GRANT INFORMATION

[0001] The research has in part been supported by a grant from the Swiss Science National Foundation (nr. 32003B_185111) to Matthias Liechti.

BACKGROUND OF THE INVENTION

1. TECHNICAL FIELD

[0002] The present invention relates to the use of mescaline and mescaline analogs or derivatives to induce a psychedelic state and assisting psychotherapy and treating medical condition.

2. BACKGROUND ART

[0003] Hallucinogens or psychedelics are substances capable of inducing exceptional subjective effects such as a dream-like alteration of consciousness, pronounced affective changes, enhanced introspective abilities, visual imagery, pseudo-hallucinations, synesthesia, mystical-type experiences, and experiences of ego dissolution (1-3).

[0004] Efficacy of psychedelics for the treatment of medical conditions has been shown in clinical trials using lysergic acid diethylamide (LSD) and in patients with addiction (4), in patients with anxiety associated with life-threatening illness (5, 6), and using psilocybin in patients with major depression (7-11), anxiety disorder or anxiety associated with terminal illness (9, 10, 12), and in different forms of addiction (13-18). There is also evidence that the psychedelic brew Ayahuasca, which contains the active psychedelic substance /V,A/-dimethyltryptamine (DMT) (19) may alleviate depression (20-22). In contrast, there are no therapeutic trials or elaborated scientific concepts regarding the use of the psychedelic substance mescaline (3,4,5- trimethoxyphenethylamine) in the treatment of medical conditions.

[0005] Psychedelics such as psilocybin and LSD can be used to assist psychotherapy for many indications including anxiety, depression, addiction, personality disorder, and others, and can also be used to treat other medical disorders such as cluster headache and migraine and others. Although no psychedelic is currently licensed for medical use, psilocybin and LSD are used already experimentally within clinical trials and special therapeutic (compassionate use) programs (4, 5, 9, 10, 12, 17, 18, 23, 24). There is no comparable therapeutic use of mescaline. [0006] Additionally, existing psychedelic treatments such as LSD, psilocybin, and DMT may not be suitable to be used in all patients suited for psychedelic-assisted therapy. The availability of several substances including novel ones with different properties is important and the present lack thereof is a therapeutic problem which will further increase with more patients needing psychedelic-assisted therapy and an increase in demand for such treatment once the efficacy of first treatments (psilocybin and LSD) will be documented in large clinical studies. For example, some patients may react with strong adverse responses to existing therapies such as psilocybin presenting with untoward effects including headaches, nausea/vomiting, anxiety, cardiovascular stimulation, or marked dysphoria. In such patients, mescaline is useful as alterative treatment to the psychedelic that produced adverse responses. In some patients, mescaline can also be useful because another experience than made with psilocybin or LSD is necessary or because a patient is not suited for therapy with these existing approaches a priori. Thus, mescaline and its derivatives can serve as alternative treatment options with characteristics sufficiently similar to other psychedelics to be therapeutic but also sufficiently different to provide added benefits or avoid negative effects of other psychedelics.

[0007] Mescaline was described early as being useful in psychiatric research to help with the discovery of the ethology of psychoses (25) and as “means to better understanding madness or the human mind” (26). A use as therapeutic tool was also mentioned (27). Several older case reports or case series were reported.

[0008] Mescaline was studied in schizophrenic patients and found to “markedly aggravate their mental symptomatology” and to induce a “disorganization of the psychic integration” in both schizophrenics and normal subjects (28). A dose of “0.5 grams of mescaline was noted to usually suffice to evoke hallucinatory an affective responses in most subjects” (27). Turns and Denber described the use of mescaline in two patients (29). One patient was diagnosed with schizophrenia, one with severe depression. Both were considered resistant to standard pharmacological treatment. Mescaline was administered weekly in doses of 500 mg orally in one and intravenously in the other patient. The sessions were terminated with administration of chlorpromazine intravenously. The patient with schizophrenia received 8 mescaline treatments and the patient with depression received 12 treatments. The patient with depression reportedly improved. Both patients reportedly benefited from effects of mescaline “to accelerate/promote psychotherapy” (29). Smith reported the use of mescaline in the treatment of alcoholism in a case series (30). Doses of 0.5 grams were used in seven patients in conjunction with psychotherapy. There was no control group or statistical analysis of the data. Favorable responses were reported but it was not possible to define the effect of mescaline separate from the psychotherapy (30). Use of mescaline “drug-induced states” as an aid in psychotherapy has also described in a case report by the psychiatrist Walter Frederking (31). A case of successful treatment with mescaline and psychotherapy for erectile dysfunction and a marriage improvement were described. The psychiatrist noted that mescaline (300-500 mg sulfate intramuscularly) was more intense and overpowering than LSD tartrate (30-60 pg orally) and more difficult to dose and that LSD had a broader spectrum in its physical effects (31). No systematic use descriptions of mescaline for specific diseases or indications have been reported and the dosing definitions are lacking.

[0009] Buchanan reported on the religious use in its publication on the “Meskalinrausch” in 1929 (32). He noted that “the sacred ritual of the eating of peyote occupies a period of about twelve to fourteen hours.” The Indians regard mescal as a panacea in medicine, as a source of inspiration and a key which opens to them the glories of another world” (32). In 1896, Heffter extracted mescaline from mescal. Mescaline was reported to have effects on the cardiovascular system including “slowing of the heart rate and a rise in systolic pressure”. However, respiratory and cardiac depressing effects were also noted (32) and solid data on the cardiovascular effect profile of defined doses have been lacking and were generated within this invention. Early reports on the acute effects of mescaline were compiled and published by (32). For example, Prentiss and Morgan (1885) cited in (32) reported that Ί could see all sorts of design in brilliant and ever-changing colors. ”...”My mind was perfectly clear and active”...and “I truly thought that I had experienced great pleasure upon many previous occasions, but the experience of this was one quite unique in this regard in the history of a lifetime” (32). Mitchell, cited in (32), reported “I had a certain sense of the things about me as having a more positive existence than usual. It is not easy to define what I meant, and at the time I searched my vocabulary for phrases or word which should fitly state my feeling. It was in vain.” It is noted that “subjects forget themselves and place and time become dominated by a feeling of absolute timelessness. There is a feeling of monumental existence, a sphinxlike experience” (32). These citations illustrate that mescaline has previously been reported to induce positive and unique experiences in humans that are difficult to describe with words.

[00010] Mescaline was the first hallucinogen used in psychiatric research, however, not as treatment but as a tool to mimic and study psychosis (33-35). These are also early scientific descriptions of the acute alterations of mind induced by psychedelics. There have been several descriptions of the mescaline effects but (25, 33, 36-39) but only few more modern studies (40, 41) on the effects of mescaline in humans. There are no contemporary studies using modern scientific psychometric methods.

[00011] In past studies in healthy subjects, effects of mescaline were compared with those of placebo and the 3,4-methylendioxymethamphetamine (MDMA)-like substance MDEA in the 1990ies (40, 41), but a modern and methodologically valid comparison with other psychedelics like LSD and psilocybin that are currently being used in patients is lacking.

[00012] There was an older study that directly compared mescaline (5mg/kg), psilocybin (0.15 mg/kg), and LSD (0.01 mg/kg) in 18 subjects (36). The substances generally produced similar effects and were considered to have been equivalent regarding their overall acute effects. However, at the dose used, mescaline tended to produce more pronounced effects than psilocybin or LSD including a higher proportion of subjects with perceptual changes and nausea as well as other adverse effects. Detailed data is not available.

[00013] Another study compared mescaline (5mg/kg), psilocybin (0.225 mg/kg) and LSD 0.015 mg/kg) and even a combination of all three drugs using one-third doses of each in 24 healthy male subjects (42). Mood effects were reported to be alike for all four treatments but, surprisingly, no perceptual or psychic effects or typical psychedelic-like effects (synesthesia, disturbed perception) were evaluated and reported (42) possibly because of the use of inappropriate methods including non-sensitive psychometric instruments.

[00014] Another old study found that subjects could not distinguish between the substances (37).

[00015] An experimenter compared in a self-study oral LSD (100 pg) with mescaline (350 mg subcutaneously) with a focus on drawing pictures of faces. LSD was reported to produce symptoms of psychopathology of the hebephrenic type while mescaline was reported to produce more catatonic type effects and more dysphoria than LSD (43).

[00016] There are no previously well-tested or well-defined medico-therapeutic uses of mescaline. One study administered mescaline to schizophrenic patients and found that mental symptoms were markedly aggravated (28). Visual hallucinations were noted to be less frequent after LSD than after mescaline indicating differences between the two (28). However, this was not documented using valid psychometric instruments.

[00017] Another preliminary study used a double-blind administration of mescaline 500 mg, psilocybin 10 mg and LSD 70 pg. Mescaline produced the most alterations in all examinations but no statistical evaluations were performed (44). The dose of mescaline was high compared to the low dose of psilocybin and thus this study did not compare equivalent doses.

[00018] An early study compared the effects of mescaline, psilocybin and LSD administered intramuscularly in humans (37). The study found similarities regarding subjective and autonomic effects and reported differences in the time courses of the three substances. Unlike contemporary research and the present invention that use oral administration, intramuscular administration of the substance was used.

[00019] In a study that could be considered more modern, Herme administered mescaline at a dose of 500 mg or mescaline-sulfate to 12 healthy male subjects. The study also used a former and already validated version of the present 5D-ASC scale called the APZ (altered states of consciousness) scale to assess the acute effects of mescaline (40). Due to differences in molecular weights, the dose of 500 mg mescaline sulfate used by Herme (40) would correspond to a dose of approximately 406 mg mescaline hydrochloride used to generate data for the present invention. Mescaline induced a state of altered consciousness with increased ratings of oceanic boundlessness (OB or OSE), anxious ego-dissolution (AEG or AIA), and visionary restructuralization (VR or VUS) in the APZ scale. An indirect comparison with the effects of the MDMA-like empathogen MDE in 14 healthy subjects showed greater average APZ scores after mescaline compared with MDE (OSE: 6.2 vs. 3.9; AIA 7.1 vs. 2.6; VUS 7.4 vs. 1.6) including mainly relatively greater anxious ego-dissolution and perceptual alterations for mescaline compared with MDE. This pattern is very broadly similar to the comparison of the psychedelic LSD with the MDMA (OB 43 vs. 9.3; AED 26 vs. 1 .3; VR 50 vs. 4.1) (45) and confirming stronger and greater perceptual effects of serotonergic psychedelics compared with empatogenic MDMA- like substances also used in substance-assisted therapy (23). Importantly, the study by Hermle used only one dose of mescaline without a direct comparison with other psychedelics and focused on imaging data (40) and not on the acute subjective and cardiovascular adverse effects relevant within the present invention.

[00020] There is no modern data on the clinical pharmacology of mescaline. An early study used C14-labeled mescaline to study the metabolism of mescaline in twelve healthy male subjects using a total dose of mescaline hydrochloride of 500 mg orally (46). Blood, urine and spinal fluid was collected repeatedly after mescaline administration. The half-life of the radioactivity ingested as mescaline was approximately six hours and 87% of the radioactivity administered was excreted within 24 hours and 92% within 48h. Mescaline was mainly excreted in urine as unchanged mescaline (55-60%). The main metabolite was 3,4,5- trimethoxyphenylacetic acid (TMPA, 27-30%). Minor metabolites were N-acetyl-(3,4,dimethoxy- 5-hydroxyphenylethalymine (5%), another O-demethylated phenylacetic acid (HMPA, 1%) and N-acetyl-mescaline (NAM, 0.1%) and others (10%). The metabolites TMPA and NAM were also produced and administered to humans and were found not to have psychoactive or cardiostimulant properties (46). Taken together, mescaline was eliminated mainly unchanged or as inactive TMPA. Subjective effects appeared within 30 min, peaked at 4 hours and lasted 12- 14 hours. There was a delay in the peak effect of the subjective response compared with the plasma peak by about 2 hours (46). A more systematic test of the duration of action in comparison with other substances with a similar action is lacking. [00021] Phase 1 studies on mescaline with a focus on maximal tolerated dose finding and safety are lacking. Acute overdoses produce mainly a sympathomimetic toxidrome (47). A retrospective review of the California poison center database search for the years 1997-2008 found 31 exposures to peyote plants (29 cases) or mescaline (only two cases). Commonly reported effects were hallucinations, tachycardia, and agitation (48). Clinical effects were usually mild or moderate, and life-threatening toxicity was not reported in this case series (48). Treatment included sedatives or was supportive only. Similar to other psychedelics, mescaline has no abuse-related rewarding effects in rodent tests (49). There was no evidence of psychological or cognitive deficits among Native Americans using peyote regularly in a religious setting (50).

[00022] Interest in mescaline is ongoing with a focus on preclinical studies (51-54) but no studies in humans.

[00023] Although mescaline is long-known psychedelic with a history of spiritual use, information on its effects in human is scarce and old, and there is no state of the art modern scientific data on the effects of mescaline in humans or a systematic evaluation of its potential use as a therapeutic.

[00024] Acute psychedelic states relevant for therapeutic use and induced by psilocybin and LSD have been very well-characterized in modern research studies (1 , 3, 7, 9, 10, 45, 55- 59). However, no such data has been available on mescaline (51).

[00025] Psychedelic substances produce their characteristic acute effects in humans via activation of the serotonin 5-HT2A receptor as specifically shown in clinical studies for psilocybin and LSD (3, 60, 61). All serotonergic psychedelics including LSD, psilocybin, DMT, and mescaline are agonists at the 5-HT2A receptor (62) and may therefore produce overall largely similar effects. However, such confirming modern studies that directly compare acute effect profiles of different substances are lacking.

[00026] Positive acute subjective psychedelic experiences after administration of psilocybin are correlated with its long-term therapeutic benefits in patients with depression or addiction (7, 9, 15). This means that the acute effects of a serotonergic psychedelic in humans can be used to predict, at least in part, the therapeutic outcome in patients. Acute effects that may contribute to positive long-term effects of psychedelics including mescaline are effects that are thought to enhance the therapeutic relationship including increased openness, trust, feelings of connectedness or emulsion with persons, insight in psychological problems and stimulation of neuroregenerative processes as described in detail elsewhere (63).

[00027] There remains a need for studies showing that mescaline can produce acute subjective effects in an individual that are sufficiently similar to those of therapeutically used psychedelics and predict therapeutic use of mescaline and mescaline derivatives as well as a need for effective psychedelic treatments. The acute effects of mescaline have not been validly described and shown to be similar to psychedelics with therapeutic use. Additionally, there is a need for defining characteristics of mescaline different from already therapeutically used psychedelics and needed in some patients such as effects that are longer-lasting, different in quality and potentially more suitable than existing substances in some patients and complementing or substituting existing substances.

SUMMARY OF THE INVENTION

[00028] The present invention provides for a method of inducing psychedelic states in an individual, by administering mescaline, a salt thereof, analogs thereof, or derivatives thereof to the individual, and inducing a psychedelic state in the individual.

[00029] The present invention provides for a method of therapy, by administering an intermediate “good effect dose” of mescaline, salt of mescaline, analogs thereof, or derivatives thereof to an individual, and inducing positive acute drug effects that are known to be associated with more positive long-term responses in psychiatric patients.

[00030] The present invention provides for a method of therapy, by administering an “ego- dissolution” dose of mescaline, a salt of mescaline, analogs thereof, or derivatives thereof to an individual, and providing the experience of ego-dissolution.

DESCRIPTION OF THE DRAWINGS

[00031] Other advantages of the present invention are readily appreciated as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings wherein:

[00032] FIGURE 1 is a drawing of the chemical structure of mescaline and of possible derivatives (sealines, 3C sealines);

[00033] FIGURE 2 is a table showing 5-FIT receptor agonist activity of mescaline, psilocin (active metabolite of psilocybin), and LSD;

[00034] FIGURE 3 is a table showing adrenergic and dopaminergic receptor binding affinity of mescaline, psilocin, and LSD;

[00035] FIGURES 4A-4H are graphs of the acute subjective effects of mescaline compared with psilocybin and LSD, showing any drug effect (4A), good drug effect (4B), bad drug effect (4C), stimulated (4D), anxiety (4E), nausea (4F), visual perception change (4G), and auditory perception change (4H);

[00036] FIGURES 5A-5FI are graphs of additional acute subjective effects of mescaline compared with psilocybin and LSD, showing sounds influenced what I saw (5A), changed time perception (5B), ego dissolution (5C), gained insight (5D), talkative (5E), open (5F), trust (5G), and focus (5H);

[00037] FIGURES 6A-6B are graphs of the acute alterations of mind induced by mescaline and compared with psilocybin and LSD, with FIGURE 6A showing six parameters, and FIGURE 6B showing additional parameters; and

[00038] FIGURES 7A-7D are graphs of the acute cardiovascular effects of mescaline compared with psilocybin and LSD, showing systolic blood pressure (7A), diastolic blood pressure (7B), heart rate (7C), and body temperature (7D).

DETAILED DESCRIPTION OF THE INVENTION [00039] The present invention provides for a method of inducing psychedelic states by administering mescaline, a salt thereof, analogs thereof, or derivatives thereof in a controlled medical/psychological setting to an individual and inducing a psychedelic state for treating various medical conditions. Mind alterations can be induced with the compositions herein for treating medical disorders similar to other psychedelics but with fewer unwanted side effects as described below.

[00040] The structure of mescaline and possible sites of chemical modification leading to analogs or derivatives of mescaline are shown in FIGURE 1. In the compound of FIGURE 1 , R is hydrogen, methyl, or ethyl, and

[00041] R’ is

[00042] C1-C5 branched or unbranched alkyl with the alkyl optionally substituted with Fi-

F5 fluorine substituents up to a fully fluorinated alkyl,

[00043] C3-C6 cycloalkyl optionally and independently substituted with one or more substituents such as F1-F5 fluorine and/or Ci - C2 alkyl,

[00044] (C3-C6 cycloalkyl)-Ci-C2 branched or unbranched alkyl optionally substituted with one or more substituents such as F1-F5 fluorine and/or C1-C2 alkyl, or

[00045] C2-C5 branched or unbranched alkenyl with E or Z vinylic, cis or trans allylic, E or

Z allylic or other double bond position in relation to the attached ether function, where any of the carbons of the branched or unbranched alkenyl substituent is optionally substituted independently with one or more C1-C2 alkyl, with F1-F5 fluorine or with D1-D5 deuteron substituents.

[00046] The mescaline is synthetic or a comparable plant-derived purified extract. The mescaline can be mescaline hydrochloride as shown in the EXAMPLES, or any other salt thereof. [00047] Mescaline can be used in doses from 1-800 mg. Specific doses can be used to provide different effects, which are further described in EXAMPLE 2. For example, a micro dose of mescaline can be 1 -100 mg, a dose of 200 mg can be a low dose, a dose of 300-400 mg can be a moderate to medium-high dose, a dose of 500 can be a medium to high dose, and a dose of 800 mg can be a high to very-high dose. More specifically, and as further described below, a micro dose (1-100 mg) can induce no to minimal subjective effects and is equivalent to < 20 pg of LSD base, a low dose (100-200 mg) can induce mild psychedelic effects and is equivalent to 20-40 pg of LSD, a moderate to medium dose (300-400 mg) can induce a moderate to medium strong psychedelic experience with mainly positive drug effects and is equivalent to 60-80 pg of LSD, a medium to high dose (500 mg) is equivalent to 100 pg of LSD base and induces a full “good effect” psychedelic response with mainly positive drug effects and moderate ego- dissolution and a moderate risk of producing anxiety, and a high dose (800 mg) is equivalent to 150-200 pg of LSD base and induces a full and very strong psychedelic response including marked “ego-dissolution” and has a high risk of producing anxiety.

[00048] Therefore, the present invention provides for a method of dosing and treating patients with mescaline, by administering mescaline, an analog thereof, or a derivative thereof at a specific dose defined as a micro dose, low dose, moderate dose, medium-high dose, high dose, or very high dose and producing positive subjective acute effects that are known to be associated with more positive long-term outcomes and minimizing negative acute effects. [00049] The psychoactive properties of the serotonergic hallucinogen mescaline have likely been familiar to indigenous American tribes for more than 5000 years (51 , 64, 65). Mescaline is a widespread cactus alkaloid found in particularly high concentrations in the buttons of the peyote cactus ( Lophophora williamsii) and the San Pedro cactus ( Trichocereus pachanoi). Its psychoactive effects were scientifically discovered over more than a century ago by Arthur Heffter (66).

[00050] The use of mescaline within the present invention is distinct from the traditional religious/ritual use (Navajo, Native American Church of North America or shamanic uses in Latin America) of plants (peyote, San Pedro cactus, or related plants (67)) containing mescaline and with the purpose of mescaline to act as “entheogen” or “pant teacher” or “access to the divine” or “realms of Spirit” or as spiritual or cognitive tool to enhance spiritual experiences and embedded in a religious context (68, 69). In such a church/religious context, peyote has been or may still be effectively used in peyotists with drinking problems and has been considered to be safe (48, 50, 70). Other reported applications by Native Americans included rather poorly defined uses as a healing tool for snakebites, burns, wounds, fever, or “strength in walking” and others (48). Although, potentially prior therapeutic use, this use of plant mescaline is certainly not a medical treatment as the specified use of pharmaceutical mescaline in psychotherapy defined in the present invention.

[00051] Early reports of mescaline use did not represent clinical experimental studies and did not use valid control conditions, blinding, randomization, exact dosing, or outcome assessments using valid methods in contrast to the studies reported as part of the present invention (EXAMPLES 1 and 2).

[00052] The present invention includes the description of a clinical study comparing the acute effects of a defined oral dose of mescaline hydrochloride with those of psilocybin, LSD, and placebo as well as a dose-response study of EXAMPLE 1. The present invention newly documents an overall similar acute positive subjective drug effect profile for mescaline compared with psilocybin and LSD. The psychedelic effect profile induced by mescaline in the present study and overall similar to that induced by LSD or psilocybin is known to be predictive of therapeutic beneficial long-term effects not only in patients but also in healthy persons (7, 15, 56, 58, 71 , 72). Thus, the present invention also describes a method of using mescaline in healthy subjects to derive positive acute effect profiles as shown in healthy subjects in the present study and known to be correlated with beneficial long-term effects and thus resulting in therapeutic effects in patients. Some of these effects including enhanced feelings of openness, trust, and gained insight were documented for mescaline in the present invention.

[00053] The present invention also provides for a method of inducing a psychedelic state in an individual that is longer-lasting than that induced by psilocybin and exhibiting partly different adverse effects and is therefore different in quality and potentially more suitable than existing substances in some patients and complementing or substituting existing substances. As EXAMPLE 1 shows, effects of mescaline were similar to those of psilocybin and LSD but typically longer lasting and with a lower and attenuated peak response at the doses used. Higher doses of mescaline can be used to reach similar peak effect as with psilocybin and LSD with a longer duration of action.

[00054] Psychedelics can be used to assist psychotherapy typically at acutely psychoactive doses and doses, for many indications including anxiety, depression, addiction, personality disorder, and others and can also be used to treat other disorders such as cluster headache, migraine, and others (1 , 2, 4, 9, 10, 13, 14, 17, 18, 73, 74). Psychedelic-assisted psychotherapy includes a defined process distinct from using psychedelics as recreational substances or within a religious context. Patients meet with therapists for several preparatory sessions, then the psychedelic is administered once or twice, typically a few weeks apart, and integration sessions are conducted after sessions (63). Thus, mescaline within the present invention is to be used similarly to be effective.

[00055] Similar to the use of other psychedelics to assist psychotherapy, relatively high doses of mescaline that are expected to induce a psychedelic response are used within the present invention and the studies testing it in human subjects in EXAMPLES 1 and 2.

[00056] The induction of an overall positive acute response to the psychedelic is critical because several studies showed that a more positive experience is predictive of a greater therapeutic long-term effect of the psychedelic (9, 10, 15). Even in healthy subjects, positive acute responses to psychedelics including LSD have been shown to be linked to more positive long-term effects on well-being (75, 76).

[00057] The present invention tests one moderate dose of mescaline of 300 mg in human subjects in EXAMPLE 1 and in comparison, with psilocybin and LSD with the aim of inducing a positively experienced psychedelic state.

[00058] A higher dose of 500 mg can be used in an extension of EXAMPLE 1 and also in comparison with psilocybin and LSD using the same design as study EXAMPLE 1.

[00059] Second, lower and higher doses of mescaline are tested to further characterize the ideal dose of mescaline aiming for a maximum of positive over negative acute effects and an optimized psychedelic response (in study 2 in EXAMPLE 2).

[00060] Third, the use of mescaline compared to other substances within the present invention aims at having an additional substance at hand in patients who did not respond adequately to other substances which could include a response that was too low or too high or adverse and necessitating a change in substance to be used. This is a common approach in medicine where often a medication within a class of medications that resulted in negative effects or an insufficient response is replaced by another medication from the same class. Similarly, the present invention replaces psilocybin or LSD with mescaline in psychedelic-assisted therapy if needed.

[00061] Mescaline is a classic serotonergic psychedelic. However, chemically, mescaline is a phenethylamine unlike LSD and psilocybin. Pharmacologically, LSD, psilocybin and mescaline are all thought to induce their subjective psychedelic effects primarily via their common stimulation of the 5-HT2A receptor. However, there are differences in the receptor activation profiles between the substances that may induce different subjective effects. LSD potently stimulates the 5-HT2A receptor but also 5-HT2B/C, 5-HTI and D1-3 receptors (Figure 2). Psilocin (the active metabolite present in the human body derived from the prodrug psilocybin) also stimulates the 5-HT2A receptor but additionally inhibits the 5-HT transporter (SERT). Mescaline binds in a similar rather low concentration range to 5-HΪ2A, 5-HTIA and 02A receptors (Figure 2-3). In contrast to LSD, psilocybin and mescaline show no affinity for D2 receptors (Figure 3). While mescaline does not directly interact with dopamine receptors (62) there is conflicting older data on potential dopaminergic effects. Effects in cats could be antagonized with the dopamine antagonist haloperidol (77). In contrast and as expected, mescaline generalized to LSD and psilocybin and other serotonergic hallucinogens in rat discrimination studies and this effect could be antagonized with 5-HΪ2A receptor blockers but not dopamine receptor blockers including haloperidol (78). Enhancement of acoustic startle by mescaline in rats was blocked by serotonin 5-HT2 receptor antagonists but not by a 5-HTi antagonist (79). Mescaline blocked the action of catecholamines potentially in line with its interaction with the adrenergic alpha2 receptor (80). However, the adrenergic properties and effects in comparison with other psychedelics are not clear. Antipsychotics with antagonistic effects on serotonin 5- HT2A and dopamine receptors blocked acute responses to mescaline in psychiatric patients (81 ). However, the study is methodologically invalid to derive conclusions.

[00062] Taken together, LSD can have greater dopaminergic activity than psilocybin and mescaline, psilocybin may have additional action at the SERT. Mescaline and derivatives do not interact with the SERT.

[00063] Furthermore, there can also be differences in the activation of the intracellular second-messenger pathways produced by different 5-HT2A receptor agonists which could also result in differential effects of different psychedelics. Thus, mescaline can also have different effects compared with LSD or psilocybin base on such yet now well-defined differences down stream activation patterns (54, 82). Finally, there can also be differences in brain wide circuit activations and neuronal activation patterns as to be further defined in future optogenetics and/or brain imaging studies that can show distinct properties of different serotonergic compounds including mescaline compared with LSD and psilocybin (83).

[00064] Within the present invention, the clinical study (EXAMPLE 1) tested whether similarities and differences in the pharmacological profiles of mescaline, psilocybin and LSD in vitro translate into similar and/or different subjective effects in humans. Because the primary action of all these hallucinogens is the activation of the 5-HT2A receptor and based on preliminary data (36), there are likely not marked differences in the subjective alterations of consciousness acutely induced by these substances making them all suitable as psychedelic therapeutics. Nevertheless, there are differences in the binding potencies of the three substances at their primary target. Therefore, it was expected to document small differences that would translate into advantages of one substance over the other in selected clinical situations. For example, psilocybin interacts with the SERT, while mescaline does not (62). Because serotonin is involved with hyperthermia and MDMA, which also interacts with the SERT (84) can induce fatal hyperpyrexia (85), psilocybin can also lead to greater thermogenic responses compared with mescaline in humans. Indeed, the present invention (Example 1) showed reduced thermogenic effects of mescaline compared to psilocybin.

[00065] LSD binds most potently to the 5-HΪ2A receptor followed by psilocybin and mescaline (62) (FIGURE 2). Mescaline is the least potent of all classic hallucinogens. It is about 1000 - 3000 times less potent than LSD and around 30 times less potent than psilocybin (86) consistent with in vitro data (62) (FIGURE 2). The binding potency of hallucinogens in vitro correlates with their potency to acutely induce alterations of subjective effects in humans (87). Importantly, mescaline has very strong hallucinogenic properties in humans despite its low potency at the 5-HT2A receptor (51) but relatively high doses are needed to produce subjective responses. Additionally, there are differences in the duration of the effects among these psychedelics. Mescaline can have a delayed onset of action possibly due to a slow brain penetration (88). The subjective effect duration of a moderate mescaline dose is 10-12 hours, therefore similar to that of a moderate dose (0.1 mg) of LSD and exceeding the duration of acute psilocybin effects (4-6 hours) (86). These previously documented preliminary effect duration times for the individual substances were tested within the present invention using a valid modern clinical study directly comparing the effects of the three substances in the same subjects and using sensitive measures.

[00066] Taken together the pharmacological profiles of LSD, psilocybin and mescaline show some differences but it is not clear whether these are reflected by differences in their psychoactive profiles in humans. Furthermore, mescaline has an old tradition of use but has not been compared with the more recently investigated psychedelics LSD and psilocybin and its therapeutic use potential has not been defined (51).

[00067] The compounds of the present invention can be used in assisting psychotherapy or treatment for many different indications, including anxiety disorder, anxiety associated with life-threatening illness, depression, addiction including substance use disorder and impulse control disorder (behavioral addiction), personality disorder, compulsive-obsessive disorder, post-traumatic stress disorder, eating disorder, cluster headache, migraine, and any other disorder where psychedelic psychotherapy or therapy can be useful.

[00068] The compounds of the present invention can be used when the individual has an insufficient therapeutic response or adverse effects after the use of other psychedelics substances and the methods herein can be used as a second-line treatment. The compounds of the present invention can be used when the individual has a need for a qualitatively different psychedelic response after the use of other psychedelics substances and the method can be used as an alternative treatment option. The individual can have a need for a more attenuated response, with a slower onset of the psychological, or physiological response of the psychedelic (attenuated and prolonged response) compared with other psychedelics such as psilocybin or LSD and the inducing step provides an effect of less nausea and vomiting than psilocybin, less cardiovascular stimulation than psilocybin, reduced thermogenic acute effects compared with psilocybin, less bad drug effects including anxiety, fewer or less intensive headaches than psilocybin, an overall slow and attenuated effect onset compared with psilocybin, reduced peak response at longer effect duration and overall effect than comparable treatment options such as psilocybin, an overall intensive subjective experience while exhibiting a favorable acute adverse effects profile, and/or combinations thereof.

[00069] Inducing a psychedelic state with the compounds of the present invention can reduce the risk of nausea or vomiting within a psychedelic treatment session, reduce the risk of cardiovascular stimulation within a psychedelics treatment session, or increase feelings of trust and openness beneficial in enhancing the therapeutic alliance and catalyze the effects of psychotherapy for any indication. Inducing a psychedelic state can also produce an inward oriented focus of attention and subjective insight to enhance psychotherapy for any indication, or induce neuroregenerative processes beneficial in medical conditions such as, but not limited to, Alzheimer’s disease, dementia, predementia, or Parkinson’s disease.

[00070] The present invention provides for a method of therapy, by administering an intermediate “good effect dose” of mescaline, salt of mescaline, analogs thereof, or derivatives thereof to an individual, and inducing positive acute drug effects that are known to be associated with more positive long-term responses in psychiatric patients. This is further described in EXAMPLE 2.

[00071] The present invention provides for a method of therapy, by administering an “ego- dissolution” dose of mescaline, a salt of mescaline, analogs thereof, or derivatives thereof to an individual, and providing the experience of ego-dissolution. This is further described in EXAMPLE 2.

[00072] Throughout this application, various publications, including United States patents, are referenced by author and year and patents by number. Full citations for the publications are listed below. The disclosures of these publications and patents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains. [00073] The invention has been described in an illustrative manner, and it is to be understood that the terminology, which has been used is intended to be in the nature of words of description rather than of limitation.

[00074] Obviously, many modifications and variations of the present invention are possible in light of the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention can be practiced otherwise than as specifically described.

[00075] EXAMPLE 1 : Clinical Study I: Direct within-subject comparison of acute effects of single oral doses of mescaline (300 mg), psilocybin (20 mg), and LSD (100 pg) in healthy subjects

[00076] The study directly compared the acute effects of single doses of three different classic hallucinogens using a cross-over design. The primary objective of this study was the comparison of the quality of subjectively altered states of consciousness induced by mescaline, psilocybin, and LSD. It was hypothesized that all three substances would induce similar psychedelic states measured using visual analog scales and the 5 dimensions of altered states questionnaire (5D-ASC). It was expected that mescaline would produce a state of altered consciousness lasting longer than after the administration of psilocybin. Some differential effects were expected regarding subjective effect qualities, autonomic responses, and adverse effects. [00077] Study design: The study used a randomized, double-blind, double-dummy, cross over design with four conditions.

[00078] Study intervention: Each subject participated in 4 x 25-hour study sessions. Conditions were 1 ) 100 pg LSD, 2) 20 mg psilocybin, 3) 300 mg mescaline and 4) placebo. Order was randomized and balanced with washout periods of at least 10 days between study days. [00079] LSD: LSD is a very potent partial 5-HT2A receptor agonist (62, 74). LSD also stimulates 5-HTi receptors, adrenergic CM receptors and dopaminergic Di receptors (62, 89). An intermediate dose of 100 pg was be used. A 100 pg dose induces intermediately strong and typical LSD effects in healthy subjects with peak responses at 3 hours and lasting for 8 hours (3, 45, 55, 90, 91).

[00080] Psilocybin: Psilocybin is a 5-HT2A receptor agonist and 5-HT transporter inhibitor. Most of the psilocybin effects are mediated by the 5-HT2A receptor (92) but psilocybin also activates the 5-HT system via 5-HT transporter inhibition (62) which can produce additional MDMA-like empathogenic effects. The present study used 20 mg of psilocybin, a dose that was previously used in healthy subjects with good tolerability (59, 93, 94). A similar dose has also been used in patients (8, 9, 74) Psilocybin has been used in similar experimental studies by several groups in human subjects (16, 17, 59, 94-96). It was expected that the 20 mg psilocybin dose would produce a similarly strong effects as the 100 pg dose of LSD.

[00081] Mescaline: Mescaline is a nonselective serotonin receptor agonist and binds to the 5-HΪ2A receptor which has ensured its categorization as a classic hallucinogen, although it does so with lower potency and higher activity compared to LSD (54, 62, 78). Unlike LSD and psilocybin, mescaline shows equally high affinity for 5-HTIA and adrenergic 02A receptors (51 , 97) and is not classified as an indolalkaloid, but as a phenethylamine, structurally resembling stimulants like amphetamine and catecholamines like norepinephrine and dopamine, which are involved in processes of both neurotransmission and neurotoxicity (98). Mescaline is 1000-3000 times less potent than LSD and around 30 times less potent than psilocybin, requiring a relatively high dose of about 300 mg to induce a full psychedelic experience (51 , 86). The psycho- pharmacological effects of mescaline are considered prototypical despite its stimulant-like chemical structure (86). Indigenous tribes across the northern and southern parts of America have used mescaline for centuries for ethnomedical purposes (50, 69, 70). Regular mescaline consumption due to these ceremonies has not been associated with significant harm, but some adverse effects like psychotic episodes and transient anxiety have been reported [Halpern, 2005 #5872).

[00082] Clinical studies on the effects of mescaline in man are scarce. There is no modern data. Physiological and psychological effects were reported to set in approximately 30 minutes after oral administration of 500 mg mescaline hydrochloride, to peak at 4 hours and to last 12 to 14 hours (46). The average half-life of mescaline is approximately six hours (46). Mescaline shows cross-tolerance with LSD in human studies (99, 100). Termed “psychotomimetic" in previous decades due to its similarity with acute psychotic states, mescaline provokes hallucinative, stuporous or paranoid appearances (39, 40, 101). It has been reported that LSD and mescaline tend to induce a wider synesthetic spectrum compared to psilocybin (102). Early studies indicate that LSD can elicit auditory-visual, music-visual, color-gustatory, color- auditory, and music-olfactory synesthesia (36, 101 , 103, 104), whereas mescaline is reportedly more likely to induce haptic-visual, auditory-visual, kinesthetic-visual, and algesic-color synesthesia (103, 105). Psilocybin on the other hand has only been shown to induce auditory- visual synesthesia (36, 106). Doses of 200-400 mg mescaline sulfate have been reported to induce hallucinations lasting for about 10-12 h (107). The oral dose used in this study (300 mg) has been described as a moderate dosage generating a full hallucinogenic experience (51 , 101) and is expected to induce acute subjective effects lasting up to 12 hours. It is assumed that the intensity of subjective effects caused by 300 mg of mescaline will correspond to the intensity of the moderate LSD and psilocybin doses used in this study. Adverse effects like psychotic episodes and transient anxiety due to depersonalization and derealization have been reported (50, 70). Adverse psychological effects following hallucinogen intoxication can be alleviated with talk-down strategies or, if necessary, benzodiazepines (108, 109). Mescaline provokes physiological effects similar to epinephrine and norepinephrine: Tachycardia, hypertension, increase in temperature, perspiration, nausea, dizziness, pupil dilation, tremor, restlessness, and dry mouth (39, 110). An analysis of 31 cases of mescaline consumers that were registered between 1997 and 2008 at the California Poison Control System database revealed that the most frequently reported effect was hallucinations, followed by tachycardia, agitation, and mydriasis (48). Interestingly, the frequently reported adverse effect of vomiting could not be confirmed in this study. The authors assumed that vomiting is more likely due to the bitter taste of the plant rather than actual gastric effects of mescaline (48). This hypothesis contradicts early investigations done in the 1930s, which reported the common occurrence of initial nausea after subcutaneous injection of 300 mg (101). Mescaline, just like all serotonergic hallucinogens, has been continuously reported neither to cause any physiological harm nor to trigger addictive behavior (59, 111). Furthermore, lifetime use of hallucinogens is not associated with increased mental health issues (112). It has been assumed that the abuse potential of the substance is very low due to bitter taste, nausea and low potency, resulting in a slow onset of subjective effects (86). On the contrary, it has been suggested that hallucinogens like mescaline can hold anti-addictive properties and that these substances might be safe and effective tools to support drug dependence recovery (113). The development of slow tolerance to repeated administration has been reported in animals (114).

[00083] Participants: The preliminary study sample shown and used herein in EXAMPLE 1 to illustrate and put into practice the present invention included healthy subjects (male and females). Inclusion criteria were: Age between 25 and 65 years old; Sufficient understanding of the German language; Understanding of procedures and risks associated with the study; Willing to adhere to the protocol and signing of the consent form; Willing to refrain from the consumption of illicit psychoactive substances during the study; Abstaining from xanthine-based liquids from the evenings prior to the study sessions to the end of the study days; Willing not to operate heavy machinery within 48 hours after substance administration; Willing to use double-barrier birth control throughout study participation; Body mass index between 18-29 kg/m2. Exclusion criteria were: Chronic or acute medical condition; Current or previous major psychiatric disorder; Psychotic disorder or bipolar disorder in first-degree relatives; Hypertension (>140/90 mmHg) or hypotension (SBP<85 mmHg); Hallucinogenic substance use (not including cannabis) more than 20 times or any time within the previous two months; Pregnancy or current breastfeeding; Participation in another clinical trial (currently or within the last 30 days); Use of medication that may interfere with the effects of the study medication; Tobacco smoking (>10 cigarettes/day); Consumption of alcoholic beverages (>20 drinks/week). Subjects were recruited via advertisement displayed on the website of the University of Basel. Mainly university students were included. Screening visits and sessions were performed in the Ambulatory Study Center, located in the Department of Clinical Research at the University Hospital of Basel. Screening procedure : Subjects were examined by a study physician. Basic health was ensured by general medical examination including medical history, physical examination, electrocardiogram, determination of body weight and blood chemistry and hematology analysis. Additionally, subjects were screened using a semi-structured clinical interview for DSM-V (115) to exclude those with a personal or first-degree relative axis I major psychiatric disorder (acute or past) or a history of drug dependence. Additionally, the ‘Self-screening Prodrome’ (116) was used to ensure early detection of psychotic tendencies. Axis I major psychiatric disorders also include addiction disorders. Informed consent: Subjects were informed about the study procedures and associated risks in advance through the written participant information.

[00084] Study procedures [00085] Psychometric assessment

[00086] Subjective Effects Questionnaire (Visual Analog Scales, VAS): VAS was repeatedly used to assess subjective alterations in consciousness overtime. Single scales were presented as 100 mm horizontal lines marked with “not at all” on the left and “extremely” on the right. The following VAS items were used: “any drug effect”, “good drug effect”, “bad drug effect”, “stimulated”, “anxiety”, “nausea”, “alteration of vision”, “alteration of hearing”, “sounds seem to influence what I see”, “alteration of sense of time”, “the boundaries between myself and my surroundings seem to blur (ego dissolution)”, “I am having insights into connections that previously puzzled me”, “talkative”, “open”, “trust”, and “insight”. Scales were administered before and repeatedly after substance administration.

[00087] 5-Dimensional Altered States of Consciousness (5D-ASC): The 5-dimensional Altered States of Consciousness (5D-ASC) Scale is a visual analog scale consisting of 94 items (117, 118). The instrument contains five main scales (FIGURE 6A) and 11 newer subscales (FIGURE 6B) assessing mood, anxiety, derealization, depersonalization, changes in perception, auditory alterations, and reduced vigilance. The scale is well-validated (118). The 5D-ASC scale was administered once at the end of the session and subjects were instructed to retrospectively rate peak alterations that have been experienced during the study session. Each item of the scale is scored on a 0-100 mm VAS. The attribution of the individual items to the subscales of the 5D-ASC was analyzed according to (117, 118) and as shown in FIGURES 6A-6B. The scale was be administered once at the end of each test session.

[00088] Autonomic measures: Blood pressure, heart rate, and body temperature were recorded at baseline and repeatedly throughout the session. Blood pressure (systolic and diastolic) and heart rate were measured with an automatic oscillometric device. Body temperature was measured with an ear thermometer.

[00089] Adverse effects (list of complaints): The list of complaints (LC) consists of 66 items offering a global score measuring physical and general discomfort (119). The LC list was administered 12 hours after administration of the drug with reference to complaints throughout the entire session.

[00090] The study included additional outcomes not discussed here.

[00091] Substance preparation and quality control: Mescaline was prepared as capsules containing 100 mg of analytically pure mescaline (ReseaChem GmbH, Burgdorf, Switzerland) and mannitol filler. Psilocybin was prepared as capsules containing 5 mg of analytically pure psilocybin (ReseaChem GmbH, Burgdorf, Switzerland) and mannitol filler. LSD was prepared as an oral solution containing 100 pg of analytically pure LSD (Lipomed AG, Arlesheim, Switzerland) in 1 ml of ethanol. All three substance formulations plus matching placebos were prepared by a GMP facility (Apotheke Dr. Hysek, Biel, Switzerland) according to GMP guidelines. LSD-placebo solutions consisted of only ethanol, psilocybin and mescaline-placebo capsules consisted of only mannitol. All placebos were prepared by the same GMP facility and looked identical to the verum preparations to ensure proper blinding. The study used a double dummy design which means that every patient received a psilocybin/mescaline placebo with the LSD verum, and an LSD placebo with the mescaline or psilocybin verum. Randomization, packaging, labelling, and quality control (QC) including stability tests were handled by the GMP facility. Subjects and study personnel involved in supervising the session were blinded to treatment order that was balanced.

[00092] Results of the clinical study I (Example 1)

[00093] A key goal of the present study as part of the present invention was to measure in humans the acute effects of mescaline that are considered to be predictive of therapeutic potential in patients.

[00094] Positive acute effects of a psychedelic on the 5D-ASC scale and other scales have previously been documented to correlate with beneficial therapeutic outcomes in patients. Specifically, psilocybin reduced alcohol or nicotine use or in dependent patients over months and positive outcomes were correlated with the intensity of positive acute mystical-type experiences that the subject reported (13, 15, 17). Improvements five weeks after psilocybin treatment of patients with treatment-resistant depression were predicted high ratings of acute effects of pleasurable ego-dissolution (OB) including feelings of bliss and unity and low scores of anxious ego-dissolution (AED) in the 5D-ASC questionnaire (7). Similarly, long-term symptom improvement in patients with anxiety and depression correlated with greater scores of acute mystical-type experiences (9, 10).

[00095] Taken together, acute alterations of self-processing, positively experienced self dissolution with feelings of connectedness or oneness with the world (similar to mystical-type experiences) have generally been associated with positive long-term treatment outcomes with the use of psychedelics in controlled settings. Positive long-term effects were even noted in healthy subjects after LSD or psilocybin use in a safe setting (75, 76).

[00096] The present invention, for the first time, demonstrated positive acute effects for mescaline that are very similar to those linked to positive long-term outcomes after LSD or psilocybin treatment in patients (63).

[00097] FIGURES 4A-4H show the acute subjective effects of psilocybin, LSD, mescaline, and placebo on the VAS (any drug effect, good drug effect, bad drug effect, stimulated) over the time of one session in six healthy volunteers. Effects of psilocybin lasted less long compared with LSD and mescaline (FIGURE 4A). Effects of LSD and mescaline lasted similarly long at the doses used (FIGURE 4A). Effects of mescaline took longer to peak compared to those of psilocybin and LSD and were lower than those of psilocybin and LSD at the doses used (FIGURES 4A and 4B). While the peak effect was greater after psilocybin and LSD compared with mescaline, the area under the effect over time curve was similar after psilocybin (higher Emax but shorter duration) and mescaline (lower Emax but longer duration) and greater after LSD (both high Emax and long time-of-action) at the doses used (FIGURES 4A and 4B).

[00098] Qualitative effect profiles were similar with all active substances having mostly positive (FIGURE 4B) over negative effects (FIGURES 4C and 4E). Bad drug effects were low, and peaks lower for LSD and mescaline compared with psilocybin (FIGURE 4C).

[00099] Both psilocybin and LSD produced greater stimulation than mescaline at the doses used (FIGURE 4D).

[000100] None of the substances produced relevant anxiety (FIGURE 4E).

[000101] Nausea was present with all substances in a few subjects and highest with psilocybin, followed by LSD and mescaline, which produced the lowest nausea ratings (FIGURE 4F).

[000102] Both visual (FIGURE 4G) and auditory (FIGURE 4H) perception were altered markedly and with highest ratings for psilocybin and LSD. Mescaline produced lower peak effects than both psilocybin and LSD (FIGURES 4G and 4H). Area under the effect-time curve values were similar for psilocybin and mescaline and greater for LSD. Thus, mescaline produced lower perceptual alterations but lasting longer compared with psilocybin (FIGURES 4G and 4H). [000103] All substances induced synesthesia as indicated by high ratings of “sounds influenced what I saw” with highest ratings after psilocybin and LSD and lower ratings after mescaline (FIGURE 5A).

[000104] Time perception was acutely altered by all substances with trends toward lower changes induced mescaline compared with LSD and indicating more attenuated changes and a greater presence in the “here and now” with mescaline) (FIGURE 5B).

[000105] Ego-dissolution was mostly increased by LSD and psilocybin with again lower ratings after administration of mescaline and rated on the VAS labeled “the border between me and my surroundings seemed to blur” (FIGURE 5C). Ego-dissolution is a typical phenomenon induced by full doses of psychedelic substances and indicating a full psychedelic experience. The ratings indicate that higher doses of mescaline than the one used (300 mg) can be used to induce a full peak psychedelic response (FIGURE 5C).

[000106] Gains in insight ratings were relatively similar across substances (FIGURE 5D). [000107] All substances also similarly tended to reduce talking during the first hours with mescaline producing the longest effect (FIGURE 5E).

[000108] Openness was increased with all substances with mescaline having the smallest peak effect but a longer lasting effect compared with psilocybin (FIGURE 5F).

[000109] Trust was similarly increased by all substances (FIGURE 5G).

[000110] Attention was oriented more inward during the session after administration of all substances (FIGURE 5H).

[000111] Taken together, effects of mescaline were similar to those of psilocybin and LSD but typically longer lasting and with a lower and attenuated peak response at the doses used. Higher doses of mescaline can be used to reach similar peak effect as with psilocybin and LSD with a longer duration of action. This is tested within the present invention by increasing the dose of mescaline from 300 mg to 500 mg in an additional cohort of healthy subjects while keeping the doses of psilocybin and LSD at the level used.

[000112] FIGURES 6A-6B show effects of psilocybin, LSD, mescaline, and placebo on the 5D-ASC scale. Data are mean ± SEM values from 6 subjects. Effects are peak responses of the substances retrospectively rated 12 hours after drug administration. At the doses used, mescaline (300 mg) produced approximately 50% of the total alterations of consciousness (total 3D-OAV score, FIGURE 6A) ratings observed with LSD (100 pg) or psilocybin (20 mg). LSD and psilocybin had equally strong overall peak effects (total 3D-OAV scores) at the doses used and produced overall similar score ratings on the different ASC sub-scores (FIGURES 6A and 6B). The overall relative effects of mescaline on the scale were similar but lower to those of LSD or psilocybin on the different dimensions of the scale and subscales. While not tested in the present study so far, a dose of 500-600 mg of mescaline, which is 1.67- to 2-fold as high as the dose used, is be expected to produce overall similar effects to LSD or psilocybin base on the present data. However, the 5D-ASC compared peak responses and the duration of the experience is longer with mescaline than with LSD or psilocybin.

[000113] FIGURES 7A-7D show the vital sign changes after administration of psilocybin, LSD, mescaline, and placebo. Data are “mean ± SEM” values from 6 subjects. All active substances produced only relatively moderate increases in blood pressure (FIGURES 7A and 7B) and heart rate (FIGURE 7C) compared with placebo. There were only minimal differences in the autonomic effects between active compounds. Psilocybin produces a more pronounced and shorter-lasting increase in blood pressure (FIGURES 7A and 7B) and body temperature (FIGURE 7D) than LSD or mescaline. Increases in blood pressure (FIGURES 7 A and 7B), heart rate (FIGURE 7C), and body temperature (FIGURE 7D) after mescaline tended to be attenuated compared with both psilocybin and LSD and tended to last longer than those of psilocybin and similar to LSD. Overall, effects of mescaline on heart rate tended to be lower than those of psilocybin and potentially also those of LSD at the doses used. However, more data is needed to confirm this finding with statistical tests.

[000114] Mescaline produced similar adverse effects and similar total LC scores to LSD and psilocybin on the LC and at the doses used. The mean total LC scores were 6.8, 5.4, 8.8, and 0.8 after psilocybin, LSD, mescaline, and placebo, respectively in six human volunteers. Thus, the overall tolerability of acute mescaline administration was overall similar to that of LSD or psilocybin.

[000115] EXAMPLE 2 (Study II): Clinical dose finding study using different single oral doses of mescaline hydrochloride in healthy subjects

[000116] The present invention also relates to the use of specific doses of mescaline to produce defined subjective drug effects in helping to treat medical conditions. Because no dose- response data was available on mescaline, the present invention also includes a dose-response study in healthy subjects to define acute effects of mescaline across different doses.

[000117] To define the doses of mescaline within the present invention a dose-finding or “dose response study” is being conducted in healthy human subjects. The study goal is to characterize the dose-response relationship in mescaline-induced altered states of consciousness. The study population consists of healthy subjects (male and female). The study design is double-blind, placebo-controlled, and cross-over. Mescaline is administered on the study days that are separated by at least 10 days in the following doses: 1) mescaline 100 mg, 2) mescaline 200 mg, 3) mescaline 400 mg, 4) mescaline 800 mg, and 5) placebo, in counterbalanced order. The primary endpoints are subjective effects (VAS, 5D-ASC) and tolerability (body temperature, blood pressure, heart rate, adverse effects). This study defines the doses of mescaline to induce alterations of consciousness and provides the amount of acute effect for each dose. This complements the study comparing mescaline at only one dose of 300 mg with LSD and psilocybin und provides a unique set of data to define the dose to be used in the present invention.

[000118] The dose-response study within the present invention provides for a method of dosing and treating patients with mescaline, by administering mescaline or an analog thereof at a specific dose defined below such as a micro dose, moderate dose, medium-high dose, high dose or very high dose and producing positive subjective acute effects that are known to be associated with more positive long-term outcomes and minimizing negative acute effects. Defined doses of the mescaline can be administered with specific acute effects defined for a dose and specific indications for defined doses of mescaline. The overall goal of the dose- response study within the present invention, using mescaline is to improve the “positive” over “negative acute subjective effect” response to this psychedelic. The method of mescaline dosing applies to indications where a positive experience after psychedelic use predicts the long-term effects such as in psychiatric disorders including (but not limited to) depression, anxiety, and addiction.

[000119] “Positive acute effects” as used herein refers primarily to an increase in subjective rating of “good drug effect” and may also include ratings of “drug liking”, “well-being”, “oceanic boundlessness”, “experience of unity”, “spiritual experience”, “blissful state”, “insightfulness”, any “mystical-type experience” and positively experienced “psychedelic effects”, and “aspects of ego-dissolution” if experienced without relevant anxiety.

[000120] “Negative acute effects” as used herein refers primarily to subjective ratings of “bad drug effect” and “anxiety” and “fear” and may additionally include increased ratings of “anxious ego-dissolution”, or descriptions of acute paranoia or states of panic an anxiety as observed by others.

[000121] The following dosing recommendations are defined within the present invention and will be further refined once more data becomes available. [000122] A “micro dose” is a dose of a psychedelic not producing distinct acute subjective drug effects compared with placebo and in line with (120, 121 ). A micro dose of mescaline is 1- 100 mg equivalent to 0.2-20 pg of LSD base. Such doses have no or minimal subjective acute effects but may have therapeutic effects in humans.

[000123] A dose of 200 mg of mescaline is a small dose that can be used as starting point in an individual with no experience or an expected high susceptibility or if a very small response is wanted in a patient. Such a small dose of 200 mg or even smaller doses (<200 mg) may also be useful when “micro dosing” is the goal and/or including repeated doses of mescaline that produce no or only minimal psychoactive effects. Such low doses may particularly be useful to treat disorders such as cluster headache or migraine with mescaline similar to the use of low doses of LSD in these disorders (122-127). A low or micro dose of mescaline is also useful when aiming to treat depression with a micro dose producing minimal acute effect but producing a therapeutic response similar as conceived for the use of low doses of other psychedelics in depression (128). A dose of mescaline hydrochloride of 200 mg is equivalent to 40 (25-50) pg of LSD.

[000124] A dose of mescaline of 300-400 mg is a moderate to medium-high dose useful in most cases as a starting dose or repeat dose in experienced persons and equivalent to doses of LSD of 60-80 (50-100) pg LSD base or 15-20 mg of psilocybin.

[000125] A dose of mescaline of 500 is a medium to high dose useful in patients with previous experience with a lower dose of mescaline or with experience with other psychedelics or in any patients where a very stronger effect is desired. This dose of 500 mg of mescaline would correspond to a dose of LSD of 100 pg of LSD base or 20 mg of psilocybin.

[000126] A dose of mescaline of 800 mg is a high to very-high dose useful in patients with previous experience with a lower dose of mescaline or with experience with other psychedelics or in any patients where a very strong effects are desired. This dose of 800 mg of mescaline would correspond to a dose of LSD of 150-200 pg of LSD base or 25-40 mg of psilocybin. [000127] Mescaline can be used to assist psychotherapy, typically at acutely psychoactive doses, for many indications including anxiety, depression, addiction, personality disorder, and others and can also be used to treat other disorders such as cluster headache, migraine, and others similar to psilocybin or LSD.

[000128] The induction of an overall positive acute response to the psychedelic is critical because several studies showed that a more positive experience is predictive of a greater therapeutic long-term effect of the psychedelic (9, 10, 15). Even in healthy subjects, positive acute responses to psychedelics such as LSD or psilocybin has been shown to be linked to more positive long-term effects on well-being (75, 76). A positive overall response similar to representative and therapeutically used doses of LSD of 100 pg or psilocybin of 20 mg was documented for mescaline (300 mg) within the present invention.

[000129] Moderate to high doses of mescaline of 300-500 are useful to enhance psychotherapy for most indications including anxiety, depression, compulsive obsessive disorder, eating disorder, post-traumatic stress disorder, addiction (alcohol, nicotine, behavioral, cocaine, amphetamines), anxiety associated with life-threatening illness, adjustment disorder, cluster headache, and migraine.

[000130] A high to very high dose of mescaline of 800 mg is particularly useful in cases where a very strong effect is desired. This includes patients were a higher degree of “ego dissolution” is targeted such as patients with cancer, pain, addiction with high tolerance such as opioid dependence and any other disorders such as personality disorder that may need high doses and high ego dissolution effects at the expense of greater acute anxiety and potentially greater adverse effects. Thus, a method of dosing mescaline at high to very high doses is appropriate for individuals experienced with lower doses of mescaline or other psychedelics and aiming for a more intense and ego-dissolving experience but also ready to risk experiencing greater anxiety when dealing with this state. Ego-dissolution as experience may be therapeutic in some indications namely in individuals with severe pain disorders, with cancer and/or in palliative care with the goal of being free of pain or at least not realizing somatic pain and the presence of the body or feeling out of the body during this experience. Ego-dissolution can also be a therapeutic experience in other disorders including personality disorder (narcissistic personality disorder) or as needed by psychiatric indications.

[000131] The psychedelics used in the methods of the present invention can be, but are not limited to, mescaline or any derivatives, any analogs or derivatives (sealines, 2C- or 3C- substances, FIGURE 1 , or prodrugs of mescaline salts thereof, analogs thereof, or homologues thereof.

[000132] Mescaline or related compounds of the present invention are administered and dosed in accordance with good medical practice, considering the clinical condition of the individual patient, the site and method of administration, scheduling of administration, patient age, sex, body weight and other factors known to medical practitioners. The pharmaceutically "effective amount" for purposes herein is thus further determined by such considerations as are known in the art. The amount must be effective to achieve improvement including but not limited to improved survival rate or more rapid recovery, or improvement or elimination of symptoms and other indicators as are selected as appropriate measures by those skilled in the art. [000133] In the method of the present invention, the compounds of the present invention can be administered in various ways. It should be noted that they can be administered as the compound orally as done in the example study and can be administered alone or as an active ingredient in combination with pharmaceutically acceptable carriers, diluents, adjuvants, and vehicles. The compounds can be administered orally, subcutaneously or parenterally including intravenous, transcutaneous, intramuscular, and intranasal administration. The patient being treated is a warm-blooded animal and, in particular, mammals including man. The pharmaceutically acceptable carriers, diluents, adjuvants, and vehicles as well as implant carriers generally refer to inert, non-toxic solid or liquid fillers, diluents or encapsulating material not reacting with the active ingredients of the invention.

[000134] The doses can be single doses or multiple doses or a continuous dose over a period of several hours.

[000135] When administering the compound of the present invention parenterally, it will generally be formulated in a unit dosage injectable form (solution, suspension, emulsion). The pharmaceutical formulations suitable for injection include sterile aqueous solutions or dispersions and sterile powders for reconstitution into sterile injectable solutions or dispersions. The carrier can be a solvent or dispersing medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetable oils.

[000136] Proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Nonaqueous vehicles such a cottonseed oil, sesame oil, olive oil, soybean oil, corn oil, sunflower oil, or peanut oil and esters, such as isopropyl myristate, may also be used as solvent systems for compound compositions. Additionally, various additives which enhance the stability, sterility, and isotonicity of the compositions, including antimicrobial preservatives, antioxidants, chelating agents, and buffers, can be added. Prevention of the action of microorganisms can be ensured by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. In many cases, it will be desirable to include isotonic agents, for example, sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the use of agents delaying absorption, for example, aluminum monostearate and gelatin. According to the present invention, however, any vehicle, diluent, or additive used would have to be compatible with the compounds.

[000137] Sterile injectable solutions can be prepared by incorporating the compounds utilized in practicing the present invention in the required amount of the appropriate solvent with various of the other ingredients, as desired.

[000138] A pharmacological formulation of the present invention can be administered to the patient in an injectable formulation containing any compatible carrier, such as various vehicle, adjuvants, additives, and diluents; or the compounds utilized in the present invention can be administered parenterally to the patient in the form of slow-release subcutaneous implants or targeted delivery systems such as monoclonal antibodies, vectored delivery, iontophoretic, polymer matrices, liposomes, and microspheres. Examples of delivery systems useful in the present invention include US Patents: 5,225,182; 5,169,383; 5,167,616; 4,959,217; 4,925,678; 4,487,603; 4,486,194; 4,447,233; 4,447,224; 4,439,196; and 4,475,196. Many other such implants, delivery systems, and modules are well known to those skilled in the art.

[000139] To summarize, the specific uses of mescaline and its analogs in the context of substance assisted psychotherapy in humans within the present invention are described as follows: Mescaline can be used to assist and enhance any type of psychotherapy. A mescaline- assisted session can be used after conducting psychotherapy sessions in a person without mescaline. A mescaline-assisted session can be integrated in non-substance assisted psychotherapy. Mescaline can also be used after other psychedelics such as psilocybin or LSD or the empathogen MDMA have been used in a patient and resulted in insufficient responses or adverse effects. Thus, mescaline expands the range of possible substances to be used to assist psychotherapy.

[000140] Mescaline can also be preferred in some patients with expected adverse effects to other substances. For example, it may not be desired to use MDMA in some patients with an increased risk for specific adverse effects such as in patients with cardiovascular disease of arterial hypertension or genetic disorders such as malignant hyperthermia. In such patients, mescaline can be used instead of another psychedelic or MDMA to reduce the risk of adverse effects to other substances.

[000141] Throughout this application, various publications, including United States patents, are referenced by author and year and patents by number. Full citations for the publications are listed below. The disclosures of these publications and patents in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art to which this invention pertains.

[000142] The invention has been described in an illustrative manner, and it is to be understood that the terminology, which has been used is intended to be in the nature of words of description rather than of limitation. [000143] Obviously, many modifications and variations of the present invention are possible considering the above teachings. It is, therefore, to be understood that within the scope of the appended claims, the invention can be practiced otherwise than as specifically described.

References Liechti ME (2017): Modern clinical research on LSD.

Neuropsychopharmacology. 42:2114-2127. Passie T, Halpern JH, Stichtenoth DO, Emrich HM, Hintzen A (2008): The pharmacology of lysergic acid diethylamide: a review. CNS Neurosci Ther. 14:295-314. Holze F, Vizeli P, Ley L, Muller F, Dolder P, Stocker M, et al.

(2021): Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology. 46:537-544. Krebs TS, Johansen PO (2012): Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. J Psychopharmacol. 26:994-1002. Gasser P, Kirchner K, Passie T (2015): LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects. J Psychopharmacol. 29:57-68. Gasser P, Holstein D, Michel Y, Doblin R, Yazar-Klosinski B,

Passie T, et al. (2014): Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J Nerv Merit Dis. 202:513-520. Roseman L, Nutt DJ, Carhart-Harris RL (2017): Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Front Pharmacol. 8:974. Carhart-Harris RL, Bolstridge M, Rucker J, Day CM, Erritzoe D, Kaelen M, et al. (2016): Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study. Lancet Psychiatry. 3:619-627. Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA,

Richards BD, et al. (2016): Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol. 30:1181-1197. Ross S, Bossis A, Guss J, Agin-Liebes G, Malone T, Cohen B, et al. (2016): Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacol. 30:1165-1180. Davis AK, Barrett FS, May DG, Cosi ano MP, Sepeda ND, Johnson MW, et al. (2021): Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA

Psychiatry. 78:481-489. Grob CS, Danforth AL, Chopra GS, Hagerty M, McKay CR, Halberstadt AL, et al. (2011): Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 68:71-78. Garcia-Romeu A, Davis AK, Erowid F, Erowid E, Griffiths RR, Johnson MW (2019): Cessation and reduction in alcohol consumption and misuse after psychedelic use. J Psychopharmacol. 33:1088-

1101. Johnson MW, Garcia-Romeu A, Griffiths RR (2016): Long-term follow-up of psilocybin-facilitated smoking cessation. Am J Drug Alcohol Abuse. 43:55-60. Garcia-Romeu A, Griffiths RR, Johnson MW (2014): Psilocybin- occasioned mystical experiences in the treatment of tobacco addiction. Curr Drug Abuse Rev. 7:157-164. Johnson MW, Garcia-Romeu A, Cosimano MP, Griffiths RR (2014): Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol. 28:983-992. Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa PC, Strassman RJ (2015): Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol. 29:289- 299. Bogenschutz MP (2013): Studying the effects of classic hallucinogens in the treatment of alcoholism: rationale, methodology, and current research with psilocybin. Curr Drug Abuse Rev. 6:17-29. Dominguez-Clave E, Soler J, Elices M, Pascual JC, Alvarez E, de la Fuente Revenga M, et al. (2016): Ayahuasca: Pharmacology, neuroscience and therapeutic potential. Brain Res Bull. 126:89- 101. Palhano-Fontes F, Barreto D, Onias H, Andrade KC, Novaes MM,

Pessoa JA, et al. (2019): Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med. 49:655-663. Dos Santos RG, Osorio FL, Crippa JA, Riba J, Zuardi AW, Hallak JE (2016): Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years. Ther Adv Psychopharmacol. 6:193-213. Sanches RF, de Lima Osorio F, Dos Santos RG, Macedo LR, Maia-de- Oliveira JP, Wichert-Ana L, et al. (2016):Antidepressant Effects of a Single Dose of Ayahuasca in Patients With Recurrent Depression: A SPECT Study. J Clin Psychopharmacol. 36:77-81. Schmid Y, Gasser P, Oehen P, Liechti ME (2021): Acute subjective effects in LSD- and MDMA-assisted psychotherapy. J

Psychopharmacol. 35:362-374. Andersson M, Persson M, Kjellgren A (2017): Psychoactive substances as a last resort-a qualitative study of self-treatment of migraine and cluster headaches. Harm Reduct J. 14:60. Koelle GB (1958): The pharmacology of mescaline and D-lysergic acid diethylamide (LSD). N Engl J Med. 258:25-32. Osmond H (1973): The medical and scientific importance of hallucinogens. Practitioner. 210:112-119. Malitz S (1966): The role of mescaline and D-lysergic acid in psychiatric treatment. Dis Nerv Syst. 7 Suppl:39-42. Hoch PH, Cattell JP, Pennes HH (1952): Effects of mescaline and lysergic acid (d-LSD-25). American Journal of Psychiatry. 108:579-584. Turns D, Denber HC (1966): Mescaline and psychotherapy. Arzneimittelforschung. 16:251-253.

Smith CM (1958): A new adjunct to the treatment of alcoholism: the hallucinogenic drugs. Q J Stud Alcohol. 19:406-417. Frederking W (1955): Intoxicant drugs (mescaline and lysergic acid diethylamide) in psychotherapy. J Nerv Ment Dis. 121:262- 266.

Buchanan DN (1929): Meskalinrausc . Br J Med Psychol. 9:67-88. Beringer K (1927): Der Meskalinrausch. Berlin Springer.

Guttmann E (1936): Artificial psychoses produced by mescaline. J Ment Sci. 82:204-221.

Guttmann E, Maclay WS (1936): Mescalin and Depersonalization: Therapeutic Experiments. J Neurol Psychopathol. 16:193-212. Hollister LE, Hartman AM (1962): Mescaline, lysergic acid diethylamide and psilocybin comparison of clinical syndromes, effects on color perception and biochemical measures. Compr Psychiatry. 3:235-242.

Wolbach AB, Jr., Miner EJ, Isbell H (1962): Comparison of psilocin with psilocybin, mescaline and LSD-25. Psychopharmacologia. 3:219-223.

Unger SM (1963): Mescaline, LSD, psilocybin, and personality change. Psychiatry. 26:111-125.

Stockings GT (1940):A clinical study of the mescaline psychosis, with special reference to the mechanism of the genesis of schizophrenic and other psychotic states. Journal of Mental Science. 86:29-47.

Hermle L, Funfgeld M, Oepen G, Botsch H, Borchardt D, Gouzoulis E, et al. (1992): Mescaline-induced psychopathological, neuropsychological, and neurometabolic effects in normal subjects: experimental psychosis as a tool for psychiatric research. Biol Psychiatry. 32:976-991.

Hermle L, Gouzoulis-Mayfrank E, Spitzer M (1998): Blood flow and cerebral laterality in the mescaline model of psychosis. Pharmacopsychiatry. 31 Suppl 2:85-91.

Hollister LE, Sjoberg BM (1964): Clinical Syndromes and

Biochemical Alterations Following Mescaline, Lysergic Acid

Diethylamide, Psilocybin and a Combination of the Three Psychotomimetic Drugs. Compr Psychiatry. 5:170-178.

Matefi L (1952): Mezcalin- und Lysergsaurediathylamid-Rausch: Selbstversuche mit besonderer Berucksichtigung eines Zeichentests. Basel: Karger.

Rinkel M, DiMascio A, Robey A, Atwell C (1961): Personality patterns and reactions to psilocybine. Int J

Neuropsychopharmacol. 2:213-219.

Holze F, Vizeli P, Muller F, Ley L, Duerig R, Varghese N, et al. (2020): Distinct acute effects of LSD, MDMA, and D-amphetamine in healthy subjects. Neuropsychopharmacology. 45:462-471. Charalampous W, Kinross-Wright (1966): Metabolic Fate of Mescaline in Man. Psychopharmacologia. 9:48-63.

Dinis-Oliveira RJ, Pereira CL, da Silva DD (2019): Pharmacokinetic and Pharmacodynamic Aspects of Peyote and Mescaline: Clinical and Forensic Repercussions. Curr Mol

Pharmacol. 12:184-194. Carstairs SD, Cantrell FL (2010): Peyote and mescaline exposures: a 12-year review of a statewide poison center database. Clinical toxicology. 48:350-353. Sakloth F, Leggett E, Moerke MJ, Townsend EA, Banks ML, Negus SS (2019): Effects of acute and repeated treatment with serotonin 5-HT2A receptor agonist hallucinogens on intracranial self stimulation in rats. Exp Clin Psychopharmacol. 27:215-226. Halpern JH, Sherwood AR, Hudson JL, Yurgelun-Todd D, Pope Jr HG (2005): Psychological and cognitive effects of long-term peyote use among Native Americans. Biological psychiatry. 58:624-631. Cassels BK, Saez-Briones P (2018): Dark Classics in Chemical Neuroscience: Mescaline. ACS Chem Neurosci. 9:2448-2458. Halberstadt AL (2015): Recent advances in the neuropsychopharmacology of serotonergic hallucinogens. Behav Brain Res. 277:99-120. Halberstadt AL, Geyer MA (2013): Serotonergic hallucinogens as translational models relevant to schizophrenia. Int J Neuropsychopharmacol. 16:2165-2180. Gonzalez-Maeso J, Weisstaub NV, Zhou M, Chan P, Ivic L, Ang R, et al. (2007): Hallucinogens recruit specific cortical 5-HT _2A receptor-mediated signaling pathways to affect behavior. Neuron. 53:439-452. Holze F, Duthaler U, Vizeli P, Muller F, Borgwardt S, Liechti ME (2019): Pharmacokinetics and subjective effects of a novel oral LSD formulation in healthy subjects. Br J Clin Pharmacol. 85:1474-1483. Liechti ME, Dolder PC, Schmid Y (2017): Alterations in conciousness and mystical-type experiences after acute LSD in humans. Psychopharmacology. 234:1499-1510. Luoma JB, Chwyl C, Bathje GJ, Davis AK, Lancelotta R (2020): A Meta-Analysis of Placebo-Controlled Trials of Psychedelic- Assisted Therapy. J Psychoactive Drugs.1-11. Carhart-Harris RL, Kaelen M, Bolstridge M, Williams TM, Williams

LT, Underwood R, et al. (2016): The paradoxical psychological effects of lysergic acid diethylamide (LSD). Psychol Med. 46:1379-1390. Studerus E, Kometer M, Hasler F, Vollenweider FX (2011): Acute, subacute and long-term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. J Psychopharmacol. 25:1434-1452. Preller KH, Herdener M, Pokorny T, Planzer A, Kraehenmann R,

Stampfli P, et al. (2017): The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation Curr Biol. 27:451-457. Vollenweider FX, Vollenweider-Scherpenhuyzen MF, Babler A, Vogel H, Hell D (1998): Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. Neuroreport. 9:3897- 3902. Rickli A, Moning OD, Hoener MC, Liechti ME (2016): Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. Eur Neuropsychopharmacol. 26:1327-

1337. Vollenweider FX, Preller KH (2020): Psychedelic drugs: neurobiology and potential for treatment of psychiatric disorders. Nat Rev Neurosci. 21:611-624. La Barre W (1979): Peyotl and mescaline. Journal of Psychedelic Drugs. 11:33-39. Bruhn JG, De Smet PA, El-Seedi HR, Beck 0 (2002): Mescaline use for 5700 years. The Lancet. 359:1866. Heffter A (1898): liber Pellote. Beitrage zur chemischen und pharmakologischen Kenntniss der Cacteen. Zweite Mittheilung.Arch Exp Path Pharmacol. 40:385-429. Ogunbodede O, McCombs D, Trout K, Daley P, Terry M (2010): New mescaline concentrations from 14 taxa/cultivars of Echinopsis spp. (Cactaceae) ("San Pedro") and their relevance to shamanic practice. J Ethnopharmacol. 131:356-362. Tupper KW (2002): Entheogens and existential intelligence: the use of plant teachers as cognitive tools. Can J Educ. 27:499-516. Glass-Coffin B (2010): Shamanism and San Pedro through Time: Some Notes on the Archaeology, History, and Continued Use of an Entheogen in Northern Peru.Anthropology of Consciousness. 21:58- 82. Bergman RL (1971): Navajo peyote use: Its apparent safety.

American Journal of Psychiatry. 128:695-699. Maclean KA, Johnson MW, Griffiths RR (2011):Mystical experiences occasioned by the hallucinogen psilocybin lead to increases in the personality domain of openness. J Psychopharmacol. 25:1453- 1461. Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U,

Jesse R (2011): Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects.

Psychopharmacology. 218:649-665. Hintzen A, Passie T (2010): The pharmacology of LSD: a critical review. Oxford: Oxford University Press. Nichols DE (2016): Psychedelics. Pharmacol Rev. 68:264-355. Schmid Y, Liechti ME (2018): Long-lasting subjective effects of LSD in normal subjects. Psychopharmacology (Berl). 235:535-545. Griffiths R, Richards W, Johnson M, McCann U, Jesse R (2008): Mystical-type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. J Psychopharmacol. 22:621-632. Trulson ME, Crisp T, Henderson LJ (1983): Mescaline elicits behavioral effects in cats by an action at both serotonin and dopamine receptors. Eur J Pharmacol. 96:151-154. Appel JB, Callahan PM (1989): Involvement of 5-HT receptor subtypes in the discriminative stimulus properties of mescaline. European journal of pharmacology. 159:41-46. Davis M (1987):Mescaline: excitatory effects on acoustic startle are blocked by serotonin2 antagonists. Psychopharmacology (Berl). 93:286-291. Clemente E, de Paul Lynch V (1968): In vitro action of mescaline. Possible mode of action. J Pharm Sci. 57:72-78. Rajotte P, Denber HC, Kauffman D (1961): Studies on mescaline. XII. Effects of prior administration of various psychotropic drugs. Recent Adv Biol Psychiatry. 4:278-287. Gonzalez-Maeso J, Yuen T, Ebersole BJ, Wurmbach E, Lira A, Zhou

M, et al. (2003): Transcriptome fingerprints distinguish hallucinogenic and nonhallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in mouse somatosensory cortex. J Neurosci. 23:8836-8843. Muller F, Holze F, Dolder P, Ley L, Vizeli P, Solterann A, et al. (2021): MDMA-induced changes in within-network connectivity contradict the specificity of these alterations for the effects of serotonergic hallucinogens. Neuropsychopharmacology. 46:545- 553. Hysek CM, Simmler LD, Nicola V, Vischer N, Donzelli M, Krahenbuhl S, et al. (2012): Duloxetine inhibits effects of MDMA ("ecstasy") in vitro and in humans in a randomized placebo-controlled laboratory study. PLoS One. 7:e36476. Liechti ME (2014): Effects of MDMA on body temperature in humans. Temperature. 1:179-187. Kovacic P, Somanathan R (2009): Novel, unifying mechanism for mescaline in the central nervous system: electrochemistry, catechol redox metabolite, receptor, cell signaling and structure activity relationships. Oxidative medicine and cellular longevity. 2:181-190. Luethi D, Liechti ME (2018): Monoamine transporter and receptor interaction profiles in vitro predict reported human doses of novel psychoactive stimulants and psychedelics. Int J

Neuropsychopharmacol. 21:926-931. Palenicek T, Balikova M, Bubenikova-Valesova V, Horacek J (2008): Mescaline effects on rat behavior and its time profile in serum and brain tissue after a single subcutaneous dose. Psychopharmacology. 196:51-62. Rickli A, Luethi D, Reinisch J, Buchy D, Hoener MC, Liechti ME (2015): Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs). Neuropharmacology. 99:546-553. Dolder PC, Schmid Y, Steuer AE, Kraemer T, Rentsch KM, Hammann F, et al. (2017): Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide in healthy subjects. Clin Pharmacokinetics. 56:1219-1230. Dolder PC, Schmid Y, Mueller F, Borgwardt S, Liechti ME (2016): LSD acutely impairs fear recognition and enhances emotional empathy and sociality. Neuropsychopharmacology. 41:2638-2646. Vollenweider FX, Csomor PA, Knappe B, Geyer MA, Quednow BB (2007): The effects of the preferential 5-HT2A agonist psilocybin on prepulse inhibition of startle in healthy human volunteers depend on interstimulus interval. Neuropsychopharmacology. 32:1876- 1887. Brown RT, Nicholas CR, Cozzi NV, Gassman MC, Cooper KM, Muller

D, et al. (2017): Pharmacokinetics of escalating doses of oral psilocybin in healthy adults. Clin Pharmacokinet. 56:1543-1554. Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX (2004): Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacology. 172:145-156. Carhart-Harris RL, Erritzoe D, Williams T, Stone JM, Reed LJ,

Colasanti A, et al. (2012): Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. Proc Natl Acad Sci USA. 109:2138-2143. Kraehenmann R, Preller KH, Scheidegger M, Pokorny T, Bosch OG,

Seifritz E, et al. (2015): Psilocybin-induced decrease in amygdala reactivity correlates with enhanced positive mood in healthy volunteers. Biol Psychiatry. 78:572-581. Ray TS (2010): Psychedelics and the human receptorome. PLoS One. 5:e9019. Jacintho JD, Kovacic P (2003): Neurotransmission and neurotoxicity by nitric oxide, catecholamines, and glutamate: unifying themes of reactive oxygen species and electron transfer. Current medicinal chemistry. 10:2693-2703. Balestrieri A, Fontanari D (1959):Acquired and crossed tolerance to mescaline, LSD-25, and BOL-148. AMA archives of general psychiatry. 1:279-282. Wolbach A, Isbell H, Miner E (1962): Cross tolerance between mescaline and LSD-25 with a comparison of the mescaline and LSD reactions. Psychopharmacology. 3:1-14. Friedrichs H, Dierssen 0, Passie T (2009): Die Psychologie des Meskalinrausches. VWB, Verlag fiir Wiss. und Bildung. Brogaard B, Gatzia DE (2016): Psilocybin, lysergic acid diethylamide, mescaline, and drug-induced synesthesia. Neuropathology of Drug Addictions and Substance Misuse:Elsevier, pp 890-905. Hartman AM, Hollister LE (1963): Effect of mescaline, lysergic acid diethylamide and psilocybin on color perception. Psychopharmacologia. 4:441-451. Masters RE, Houston J (1966): The varieties of psychedelic experience. Holt, Rinehart and Winston New York. Kelly J (1954): The influence of mescaline on Rorschach responses. Psychological Research. 24:542-556. Carhart-Harris RL, Williams TM, Sessa B, Tyacke RJ, Rich AS,

Feilding A, et al. (2011): The administration of psilocybin to healthy, hallucinogen-experienced volunteers in a mock- functional magnetic resonance imaging environment: a preliminary investigation of tolerability. J Psychopharmacol. 25:1562-1567. Laing R, Laing RR, Beyerstein BL, Siegel JA (2003): Hallucinogens: a forensic drug handbook. Academic Press.

Johnson M, Richards W, Griffiths R (2008): Human hallucinogen research: guidelines for safety. J Psychopharmacol. 22:603-620. Frecska E, Luna L (2006): The adverse effects of hallucinogens from intramural perspective. Neuropsychopharmacologia Hungarica: A Magyar Pszichofarmakologiai Egyesulet Lapja= Official Journal of the Hungarian Association of Psychopharmacology. 8:189-200. Hollister LE (1984): Effects of hallucinogens in humans.

Hallucinogens: Neurochemical, behavioral, and clinical perspectives.19-33. Nichols DE (2004): Hallucinogens. Pharmacol Ther. 101:131-181. Johansen PO, Krebs TS (2015): Psychedelics not linked to mental health problems or suicidal behavior: a population study. J Psychopharmacol. 29:270-279. Winkelman M (2014): Psychedelics as medicines for substance abuse rehabilitation: evaluating treatments with LSD, Peyote, Lbogaine and Ayahuasca. Current drug abuse reviews. 7:101-116. Murray TF, Craigmill A, Fischer G (1977): Pharmacological and behavioral components of tolerance to LSD and mescaline in rats. Pharmacology Biochemistry and Behavior. 7:239-244. Wittchen HU, Wunderlich U, Gruschwitz S, Zaudig M (1997): SKID- I: Strukturiertes Klinisches Interview fur DSM-IV. Gottingen: Hogrefe-Verlag. Kammermann J, Stieglitz RD, Riecher-Rossler A (2009): Self-screen prodrome"- self-rating for the early detection of mental disorders and psychoses. Fortschr Neurol Psychiatr. 77:278-284. Dittrich A (1998): The standardized psychometric assessment of altered states of consciousness (ASCs) in humans. Pharmacopsychiatry. 31 (Suppl 2):80-84. Studerus E, Gamma A, Vollenweider FX (2010): Psychometric evaluation of the altered states of consciousness rating scale (OAV). PLoS One. 5:el2412. Zerssen DV (1976): Die Beschwerden-Liste. Munchener

Informationssystem. Miinchen: Psychis. Kuypers KP, Ng L, Erritzoe D, Knudsen GM, Nichols CD, Nichols DE, et al. (2019): Microdosing psychedelics: more questions than answers? An overview and suggestions for future research. J Psychopharmacol. 33:1039-1057. Holze F, Liechti ME, Hutten N, Mason NL, Dolder PC, Theunissen

EL, et al. (2021): Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide microdoses in healthy participants. Clin Pharmacol Ther. 109:658-666. Schindler EAD, Sewell RA, Gottschalk CH, Luddy C, Flynn LT,

Lindsey H, et al. (2020): Exploratory Controlled Study of the

Migraine-Suppressing Effects of Psilocybin. Neurotherapeutics. Schindler EA, Gottschalk CH, Weil MJ, Shapiro RE, Wright DA, Sewell RA (2015): Indoleamine hallucinogens in cluster headache: results of the clusterbusters medication use survey. J Psychoactive Drugs. 47:372-381. Lea T, Amada N, Jungaberle H, Schecke H, Klein M (2020): Microdosing psychedelics: motivations, subjective effects and harm reduction. Int J Drug Policy. 75:102600.

Lea T, Amada N, Jungaberle H (2019): Psychedelic microdosing: a subreddit analysis. J Psychoactive Drugs.1-12. Davenport WJ (2016): Psychedelic and nonpsychedelic LSD and psilocybin for cluster headache. CMAJ. 188:217. Karst M, Halpern JH, Bernateck M, Passie T (2010): The non hallucinogen 2-bromo-lysergic acid diethylamide as preventative treatment for cluster headache: an open, non-rando ized case series. Cephalalgia. 30:1140-1144. Kuypers KPC (2020): The therapeutic potential of microdosing psychedelics in depression. Ther Adv Psychopharmacol. 10:2045125320950567.