Entheogens and Psychedelics (including Ayahuasca, LSD, Peyote, Mescaline, Psilocybin Mushrooms, Salvia)

"An entheogen is a psychoactive compound, typically from natural sources such as plants or fungi, that can be used to alter consciousness for spiritual purposes (Johnstad, 2018). Thousands of years of knowledge from traditional medicine practices outlined the dose, efficacy, and preparation of many natural medicines and have demonstrated that entheogens are a powerful tool for healing various conditions (Yuan, Ma, Ye, & Piao, 2016). There is early evidence that these substances can provide unique interventions for patients with mental health conditions that do not respond well to standard psychopharmaceuticals (Agin-Liebes et al., 2021; Bogenschutz et al., 2022).

"Entheogens are most often complex biological organisms with diverse bioactive compounds."

"Another peculiar effect of these drugs is a dramatic change in perception: it appears to the person as if the eyes (the 'doors of perception') have been cleansed and the person could see the world as new in all respects — 'as Adam may have seen it on the day of creation' as Aldous Huxley (1954, p. 17) pointed out in his popular and influential book. This new reality is perceived and interpreted by some individuals as manifestation of the true nature of their mind; hence, the term 'psychedelic' was suggested by Osmond (1957). This interpretation has been embraced not only by professional therapists but also by some segments of the public, and gave rise to the 'Summer of Love' in San Francisco in 1967 with free distribution of LSD. This perception resulted in the formation of numerous cults, communes, and drug-oriented religious groups (Freedman 1968), permeated the lyrics and style of popular music (acid rock), and was viewed by some as one of the contributing sources of the occasional resurgence of popularity of illegal drug use (Cohen 1966, Szára 1968)."

"The term 'hallucinogen' is widely used and understood in both professional and lay circles, in spite of the fact that hallucinations in the strict psychiatric sense of the word are a relatively rare effect of these drugs (Hollister 1962). What is probably the first reference to hallucinations as produced by peyote appears in Louis Lewin’s book published in 1924 in German and later translated into English with the nearly identical title Phantastica (Lewin 1924, 1964). In this book by the noted German toxicologist, the term 'hallucinatoria' appears as a synonym for phantastica to designate the class of drugs that can produce transitory visionary states 'without any physical inconvenience for a certain time in persons of perfectly normal mentality who are partly or fully conscious of the action of the drug' (Lewin 1964, p. 92). Lewin lists peyotl (also spelled 'peyote') (Anhalonium lewinii), Indian hemp (Cannabis indica), fly agaric (Agaricus muscarius), thornapple (Datura stramonium), and the South American yahe (also spelled 'yage') (Banisteria caapi) as representatives of this class."

"Psilocybin is a molecule present in over 200 species of psychoactive mushrooms. It has a dose-dependent capacity to facilitate the experience of non-ordinary states of consciousness, and together with compounds like lysergic acid diethylamide (LSD), mescaline, and N,N-Dimethyltryptamine (DMT), is part of a group of drugs called psychedelics. Psilocybin is a partial agonist of the 5HT group of receptors, including the 5HT2A receptor subtype. The activation of 5HT2AR results in subjective alterations of perception, mood and cognition during the acute effects of psilocybin. This has potential benefits for mood disorders, as perception and cognition appear to become more flexible, enabling opportunities for new perspectives and insights to be generated, potentially leading to new and novel solutions for ongoing psychological distress (1). Psilocybin effects generally peak around 90 min after ingestion, then gradually subside and resolve in 4–6 h.

"Psilocybin and other psychedelic compounds have attracted attention from researchers and clinicians for their potential to catalyze therapeutic change, when taken within a therapeutic setting, in people diagnosed with depression (1), obsessive-compulsive disorder (2), alcohol dependence (3), nicotine dependence (4), and anxiety associated with cancer (5–7). The effects of psychedelics in general, and specifically psilocybin, for other problems are currently being investigated in several pilot studies. Early research with psilocybin has shown signals of immediate, significant and often enduring clinical improvements in depression and anxiety. Such effects are thought to result from a combination of the psychopharmacological effects of psilocybin and the participants’ subjective experiences, including generation of insights and subsequent changes in cognition and behavior (8, 9)."

"In this randomized clinical trial of psilocybin-assisted psychotherapy treatment for AUD [Alcohol Use Disorder], psilocybin treatment was associated with improved drinking outcomes during 32 weeks of double-blind observation. PHDD [Percentage of Heavy Drinking Days] among participants treated with psilocybin was 41% of that observed in the diphenhydramine-treated group. Exploratory analyses confirmed a between-group effect across a range of secondary drinking measures. Although this was, to our knowledge, the first controlled trial of psilocybin for AUD, these findings are consistent with a meta-analysis³⁹ of trials conducted in the 1960s evaluating LSD as a treatment for AUD.

"Adverse events associated with psilocybin administration were mostly mild and self-limiting, consistent with other recent trials evaluating the effects of psilocybin in various conditions.^1-8 However, it must be emphasized that these safety findings cannot be generalized to other contexts. The study implemented measures to ensure safety, including careful medical and psychiatric screening, therapy and monitoring provided by 2 well-trained therapists including a licensed psychiatrist, and the availability of medications to treat acute psychiatric reactions."

"Several limitations of the study warrant discussion. First, diphenhydramine was ineffective in maintaining the blind after drug administration, so biased expectancies could have influenced results. Control medications such as methylphenidate,⁴² niacin,² and low-dose psilocybin¹ likewise did not adequately maintain blinding in past psilocybin trials, so this issue remains a challenge for clinical research on psychedelics. Second, EtG samples, used to validate self-reported drinking outcomes, were available for only 53.8% of treated participants. Third, the study did not have adequate power to evaluate effects in subgroups, such as women, ethnic and racial minority groups, and individuals with psychiatric comorbidity, nor was it designed to identify causal mechanisms, optimal dosing, or predictors of treatment response. Fourth, the study population was lower in drinking intensity at screening than in most AUD medication trials, and results cannot be assumed to generalize to populations with more severe AUD. Fifth, the 2-group design does not permit evaluation of the effects of psychotherapy or the interaction between psychotherapy and medication. Sixth, the study does not provide information on the duration of the effects of psilocybin beyond the 32-week double-blind observation period, which is important given the often chronic, relapsing course of AUD. Further studies will be necessary to address these questions and many others concerning the use of psilocybin in the treatment of AUD."

"Our investigations provided no cause for concern that administration of PY [psilocybin] to healthy subjects is hazardous with respect to somatic health. However, as our data revealed tendencies of PY to temporarily increase blood pressure, we advise subjects suffering from cardiovascular conditions, especially untreated hypertension, to abstain from using PY or PY-containing mushrooms. Furthermore, our results indicate that PY-induced ASC [altered states of consciousness] are generally well tolerated and integrated by healthy subjects. However, a controlled clinical setting is needful, since also mentally stable personalities may, following ingestion of higher doses of PY, transiently experience anxiety as a consequence of loosening of ego-boundaries."

"This paper presents updated and extended data from an open-label clinical trial assessing psilocybin with psychological support for treatment-resistant depression. Findings corroborate our (Carhart-Harris et al. 2016) and others’ previous results (Griffiths et al. 2016; Ross et al. 2016; Grob et al. 2011) supporting the safety and efficacy of psilocybin for depressive and anxiety symptoms. A fast and sustained response exceeding what might be expected from a placebo response was observed in many of the patients (see Carhart-Harris and Nutt (2016) for a relevant discussion). Notably, all 19 completers showed some reductions in the QIDS-SR16 scores at 1-week post-treatment and (nominally) maximal effects were seen at 5 weeks. Other interventions, not formally part of the present trial, confounded outcomes at 3 and 6 months, although safety was maintained and a sizeable proportion of the sample continued to demonstrate benefit (see Watts et al. (2017) for more details). Conclusions on efficacy are limited by the absence of a control condition in this trial, however.

"Recent studies (Griffiths et al. 2016; Ross et al. 2016; Carhart-Harris et al. 2016), including the present one, help demonstrate the feasibility of treating patients with major depressive disorder with psilocybin plus psychological support. Two recent double-blind randomised control trials (RCTs) of psilocybin for depression and anxiety symptoms in a combined sample of 80 patients with life-threatening cancer found consistent safety and efficacy outcomes with those reported here (Griffiths et al. 2016; Ross et al. 2016). Only a subset of patients recruited into these studies met the criteria for major depressive disorder however, and symptoms were not of the same severity as those seen here (i.e. mean baseline BDI scores were 18.1 and 16 in the Griffiths et al. and Ross et al. studies, respectively, whereas they were 35 in the present study). A comprehensive RCT designed to properly assess psilocybin’s efficacy for major depressive disorder, with some form of placebo control, is therefore warranted (Carhart-Harris and Goodwin 2017)."

• "Among young adults (aged 15 to 34), recent national surveys show last year prevalence estimates for both LSD and hallucinogenic mushrooms equal to or less than 1 %. Exceptions for hallucinogenic mushrooms include Czechia (2.7 % in 2021), Finland (2.0 % in 2018), the Netherlands (1.9 % in 2021), Estonia (1.6 % in 2018, 16–34), Denmark (1.5 % in 2021), Spain (1.1 % in 2022) and Germany (1.1 % in 2021). Exceptions for LSD include Ireland (2.4 % in 2019), Finland (2.0 % in 2018), Estonia (1.7 % in 2018, 16–34), Latvia (1.4 % in 2020), Norway (1.3 % in 2021) and the Netherlands (1.2 % in 2021).
• "Among respondents to the European Web Survey on Drugs, 20 % of those who had used drugs within the last 12 months had used LSD, while 13 % had used ketamine.
• "Recent estimates of last year prevalence of ketamine use among young adults (15–34) range from 0.4 % in Denmark (2021, 16–34) to 0.8 % in Romania (2019). The Netherlands reported that ketamine use has increased among young people in nightlife settings.
• "In 2022, generally very low levels of ketamine residues in municipal wastewater were reported by 15 cities, with the highest mass loads being detected in cities in Denmark, Spain, Italy and Portugal (see the figure Ketamine residues in wastewater in selected European cities, 2022, below)."

"Psilocybin is a non-addictive classic psychedelic (22, 23) with neuroplasticity-inducing properties (24, 25). It is consistently ranked as one of the least harmful illicit psychoactive substances (4, 5), despite being among the most highly regulated substances globally. Psilocybin is a tryptamine alkaloid with serotonin 2A receptor (5-HT2A) agonism (26)—and complex pharmacology at many additional serotonin and non-serotonin receptors—that induces marked transitory changes in perception, cognition, and affect. Early phase clinical trials demonstrate that one to three moderate-to-high doses (20 mg to 30 mg/70 kg or more) of psilocybin combined with a brief course of psychotherapy (i.e., psilocybin-assisted psychotherapy) is safe, feasible, and preliminarily efficacious at alleviating symptoms of major depressive disorder, anxiety and depression associated with end-of-life diagnoses, and alcohol and tobacco use disorder (27–30). Psilocybin-assisted psychotherapy received a ‘Breakthrough Therapy’ designation from the United States Food and Drug Administration for both major depressive disorder and treatment-resistant depression. This designation was created to expedite the development and review of drugs intended to treat serious or life-threatening conditions for which preliminary evidence suggests substantial improvement over available options."

"Despite the limitations, this study demonstrates that the careful and controlled use of psilocybin may provide an alternative model for the treatment of conditions that are often minimally responsive to conventional therapies, including the profound existential anxiety and despair that often accompany advanced-stage cancers. A recent review from the psilocybin research group at Johns Hopkins University describes the critical components necessary for ensuring subject safety in hallucinogen research.³⁶ Taking into account these essential provisions for optimizing safety as well as adhering to strict ethical standards of conduct for treatment facilitators, the results provided herein indicate the safety and promise of continued investigations into the range of medical effects of hallucinogenic compounds such as psilocybin."

"Ayahuasca is a hallucinogenic tea originally from the Amazon Basin that is supposedly able to induce strikingly similar visions in people independent of their cultural background. Ayahuasca users commonly claim that this regularity across people’s visions is evidence that their visions are not simply the products of their own brains, but rather are representations of spiritual information learned from plant-spirits that one gains access to by drinking the tea."

"Ayahuasca is a psychedelic decoction made from plants native to the Amazon Basin—most often Banisteriopsis caapi and Psychotria viridis—and which contains harmala alkaloids and N,Ndimethyltryptamine (DMT), the latter being a controlled substance scheduled under the 1971 Convention on Psychotropic Substances."

"Vegetalismo is a Peruvian Spanish term denoting the folk healing traditions of mestizo curanderos, or healers of mixed indigenous and non-indigenous ancestry who use ayahuasca and other 'master' plants for diagnosis and treatment of illnesses (Beyer, 2009; Dobkin de Rios, 1972; Luna, 1986). Known as ayahuasqueros, such folk healers undergo a rigorous process of initiation and training, requiring adherence to strict dietary and sexual abstinence protocols, and sometimes prolonged isolation in the jungle."

"On February 21 of this year, 2006, the US Supreme Court ruled in favor of the Centro Espírita Beneficente União do Vegetal (the UDV) in the case “Alberto R. Gonzales, Attorney General, et al. Petitioners v. O Centro Espirita Beneficente União do Vegetal et al.” The UDV is now legally allowed to drink ayahuasca (which contains the controlled substance DMT) in their ceremonies here in the US."

"Aside from indicating a general lack of harm from the religious use of ayahuasca, biomedical and ethnographic studies have also generated preliminary evidence in support of the therapeutic potentials of ayahuasca or its constituents for alleviating substance dependence (Grob et al., 1996; Labate, Santos, Anderson, Mercante, & Barbosa, 2010) and mood and anxiety disorders (Fortunato et al., 2010; Santos, Landeira-Fernandez, Strassman, Motta, & Cruz, 2007). The study of ayahuasca could thus contribute to advances in ethnopharmacology and the cognitive sciences (Shanon, 2002), yet such studies are severely compromised when these traditions face the threat of legal sanction."

"LSD (d-lysergic acid diethylamide)—also known as acid, blotter, doses, hits, microdots, sugar cubes, trips, tabs, or window panes — is one of the most potent moodand perception-altering hallucinogenic drugs. It is a clear or white, odorless, water-soluble material synthesized from lysergic acid, a compound derived from a rye fungus. LSD is initially produced in crystalline form, which can then be used to produce tablets known as 'microdots' or thin squares of gelatin called 'window panes.' It can also be diluted with water or alcohol and sold in liquid form. The most common form, however, is LSD-soaked paper punched into small individual squares, known as 'blotters.'"

"LSD (d-lysergic acid diethylamide) is one of the most potent mood-changing chemicals. It was discovered in 1938 and is manufactured from lysergic acid, which is found in ergot, a fungus that grows on rye and other grains."

"Sensations and feelings change much more dramatically than the physical signs in people under the influence of LSD. The user may feel several different emotions at once or swing rapidly from one emotion to another. If taken in large enough doses, the drug produces delusions and visual hallucinations. The user’s sense of time and self is altered. Experiences may seem to “cross over” different senses, giving the user the feeling of hearing colors and seeing sounds. These changes can be frightening and can cause panic. Some LSD users experience severe, terrifying thoughts and feelings of despair, fear of losing control, or fear of insanity and death while using LSD.

"LSD users can also experience flashbacks, or recurrences of certain aspects of the drug experience. Flashbacks occur suddenly, often without warning, and may do so within a few days or more than a year after LSD use. In some individuals, the flashbacks can persist and cause significant distress or impairment in social or occupational functioning, a condition known as hallucinogen-induced persisting perceptual disorder (HPPD).

"Most users of LSD voluntarily decrease or stop its use over time. LSD is not considered an addictive drug since it does not produce compulsive drug-seeking behavior. However, LSD does produce tolerance, so some users who take the drug repeatedly must take progressively higher doses to achieve the state of intoxication that they had previously achieved. This is an extremely dangerous practice, given the unpredictability of the drug. In addition, cross-tolerance between LSD and other hallucinogens has been reported."

"Hallucinogens is another fairly widely used class of illicit substances. Lifetime prevalence of use is 2.4% for 8th graders, 4.7% for 10th graders, and 6.9% for 12th graders. Until 2001, hallucinogen prevalence ranked this high primarily due to the prevalence of LSD use. But in 2019, similar proportions of students indicated lifetime use of hallucinogens other than LSD – 1.7%, 3.3%, and 4.3% for 8th, 10th, and 12th grade, respectively – (particularly “shrooms” or psylocibin), compared to 1.6%, 3.6%, and 5.6% for LSD."

"Our results indicate that this population of sexually active female adolescents and young adults have similar rates of lifetime use of LSD (13%) as reported in other surveys,^1,30 and half of these young women report using LSD one or more times in the last year. Prior data suggests that the use of hallucinogens by African Americans is virtually nonexistent across all ages of adolescents and young adults.^2,9 In fact, we found that none of our African American young women reported using LSD. However, the proportion of African Americans who reported using marijuana was much greater than either caucasian or Mexican American women."

"Chemist Albert Hofmann, working at the Sandoz Corporation pharmaceutical laboratory in Switzerland, first synthesized LSD in 1938. He was conducting research on possible medical applications of various lysergic acid compounds derived from ergot, a fungus that develops on rye grass. Searching for compounds with therapeutic value, Hofmann created more than two dozen ergot-derived synthetic molecules. The 25th was called, in German, Lyserg-Säure-Diäthylamid 25, or LSD-25."

"Most users of LSD voluntarily decrease or stop its use over time. LSD is not considered an addictive drug since it does not produce compulsive drug-seeking behavior. However, LSD does produce tolerance, so some users who take the drug repeatedly must take progressively higher doses to achieve the state of intoxication that they had previously achieved. This is an extremely dangerous practice, given the unpredictability of the drug. In addition, cross-tolerance between LSD and other hallucinogens has been reported."

"The effects of LSD depend largely on the amount taken. LSD causes dilated pupils; can raise body temperature and increase heart rate and blood pressure; and can cause profuse sweating, loss of appetite, sleeplessness, dry mouth, and tremors."

"The physiological effects of this powerful drug have been well documented. These effects can be grouped into five general areas of action: LSD works on the sympathetic nervous system (which is involved in regulation of heart muscle, smooth muscle and glandular organs in a response to stressful situations); the motor system (which is involved in carrying out limb movements); the affective states; thought processes; and it has profound effects upon the sensory and perceptual experience.

"LSD is a semisynthetic preparation originally derived from ergot, an extract of the fungus Claviceps purpurea, which grows as a parasite on rye wheat. The dosage that is required to produce a moderate effect in most subjects is 1 to 3mcg per kilogram of body mass, and the effects can last from seven to 10 hours (Bowman & Rand 1980).

"Stimulation of the sympathetic nervous system following LSD ingestion can lead to effects such as hypothermia with piloerection (hairs standing on end, such as can be found in reports of religious ecstasy), sweating, increased heart rate with palpitations, and elevation of blood pressure and blood glucose levels. These reactions of the autonomic nervous system are not as significant as other effects upon the body: action on the motor system can lead to increased activity of monosynaptic reflexes (such as the knee-jerk response), an increase in muscle tension, tremors, and muscular incoordination. This latter effect of muscular incoordination is also a symptom of religious ecstasy in many cultures, where the worshipper has such a profound feeling of love of God that he is said to be 'intoxicated by God.'"

"Peyote is a small, spineless cactus in which the principal active ingredient is mescaline. This plant has been used by natives in northern Mexico and the southwestern United States as a part of religious ceremonies. Mescaline can also be produced through chemical synthesis."

"The top of the peyote cactus, also referred to as the crown, consists of disc-shaped buttons that are cut from the roots and dried. These buttons are generally chewed or soaked in water to produce an intoxicating liquid. The hallucinogenic dose of mescaline is about 0.3 to 0.5 grams, and its effects last about 12 hours. Because the extract is so bitter, some individuals prefer to prepare a tea by boiling the cacti for several hours."

"The long-term residual psychological and cognitive effects of mescaline, peyote’s principal active ingredient, remain poorly understood. A recent study found no evidence of psychological or cognitive deficits among Native Americans that use peyote regularly in a religious setting.² It should be mentioned, however, that these findings may not generalize to those who repeatedly abuse the drug for recreational purposes. Peyote abusers may also experience flashbacks."

"Its effects can be similar to those of LSD, including increased body temperature and heart rate, uncoordinated movements (ataxia), profound sweating, and flushing. The active ingredient mescaline has also been associated, in at least one report, to fetal abnormalities."

"Because this was a small-scale feasibility study with an open-label design, strong inferences cannot be made about the treatment's therapeutic efficacy. However, the data do suggest that further research is warranted. The response rate to psilocybin was 67% (n=8) at 1 week after treatment (HAM-D and BDI), and seven of these eight patients also met criteria for remission. Moreover, 58% (n=7) of the patients maintained their response for 3 months, and 42% (n=5) remained in remission. It is also worth noting that psilocybin has a favourable toxicity profile and is not associated with compulsive drug-seeking behaviours in animals or human beings. The side-effects that we noted were minor, and expected in light of previous studies of psilocybin.²⁷

"Spontaneous recovery in refractory depression is rare, and many of the patients in the present study reported having depression for much of their adult lives (mean estimated illness duration 17·8 years [SD 8]). Key questions for future research therefore should address why the therapeutic effect observed in the present study is so large, and if it can be replicated when tighter experimental controls are introduced. Because the treatment in our study consisted of not just two psilocybin administrations but also psychological support before, during, and after these sessions, as well as a positive therapeutic environment for the sessions, the relative effects of these factors need to be determined, which can only be done by conducting further trials with appropriate control conditions."

"All studies included in this review have suggested that psilocybin has a favorable safety profile, being well tolerated in general (see Table 2). The most common adverse events reported were transient hypertension, anxiety and nausea, and headaches that were limited to the experimental sessions in the majority of cases. These events go in accordance with previous reports.^13,42,54,55 The occurrence of adverse events was more often reported with higher doses of psilocybin²⁷; however, out of all studies, there were no reports of serious adverse events and all adverse events were readily managed by the staff without the need of pharmacological intervention. The safety of psilocybin use is conditioned mainly by the individual’s expectations and the surrounding environment, which explains the wide amplitude of subjective effects⁴ and the concern about the conditions under which drug sessions were conducted in many of the studies cited."

"Mushrooms containing psilocybin are available fresh or dried and are typically taken orally. Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) and its biologically active form, psilocin (4-hydroxy-N,N-dimethyltryptamine), cannot be inactivated by cooking or freezing preparations. Thus, they may also be brewed as a tea or added to other foods to mask their bitter flavor. The effects of psilocybin, which appear within 20 minutes of ingestion, last approximately 6 hours."

"The active compounds in psilocybin-containing 'magic' mushrooms have LSD-like properties and produce alterations of autonomic function, motor reflexes, behavior, and perception.³ The psychological consequences of psilocybin use include hallucinations, an altered perception of time, and an inability to discern fantasy from reality. Panic reactions and psychosis also may occur, particularly if a user ingests a large dose. Long-term effects such as flashbacks, risk of psychiatric illness, impaired memory, and tolerance have been described in case reports."

"[Psilocybin] can produce muscle relaxation or weakness, ataxia, excessive pupil dilation, nausea, vomiting, and drowsiness. Individuals who abuse psilocybin mushrooms also risk poisoning if one of many existing varieties of poisonous mushrooms is incorrectly identified as a psilocybin mushroom."

"Overall, the present study shows that psilocybin can dose-dependently occasion mystical-type experiences having persisting positive effects on attitudes, mood, and behavior. The observations that episodes of extreme fear, feeling trapped, or delusions occur at the highest dose in almost 40% of volunteers, that anxiety and fear have an unpredictable time course across the session, and that an ascending sequence of dose exposure may be associated with long-lasting positive changes have implications for the design of therapeutic trials with psilocybin. Considering the rarity of spontaneous mystical experiences in the general population, the finding that more than 70% of volunteers in the current study had 'complete' mystical experiences suggests that most people have the capacity for such experiences under appropriate conditions and, therefore, such experiences are biologically normal."

"An important finding of the present study is that, with careful volunteer screening and preparation and when sessions are conducted in a comfortable, well-supervised setting, a high dose of 30 mg/70 kg psilocybin can be administered safely. . It is also noteworthy that, despite meetings and prior sessions with monitors ranging from 8 h (when psilocybin was administered on the first session) up to 24 h (when psilocybin was administered on the third session) of contact time, 22% (8 of 36) of the volunteers experienced a period of notable anxiety/dysphoria during the session, sometimes including transient ideas of reference/paranoia. No volunteer required pharmacological intervention and the psychological effects were readily managed with reassurance. The primary monitor remained accessible via beeper/phone to each volunteer for 24 h after each session, but no volunteer called before the scheduled follow-up meeting on the next day. The 1-year follow-up is ongoing but has been completed by most volunteers (30 of 36). In that follow-up, an open-ended clinical interview reflecting on the study experiences and current life situation provides a clinical context conducive to the spontaneous reporting of study-associated adverse events. To date, there have been no reports of persisting perceptional phenomena sometimes attributed to hallucinogen use or of recreational abuse of hallucinogens, and all participants appear to continue to be high-functioning, productive members of society."

"Today, the medical value of hallucinogens is again being examined in formal psychiatric settings. One substance under investigation is psilocybin, 4-phosphoryloxy-N,N-dimethyltryptamine, which occurs in nature in various species of mushrooms. Psilocybin is rapidly metabolized to psilocin, which is a potent agonist at serotonin 5-HT1A/2A/2C receptors, with 5-HT2A receptor activation directly correlated with human hallucinogenic activity.¹⁶ Psilocybin was studied during the 1960s to establish its psychopharmacological profile; it was found to be active orally at around 10 mg, with stronger effects at higher doses, and to have a 4- to 6-hour duration of experience. Psychological effects were similar to those of lysergic acid diethylamide (LSD), with psilocybin considered to be more strongly visual, less emotionally intense, more euphoric, and with fewer panic reactions and less chance of paranoia than LSD."^17,18

"The training of clinicians for clinical work with psychedelics has not yet been a subject of formal inquiry or research. Related programs run by research centers or sponsors of psychedelic drugs progressing through the FDA drug development process are drug, indication, and trial specific¹. Outside clinical trials, some postgraduate certificate programs offer training for licensed therapists wishing to add education and skills related to psychedelic medicines to their professional development, but do not directly or fully authorize graduates to participate as research therapists^{2, 3}. Although other programs are related in their focus on the clinical applications of psychedelics, they are not specific to the COMPASS protocol, and are not a substitute for the training program described herein.

"Another salient question in the field of psychedelic therapy training is the need for, or relevance, of a therapist’s personal experience of the study drug. Some advocate for the inclusion of such experiences in training programs (23), and others have cautioned that the decision to have and discuss such experiences requires careful forethought by clinicians (31). No research has yet demonstrated the impact of therapists’ training, or other kinds of personal experience, with psychedelics on clinical outcomes, and the inclusion of such experiences may be a barrier to the inclusion of a diverse group of therapists, place trainers and trainees in dual roles, and even stigmatize those who choose to pursue psychedelic-assisted therapy as a professional.

"Still, there is anecdotal evidence that some therapists find some personal experiences to be helpful in their professional development [e.g., Halberstadt (32)]. The current program does not include opportunities for personal experience of psychedelics yet respects and allows for discussion of therapists’ experiences during training."

"Salvia divinorum is a perennial herb in the mint family native to certain areas of the Sierra Mazateca region of Oaxaca, Mexico. The plant, which can grow to over three feet in height, has large green leaves, hollow square stems and white flowers with purple calyces, can also be grown successfully outside of this region. Salvia divinorum has been used by the Mazatec Indians for its ritual divination and healing. The active constituent of Salvia divinorum has been identified as salvinorin A. Currently, neither Salvia divinorum nor any of its constituents, including salvinorin A, are controlled under the federal Controlled Substances Act (CSA)."

"Consistent with results from nonhuman animal research (Mowry et al.,2003), the present results suggest a safe physiological profile for salvinorin A at the studied doses, under controlled conditions, and in psychologically and physically healthy hallucinogen-experienced participants. Salvinorin A produced no significant changes in heart rate or blood pressure; no tremor was observed; and no adverse events were reported. Participants tolerated all doses. However, because of the small sample and the healthy, hallucinogen-experienced status of participants, conclusions regarding safety are limited."

"Salvia divinorum is a psychoactive plant that can induce dissociative effects and is a potent producer of visual and other hallucinatory experiences. By mass, salvinorin A, the psychoactive substance in the plant, appears to be the most potent naturally occurring hallucinogen. Its native habitat is the cloud forests in Mexico. It has been consumed for hundreds of years by local Mazatec shamans, who use it to facilitate visionary states of consciousness during spiritual healing sessions.⁵⁷ It is also used in traditional medicine at lower doses as a diuretic to treat ailments including diarrhoea, anaemia, headaches and rheumatism. Effects include various psychedelic experiences, including past memories (e.g. revisiting places from childhood memory), merging with objects and overlapping realities (such as the perception of being in several locations at the same time).⁵⁸ In contrast to other drugs, its use often prompts dysphoria, i.e. feelings of sadness and depression, as well as fear. In addition, it may prompt a decreased heart rate, slurred speech, lack of coordination and possibly loss of consciousness.⁵⁹"

"The putative primary psychoactive agent in SD [Salvia divinorum] is a structurally novel KOR [kappa opioid receptor] agonist named salvinorin A (Ortega et al., 1982; Valdés et al., 1984). Consistent with KOR agonist activity, users describe SD in lay literature as hallucinogenic: it produces perceptual distortions, pseudo-hallucinations, and a profoundly altered sense of self and environment, including out-of-body experiences (Aardvark, 1998; Erowid, 2008; Siebert, 1994b; Turner, 1996). SD therefore appears to have the potential to elucidate the role of the KOR receptor system in health and disease (Butelman et al., 2004; Chavkin et al., 2004; Roth et al., 2002)."

"There was little evidence of dependence in our survey population. At some point, 0.6% (3 people) felt addicted to or dependent upon SD, while 1.2% (6) reported strong cravings for SD. The DSM-IV-R psychiatric diagnostic system in the United States classifies people as drug dependent based on seven criteria. Of the three who reported feelings of addiction or dependence on SD, only one endorsed any DSM-IV criteria (strong cravings and using more SD than planned). When asked about these signs and symptoms individually, 2 additional respondents (0.4%) reported three dependence criteria. None of these individuals reported more than 2 of 13 after-effects characteristic of mu-opioid withdrawal (such as increased sweating, gooseflesh, worsened mood, and diarrhea)."

"A tripwire question asks about use of salvia (or salvia divinorum) in the last 12 months. Salvia is an herb with hallucinogenic properties, common to southern Mexico and Central and South Americas. Although it currently is not a drug regulated by the Controlled Substances Act, several states have passed legislation to regulate its use, as have several countries. The Drug Enforcement Agency lists salvia as a drug of concern and has considered classifying it as a Schedule I drug, like LSD or marijuana. Annual prevalence of this drug has been in a steady decline, and in 2019 levels were less than 1% in all grades at 0.8%, 0.9%, and 0.7% among 8th, 10th, and 12th graders, respectively."