the effects of a 5-HT2A agonist on the human mind. Since the 5-HT2A agonist would quickly loose its effect on the human mind at a constant dose, it had to be expected that the combination of a 5-HT2A agonist and a NMDA antagonist would also quickly become ineffective. This would significantly limit the usefulness of the invention. Research conducted so far indicates, however, that such an expected tolerance to the effects of a combination of a 5-HT2A agonist and a NMDA antagonist does surprisingly not occur to the expected degree. While some tolerance to the effects of the 5-HT2A agonist and also the NMDA antagonist may develop over time and may require an adjustment of the dose of the drugs, it has been found that the effects are generally sustainable.

[24] It appears therefore that the NMDA antagonist inhibits the development of tolerance towards the effects of the 5-HT2A agonist. This finding resembles the known effect of reduced development of tolerance to the analgesic effects of opioids by concurrent administration of a NMDA antagonist as disclosed in Science 251(4989):85-7, 1991 (PMID: 1824728). Additional research needs to be conducted to elucidate if and how NMDA antagonists inhibit the development of tolerance towards 5-HT2A agonists.

[25] Research published in Prog Neuropsychopharmacol Biol Psychiatry 23(7): 1259-75,

1999 (PMID: 10581647) indicates that the concurrent administration of a 5-HT2A agonist with the NMDA antagonist and drug of abuse PCP inhibits the release of the neurotransmitter dopamine in the rat medial prefrontal cortex, which is caused by the administration of PCP alone. Unfortunately, the findings this study are somewhat ambiguous, because the dopamine release caused by the NMDA antagonist MK-801 was not prevented by a 5-HT2A agonist. However, it is well established in the art that the activation of dopaminergic pathways plays a crucial role in the addictive properties of drugs of abuse. Since the combination of a 5-HT2A agonist and a NMDA antagonist does not seem to activate dopaminergic pathways, it is likely that this drug combination is not addictive. This is a further important aspect in the practical applicability of the invention and supports the initial findings of the Applicant that this drug combination is indeed not addictive, nor causing any form of dependence. Drugs of abuse generally activate the primitive reward mechanisms of the brain and thereby cause addiction. Even rats get addicted to those drugs. The disclosed drug combination only activates higher, mental functions. It might therefore be addictive in the same sense how good books or movies are addictive. The Applicant believes, however, that rats will show little interest in this drug combination, just how rats show little interest in good books or movies. Still, studies to determine the addictive properties of this drug combination and its influence on the dopaminergic and reward circuitries of the brain are desirable.

[26] The Applicant has found that the effect is somewhat variable, depending on which

NMDA antagonist compound and which 5-HT2A agonist compound is used. It is therefore necessary to conduct further research to identify the most suitable 5-HT2A agonists and NMDA antagonist for the induction of this novel state or mode of the human mind.

[27] The art of medicinal chemistry has provided us with a vast and diverse array of sophisticated and highly optimized NMDA antagonists. Since 5-HT2A agonists were thus far thought to have no value for therapeutic applications, little effort has been spend to develop such drugs. Most 5-HT2A agonists are classified as controlled substances, and the Applicant is not able to conduct research with controlled substances. The Applicant is therefore grateful that the research conducted by David Nichols, John Macor and particularly by Alexander Shulgin has provided him with the tools which made this discovery possible.

[28] Now, that a new and legitimate use for 5-HT2A agonists has been discovered, it is desirable to develop novel and improved 5-HT2A agonists which are not covered by existing controlled substance laws in order to facilitate research into this novel state of the human mind. By methods well known in the art of medicinal chemistry, the Applicant intends to develop such novel and improved 5-HT2A agonists.

[29] The discovery made by the Applicant is also stark evidence that the current policy in most countries, and particularly in the USA, to totally prohibit all research with psychotropic substances in humans is severely hampering the progress of science. It is utter nonsense to force scientists to use trained rats to determine the effects of drugs on the mind. If the Applicant wasn't an independent, private researcher who can do whatever he pleases (and found ways to work around controlled substance laws), this important discovery may have never been made.

Advantageous Effects

[30] This novel state or mode of the human mind, which can be induced as disclosed by the Applicant, may be useful for therapeutic, recreational or other beneficial purposes. Much research is needed to develop all its possibilities.

[31] In this enhanced state or mode of the mind, an individual experiences enhanced intelligence and creativity. The individual is therefore better able to solve complex mental tasks. This is very valuable, desirable and beneficial for all sorts of professional activity.

[32] The induction of this novel mental state may also be used in the treatment of a wide variety of conditions, disorders and diseases, which include, but are not limited to, mental and neurological diseases and disorders, neurodegenerative diseases, drug addiction and withdrawal, pain, cerebral trauma and hypoxia, stroke and epilepsy. Research needs to be conducted to further develop these applications.

[33] The NMDA antagonist memantine is successfully used in the treatment of

Alzheimer's disease. It is therefore quite likely that other NMDA antagonists are also useful in the treatment of this disease. The Applicant believes that the combination of a NMDA antagonist and a 5-HT2A agonist is particularly useful for the treatment of Alzheimer's disease, because it strengthens and activates the highest functions of the human brain, which are impaired in patients suffering from Alzheimer's disease.

[34] Similarly, patients suffering from Down's syndrome and autism may benefit from the mind enhancing effects of the combination of a 5-HT2A agonist and a NMDA antagonist.

[35] Overactivity at the 5-HT2A receptor is thought to play an important role in the etiology of schizophrenia, and many drugs to treat this disease are 5-HT2A antagonists. Since it has now been found that the psychosis inducing and hallucinogenic effects of stimulating or activating 5-HT2A receptors can not only be counteracted, but inverted into beneficial mental activity by antagonizing NMDA receptors, it seems possible to treat both the positive and the negative symptoms of schizophrenia with an NMDA antagonist. It needs to be tested if a NMDA antagonist alone or in combination with a 5-HT2A agonist is more suitable to treat this disease.

[36] Since the Applicant has now discovered that the psychosis inducing properties of hallucinogenic 5-HT2A agonists are not an obstacle for their therapeutic use if they are administered in combination with a NMDA antagonist, the combination of a hallucinogenic 5-HT2A agonist and a NMDA antagonist my now also be used for all methods and uses claimed in patent US 5,902,815. Patent US 5,902,815 is included in this disclosure by reference.

[37] As mentioned above, it is well known in the art that the development of tolerance to the analgesic effects of opioids can be prevented by concurrent administration of a NMDA antagonist. This discovery is of little practical value because of the psychosis inducing effects of NMDA antagonists. Since it has now been found that the psychosis inducing effects of NMDA antagonists can be prevented by concurrent administration of a 5-HT2A agonist, the prevention of the development of tolerance to opioid analgesics with NMDA antagonists may become practically viable by concurrent administration of a 5-HT2A agonist.

[38] The Applicant has discovered that the administration of a combination of a 5-HT2A agonist and a NMDA antagonist to an individual shifts the interest of the individual away for the consumption of food. Therefore, this combination of drugs may be used in the treatment of obesity and overweight and to promote weight loss.

[39] Since the combination of a 5-HT2A agonist and a NMDA antagonist can induce an effect which the individual experiences as subjectively desirable, and which is objectively not detrimental for the individual, it may constitute a viable, safe and non- harmful alternative to and replacement for drugs of abuse. By making such a viable alternative to drugs of abuse available, the immense problems created by drugs of abuse can be diminished.

[40] It is of course also very advantageous that the combination of a 5-HT2A agonist and a NMDA antagonist has already been shown to be non-neurotoxic. This greatly enhances the practical value of the disclosed discovery.

Best Mode

[41] Relatively small, sub-anesthetic doses of the NMDA antagonist are sufficient.

Generally, the doses are in the same range at which NMDA antagonists have shown neuroprotective properties and were explored in clinical trials for conditions such as stroke and traumatic brain injury. They are also in the same range in which the NMDA antagonist ketamine is used for therapeutic purposes.

[42] Research published in Anesthesiology 88(l):82-8, 1998 (PMID: 9447860) has shown that the relationship between the psychotomimetic effects of the NMDA antagonist ketamine and its steady-state venous plasma concentrations is highly linear. The Applicant has found that the most suitable and desirable dose of the NMDA antagonist is the threshold dose, or somewhat below the threshold dose, for the induction of psychotomimetic effects. The threshold dose is that dose at which the subject experiences the first psychotomimetic mental alterations caused by an NMDA antagonist, but they are mild and not troublesome. While higher doses, which cause more pronounced psychotomimetic effects, might still be useful in certain cases, they are generally considered less desirable and less suitable for the induction of the disclosed effect.

[43] The dose of the 5-HT2A agonist may be varied depending on the individual's response and the desired effect. While lower doses might be sufficient and more desirable in many cases, even high doses of the 5-HT2A agonist, which when administered alone would have a very strong hallucinogenic effect, can be used without causing hallucinations or psychosis.

[44] Thus, while the Applicant has generally worked in his research with the threshold dose of the NMDA antagonist and a clearly hallucinogenic dose of a 5-HT2A agonist to cause a pronounced effect on the mind, smaller doses of the two drugs which cause a less pronounced, more subtle effect on the mind may be quite sufficient and more desirable for many practical and therapeutic applications of the disclosed effect.

[45] The NMDA antagonist and the 5-HT2A agonist may be administered either simultaneously, or the drugs may be administered sequentially in such a way that their tissue concentrations and pharmacological effects develop uniformly and synchronously. While it is most desirable that the agonistic activity at the 5-HT2A receptor and the antagonistic activity at the NMDA receptor develop uniformly and synchronously, it may in certain cases be advantageous to cause either the 5-HT2A agonistic or NMDA antagonistic effect first, and then cause the other effect thereafter.

[46] The NMDA antagonist and the 5-HT2A agonist may be administered in any form which is physiologically compatible. The method of administration may be freely chosen from the many methods known in the art to administer a drug to a human being.

[47] While there is currently no compound know in the art which combines 5-HT2A agonistic activity and NMDA antagonistic activity in one molecule, it is contemplated that such a compound may be developed in the future. Thus, a combination of a 5-HT2A agonist and a NMDA antagonist may either be in the form of two compounds, or in the form of one compound which has both 5-HT2A agonistic and NMDA antagonistic activity. Any composition of matter which concurrently has agonistic activity at the 5-HT2A receptor and antagonistic activity at the NMDA receptor is therefore also considered as a combination of a 5-HT2A agonist and a NMDA antagonist.

[48] It should be noted that the combination of a 5-HT2A agonist and a NMDA antagonist might be usefully combined with various other drugs for the treatment of certain patients, certain diseases, disorders and conditions, or to achieve certain additional effects. Future research will certainly discover many new and useful combinations.

Mode for Invention

[49] Using the well known 5-HT2A agonist (±)-DOI and the well known NMDA antagonist (+)-MK-801, also known as dizocilpine, the above described mental state has been induced in an adult human being of about 85 kg body weight with a dose of 0.5 mg (+)-MK-801 and 1.8 mg (±)-DOI.

[50] While it was important to provide proof of principle by using well known standard drugs widely used in research, (±)-DOI is not a preferable 5-HT2A agonist for the induction of the disclosed effect. The Applicant has worked with less well known drugs and has achieved better results with those.

[51] The Applicant was initially interested in exploring the effects of sub-threshold and threshold doses of NMDA antagonists on the human mind. The Applicant therefore needed to obtain a suitable NMDA antagonist for his research. Most NMDA antagonists are either controlled substances and therefore inaccessible for the Applicant, or are difficult to synthesize and therefore beyond the limited means of the Applicant. The Applicant was however able to identify N-ethyl-l,2-diphenylethylamine as a suitable candidate as NMDA antagonist for his research. This compound has been disclosed in NIDA Res Monogr. 1989;95:51-6 (PMID: 2561843) as a reasonably potent NMDA antagonist. Further research revealed that this compound, and some derivatives, had already been investigated in 1943. (Actions of a series of diphenylethylamines. Tainter, M. L.; Luduena, F. P.; Lackey, R. W.; Neuru, E. N. J. Pharmacol. (1943), 77 317-23.)

[52] A synopsis of the available data led the Applicant to believe that a NMDA antagonist suitable for his research needs can be found amongst this series of diphenylethylamines. The Applicant therefore synthesized a series of diphenylethylamines using methods disclosed in the Journal of the American Chemical Society (1946), 68, 2174-5. Upon exploration of the effects of these compounds on his mind, the Applicant found N-isopropyl-l,2-diphenylethylamine to be most suitable for his research needs and named it K3.

[53] The Applicant found K3 to have all the typical effects on the human mind which had to be expected for a NMDA antagonist. The threshold dose, where psychotomimetic effects would start to become noticeable, was found to be between 75 mg and 100 mg for an adult human being. The main disadvantages of K3 are the slow onset of activity and the short duration. Effects take about 2 hours to fully develop and last about 4 hours. Concurrent food intake seems to enhance and accelerate the resorption of K3.

[54] In the course of further research, the Applicant noticed some interesting and potentially useful effects of sub-threshold doses of K3 in the range of 50 mg on his mind. It appeared to the Applicant that such small doses of K3 seemed to improve his cognitive abilities. This resembles the finding that the NMDA antagonist memantine can improve cognitive functions in Alzheimer's disease. Apparently, in a certain, relatively low dose range, NMDA antagonists can not only improve impaired cognitive functions in Alzheimer's disease, but can actually improve the cognitive abilities of the healthy human brain.

[55] Another line of research had provided the Applicant with the hallucinogenic

5-HT2A agonist known as 2C-D, developed by Alexander Shulgin and described in his book PiHKAL. While using small doses of K3 to improve his cognitive abilities, the Applicant decided to further explore the effects of the 5-HT2A agonist 2C-D on his mind. In an experiment conducted on February 2nd, 2006, the Applicant noticed novel and unexpected effects of the 5-HT2A agonist on his mind. Further research and diligent experimentation led to the disclosed discoveries.

[56] Resources provided by Smartchem LLC gave the Applicant access to the NMDA antagonist (+)-MK-801 and the 5-HT2A agonists (±)-DOI and (R )-5-methoxy-3-((l-methylpyrrolidin-2-yl)methyl)-lH-indole, which will be referred to as 5-MeO-MPMI. The Applicant gratefully acknowledges the help which Armand Tuzel of Smartchem LLC provided in the process of developing the initial discovery.

[57] (+)-MK-801 has been found to be an excellent and clearly superior replacement for

K3. A dose of 0.5 mg (+)-MK-801 appears to be equivalent to 75 mg of K3 and is just below the threshold dose. The effects of (+)-MK-801 are well developed at 1 hour after oral administration and last an estimated 6 - 8 hours. (+)-MK-801 can be administered simultaneously with the 5-HT2A agonist, while K3 had to be administered before the 5-HT2A agonist due to its slow onset of activity, which made it difficult to synchronize the effects. Data disclosed by Wender et al. in Psychopharmacol Bull. 22(l):237-42, 1986 (PMID: 3523579) were helpful in finding a suitable dose of (+)-MK-801.

[58] 5-MeO-MPMI was developed by Macor et al. and is disclosed in patent application

WO 9206973 and in J Med Chem 35(23), 4503-5, 1992. It was further characterized by Nichols et al. as a hallucinogenic 5-HT2A agonist, see J Med Chem 42(20), 4257-63, 1999 (PMID: 10514296).

[59] 5-MeO-MPMI has been found by the Applicant to have rather unpleasant effects on the human mind and therefore has little potential to become a drug of abuse. However, the Applicant has found 5-MeO-MPMI to be an excellent 5-HT2A agonist for the induction of the disclosed effect. Currently, the most reliable and preferred way to induce the disclosed novel state of mind consists in the oral administration of 0.5 mg (+)-MK-801 as maleate and 2.0 mg 5-MeO-MPMI as free base to an adult human being of 85 kg body weight. The dose of (+)-MK-801 has been found to be rather critical for a smooth induction. If higher doses of 5-MeO-MPMI are desired for a more pronounced effect, it is best to administer an additional dose of 1.0 - 2.0 mg after induction. [60] The main disadvantage of 5-MeO-MPMI is its pronounced sedative effect. It is therefore desirable to administer a mild psychostimulant to counteract this sedative effect. The Applicant has found cyclazodone to be an excellent, mild psychostimulant for this purpose.

[61] Eventually, the Applicant reached a point where he fully understood the effect, and where he was able to induce it very reliably and smoothly. He could not gain further insight with further experiments. At this point, the need arose to verify the effect in a second person as a final experiment. Upon careful consideration and discussion, the Applicant's wife, Elizabeth, volunteered to be the subject of this final experiment. Elizabeth is the ideal subject for this verification, because her mind is very sensitive and prone to psychosis. Elizabeth suffers from paranoid personality disorder and from ADHD. She needs constant medication to be in a healthy state of mind. Elizabeth strongly dislikes mind altering drugs and poorly tolerates them. If the combination of a 5-HT2A agonist and a NMDA antagonist would have the same benign effect on her and would induce a similar state of mind, it would be reasonable proof that the effect is general.

[62] This final experiment was conducted on April 1st, 2006, using 0.5 mg (+)-MK-801 maleate and 2.0 mg 5-MeO-MPMI free base. The effect was fully verified and found general. Furthermore, in Elizabeth's case there are first indications that the induction of this novel state or mode of mind may have beneficial effects on the individual which outlast the pharmacological effect at least by several days, and may even be permanent.

Claims

[I] The method of inducing a novel and particular state or mode of the human mind by concurrently antagonizing NMDA receptors and activating or stimulating 5-HT2A receptors in the human brain.

[2] The method of inducing a novel and particular state or mode of the human mind by the concurrent administration of a NMDA antagonist and a 5-HT2A agonist to a human being. [3] The use of a combination of a NMDA antagonist and a 5-HT2A antagonist to induce a novel and particular state or mode of the human mind. [4] The use of a combination of a NMDA antagonist and a 5-HT2A agonist to induce a novel and particular state or mode of the human mind for therapeutic, recreational or other useful purposes. [5] The use of a combination of a NMDA antagonist and a 5-HT2A agonist to induce a novel and particular state or mode of the human mind and administration of additional drugs for therapeutic, recreational or other useful purposes. [6] The method of reducing the psychosis inducing effects of antagonizing NMDA receptors in the human brain by concurrently activating or stimulating 5-HT2A receptors in the human brain. [7] The method of reducing the psychosis inducing effects of a NMDA antagonist by the concurrent administration of a 5-HT2A agonist to a human being. [8] The use of a 5-HT2A agonist to reduce the psychosis inducing effects of a

NMDA antagonist. [9] The method of reducing the psychosis inducing effects of activating or stimulating 5-HT2A receptors in the human brain by concurrently antagonizing

NMDA receptors in the human brain. [10] The method of reducing the psychosis inducing effects of a 5-HT2A agonist by the concurrent administration of a NMDA antagonist to a human being.

[II] The use of a NMDA antagonist to reduce the psychosis-inducing effects of a 5-HT2A agonist.

[12] The method of increasing human intelligence, creativity or empathy by concurrently activating or stimulating 5-HT2A receptors and antagonizing NMDA receptors in the human brain.

[13] The method of increasing human intelligence, creativity or empathy by the concurrent administration of a 5-HT2A agonist and a NMDA antagonist to a human being.

[14] The use of a combination of a NMDA antagonist and a 5-HT2A agonist to increase human intelligence, creativity or empathy. [15] The method of inducing, enhancing or increasing sensory perception, sense of beauty, or pleasure in a human being by concurrently activating or stimulating 5-HT2A receptors and antagonizing NMDA receptors in the human brain.

[16] The method of inducing, enhancing or increasing sensory perception, sense of beauty, or pleasure in a human being by the concurrent administration of a 5-HT2A agonist and a NMDA antagonist to a human being.

[17] The use of a combination of a NMDA antagonist and a 5-HT2A agonist to induce, enhance or increase sensory perception, sense of beauty, or pleasure in a human being.

[18] The method of inducing a feeling of well-being, pleasure or enhancedness in a human being by concurrently activating or stimulating 5-HT2A receptors and antagonizing NMDA receptors in the human brain.

[19] The method of inducing a feeling of well-being, pleasure or enhancedness in a human being by the concurrent administration of a 5-HT2A agonist and a NMDA antagonist to a human being.

[20] The use of a combination of a NMDA antagonist and a 5-HT2A agonist to induce a feeling of well-being, pleasure or enhancedness in a human being.

[21] The method of alleviating pain by concurrently activating or stimulating μ-opioid receptors and 5-HT2A receptors and antagonizing NMDA receptors in the human brain.

[22] The method of alleviating pain by the concurrent administration of an opioid analgesic, a hallucinogenic 5-HT2A agonist and a NMDA antagonist to a human being.

[23] The use of a combination of an opioid analgesic, a hallucinogenic 5-HT2A agonist and a NMDA antagonist to alleviate pain in a human being.

[24] The method of treating stroke, cerebral trauma or cerebral hypoxia by concurrently activating or stimulating 5-HT2A receptors and antagonizing NMDA receptors in the human brain.

[25] The method of treating stroke, cerebral trauma or cerebral hypoxia by the concurrent administration of a NMDA antagonist and a hallucinogenic 5-HT2A agonist to a human being.

[26] The use of a combination of a NMDA antagonist and a hallucinogenic 5-HT2A agonist for the treatment of stroke, cerberal trauma or cerebral hypoxia.

[27] The method of reducing appetite and food consumption and promoting weight loss in a human being by concurrently activating or stimulating 5-HT2A receptors and antagonizing NMDA receptors in the human brain.

[28] The method of reducing appetite and food consumption and promoting weight loss in a human being by the concurrent administration of a 5-HT2A agonist and a NMDA antagonist to a human being. [29] The use of a combination of a NMDA antagonist and a 5-HT2A agonist to reduce appetite and food consumption and promote weight loss in a human being. [30] The method of treating Alzheimer's disease by concurrently activating or stimulating 5-HT2A receptors and antagonizing NMDA receptors in the brain of a patient suffering from this disease. [31] The method of treating Alzheimer's disease by the concurrent administration of a

5-HT2A agonist and a NMDA antagonist to a patient suffering from this disease. [32] The use of a combination of a 5-HT2A agonist and a NMDA antagonist to treat

Alzheimer's disease. [33] The method of treating Down's syndrome by concurrently activating or stimulating 5-HT2A receptors and antagonizing NMDA receptors in the brain of a patient suffering from this disease. [34] The method of treating Down's syndrome by the concurrent administration of a

5-HT2A agonist and a NMDA antagonist to a patient suffering from this disease. [35] The use of a combination of a 5-HT2A agonist and a NMDA antagonist to treat

Down's syndrome. [36] The method of treating autism by concurrently activating or stimulating 5-HT2A receptors and antagonizing NMDA receptors in the brain of a patient suffering from this disease. [37] The method of treating autism by the concurrent administration of a 5-HT2A agonist and a NMDA antagonist to a patient suffering from this disease. [38] The use of a combination of a 5-HT2A agonist and a NMDA antagonist to treat autism. [39] The method of treating schizophrenia by concurrently activating or stimulating

5-HT2A receptors and antagonizing NMDA receptors in the brain of a patient suffering from this disease. [40] The method of treating schizophrenia by the concurrent administration of a

5-HT2A agonist and a NMDA antagonist to a patient suffering from this disease. [41] The use of a combination of a 5-HT2A agonist and a NMDA antagonist to treat schizophrenia. [42] The method of treating schizophrenia by antagonizing NMDA receptors in the brain of a patient suffering from this disease. [43] The method of treating schizophrenia by the administration of small, non- psychotomimetic or threshold doses of a NMDA antagonist to a patient suffering from this disease. [44] The use of a NMDA antagonist in small, non-psychotomimetic or threshold doses to treat schizophrenia.

[45] The method of improving the cognitive abilities of a human being by antagonizing NMDA receptors in the human brain.

[46] The method of improving the cognitive abilities of a human being by the administration of small, non-psychotomimetic doses of a NMDA antagonist to a human being.

[47] The use of a NMDA antagonist in small, non-psychotomimetic doses to improve human cognitive abilities.

[48] All claims of patent US 5,902,815 using hallucinogenic instead of non- hallucinogenic 5-HT2A agonists.

[49] The use of a combination of a 5-HT2A agonist and a NMDA antagonist as a safe, non-harmful replacement for drugs of abuse.