ABSTRACT

Interest in the potential therapeutic value of psychedelic drugs goes back more than 6 decades, but legal restrictions have hampered research. Recently, interest in these substances has been rekindled and clinical studies have demonstrated potential activity in a variety of psychiatric conditions. This continuing education activity will review the pharmacological and pharmacokinetic characteristics of psychedelic drugs and the results from recent clinical investigations with an emphasis on psilocybin obtained from mushrooms. In addition, it will examine recent efforts by a small but growing number of cities and states to ease limitations on use of psychedelic drugs.

INTRODUCTION

April 16, 1943. “I was forced to interrupt my work in the laboratory in the middle of the afternoon and proceed home, being affected by a remarkable restlessness, combined with a slight dizziness. At home I lay down and sank into a not unpleasant, intoxicated-like condition characterized by an extremely stimulated imagination. In a dreamlike state, with eyes closed (I found the daylight to be unpleasantly glaring), I perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors.” Pharmaceutical Chemist Albert Hofmann describing his first experience with LSD.¹

Say “magic mushrooms” and it may conger thoughts of hallucinations, “hippies,” spirituality, “bad trips,” synesthesia (a subjective sensation or image of a sense other than the one being stimulated; for example a person might hear a sound and see colors), and other fanciful imagery. However, for pharmacists and other health care practitioners, mushrooms may become part of their future armamentarium. Psychedelic drugs, including mushrooms, were promoted as possibly having beneficial effects in psychiatry and as adjuncts to psychotherapy in the 1950s and 1960s, but fell out of favor in the anti-drug movement of the 1970s.² Researchers are currently re-evaluating several serotonergic psychedelic agents (LSD, N,N-Dimethyltryptamine [DMT], ayahuasca, psilocybin) for therapeutic use.³ Although still far from the mainstream, recent studies have shown promising effects in a variety of psychiatric conditions.⁴ However, the current listing of these products as Schedule I drugs by the Controlled Substances Act (CSA) has hampered research and their medical use.⁴ Will these agents follow a path similar to another Schedule I substance, medical marijuana, and gain wider acceptance or stay on the fringe of Western medicine?

This continuing education activity will review the pharmacological and clinical activity of psychedelic drugs, with an emphasis on psilocybin, the psychoactive component obtained from mushrooms. It will focus on psilocybin’s potential for treating psychiatric disorders. It will not cover recreational use of mushrooms in detail. This continuing education activity will also examine psilocybin’s regulatory status and efforts by some states and municipalities to allow its medical use.

PSYCHEDELIC MUSHROOMS

“Psychedelics may be the oldest class of psychopharmacological agents known to man.” Researcher David Nichols²

There are many hallucinogenic mushrooms, most notably members of the genus Psilocybe.⁵ The main psychoactive ingredient in these mushrooms is psilocybin, which is found in more than 200 species of mushrooms.^3,5

Evidence from stone paintings points to the likelihood that mushroom use among aboriginal tribes in North Africa dates to 9000 BC and that use in religious ceremonies in Spain occurred 6000 years ago.⁶ Artifacts and paintings indicate that Native American cultures like the Mayas and Aztecs consumed psilocybin mushrooms as a way to communicate with deities; the Aztec “Flesh of the Gods” (“teonanácat”) is believed to be a type of psilocybe mushroom.⁶ Psilocybin was probably introduced to the Western world in the 1950s after mycologist R. Gordon Wasson and botanist Roger Heim encountered it during expeditions in Mexico. Wasson claimed to be the first Westerner to participate in a mushroom religious ritual by indigenous natives. He described his experience in a photoessay published in Life magazine in 1957 entitled, “Seeking the Magic Mushroom,” bringing mushrooms to a wider audience and influencing the counterculture movement.^5,6 It was later revealed that the Central Intelligence Agency (CIA)—interested in using psychedelic drugs to manipulate behavior—secretly subsidized the Life expedition.⁷ The CIA became interested in psychedelics, including LSD and mushrooms, in the 1950s as a means of mind control; its project, known as MKULTRA, involved extensive research among universities, hospitals, and pharmaceutical companies.⁷

Albert Hofmann, a researcher at Sandoz who also identified and synthesized LSD, first isolated, identified, and synthesized psilocybin in 1958.⁸ Sandoz (now part of Novartis) marketed psilocybin under the trade name Indocybin for psychopharmacological clinical research, but interest subsided when the newly enacted CSA classified it as a Schedule I drug in 1970.² Psilocybin and other psychedelics continue to be categorized today as Schedule I drugs, although some states and municipalities have begun efforts to permit their use.

PHARMACODYNAMICS AND PHARMACOKINETICS

“The feature that distinguishes the psychedelic agents from other classes of drug is their capacity reliably to induce states of altered perception, thought, and feeling that are not experienced otherwise except in dreams or at times of religious exaltation.” Psychiatrist Jerome H. Jaffe⁹

Psychedelics are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes through actions on serotonergic receptors.² The most common and consistent changes are perceptual distortions especially visual changes (illusions, hallucinations); impaired perception of time, space, and body image; synesthesia; paresthesia; delusions; and unusual thoughts. Some other striking effects are impaired concentration, dream-like states, depersonalization, changes in emotion (elation, anxiety), and occasional mood swings.^5,10,11

The main psychoactive ingredient in mushrooms, psilocybin, has an oral onset of action of 20 to 40 minutes and a duration of 4 to 8 hours with peak effects usually seen at 60 to 90 minutes.^5,11 Recently, a small Canadian start-up developed a sublingual film dosage form for psilocybin that bypasses first-pass metabolism and has a very rapid onset of action.¹²

Psychedelic effects are observed at oral doses above 8 to 25 mg although subjective effects have been reported with as little as 3 mg. ^11,13 Psilocybin taken orally is approximately 45 to 100 times less potent than LSD and approximately 65 times more potent than mescaline.^5,14 Recreationally, the mushrooms are consumed whole or in dried form, brewed as a tea, or may be mixed with foods to mask their bitter taste.¹⁴

Alkaline phosphatase and non-specific esterases rapidly dephosphorylate psilocybin to its active metabolite, psilocin, in the intestinal mucosa and liver.^5,13 Intact psilocybin is only weakly active and thus acts as a pro drug.¹⁵ Psilocin rapidly crosses the blood-brain barrier and produces the characteristic CNS effects.¹³

Due to its structural similarity to serotonin, psilocin undergoes comparable metabolic transformation.¹³ Psilocin is metabolized in the liver via demethylation and oxidative deamination catalyzed by monoamine oxidase (MAO) or aldehyde dehydrogenase, yielding 4-hydroxy-indole-3-acetic acid, 4-hydroxy-indole-3-acetaldehyde and 4-hydroxytryptophole.^13,17 MAO inhibitors, which are also produced by the mushroom itself, may intensify psilocin’s hallucinogenic effects and may be co-consumed recreationally.^13,17,18 Ethanol may also enhance the psilocybin experience since its primary metabolite, acetaldehyde, may produce MAO inhibitors in vivo.¹⁷ Tobacco smoking lowers MAO levels and psilocybin’s effects may be more pronounced in smokers.¹⁷

The most common adverse events associated with ingestion of psilocybin-containing mushrooms are tachycardia, anxiety, diarrhea, rapid mood changes, delusions, feelings of impending doom, and confusion.^11,16 Mild subjectively detectable sympathomimetic effects may be observed with a low dose (3 to 5 mg).¹¹ One of the most common adverse effects of consuming the mushrooms is nausea, which may be due to the components of the mushroom itself and not directly related to psilocybin.¹⁶ A more serious adverse event is hallucinogen persisting perception disorder, characterized by prolonged, frequent or overly intense psychedelic experiences and occasionally “flashbacks.” Rarely, consumption may result in seizures and a hypothetical risk of a type of cardiac valvulopathy exists. Tramadol, when administered concurrently, may further lower the seizure threshold.¹⁶ Significant tolerance is known to develop with repeated psilocybin use, along with cross-tolerance to LSD. However, development of physical dependence has not been reported.¹¹ After-effects are dose-dependent and may last up to 24 hours may occur.¹⁶

Psilocin, like most tryptamine psychedelics, binds to serotonin receptors.¹⁴ Particular interest resides in psilocin’s activity at the 5-HT2_A receptor, where most tryptamine psychedelics act as partial or full agonists.^14,19 Binding affinity to the 5-HT2_A receptor correlates with the reported psychoactive doses of tryptamine psychedelics in humans.¹⁴ LSD has the highest 5HT2_A receptor affinity, estimated to be 10 to 100 times more potent at these receptors than psilocin.^14,16 Other data provide additional evidence that 5-HT2_A receptor stimulation is a key element responsible for the psychedelic activity. Consumption of psilocybin leads to significant 5-HT2_A receptor occupancy in the human brain. Subjective intensity ratings are closely associated with both psilocin plasma levels and 5-HT2_A receptor occupancy.²⁰ Moreover, 5-HT2_A receptor antagonists such as the unapproved antihypertensive ketanserin block psychedelic effects.⁵ Other serotonin receptor antagonists, such as those blocking the related 5-HT2_C receptor, where psilocin has only a 10-fold lower affinity than for 5HT2A, are ineffective. ^14,16 Pharmacists should recall that many so-called atypical anti-psychotic drugs are potent 5HT2_A receptor antagonists in addition to dopamine,²¹ lending further support to the importance of 5HT2_A involvement. Psilocin also binds moderately to other serotonin receptors including 5HT1_A and 5HT2_C, with weaker affinity for 5-HT1_B, 5-HT4, 5-HT5, 5-HT6, and 5-HT7.^14,17,22 Psilocin also interacts with the serotonin and norepinephrine (but not dopamine), transporters, and has weak affinity for dopamine (D1 and D3) and adrenergic (α_1a, α_2a)) receptors.^14,22

Although much of the focus on psychedelic compounds’ mechanisms has been on the serotonergic system, group II metabotropic glutamate (mGlu 2) receptors seem to beinvolved.^2,19 Glutamate has also been implicated in psychiatric disorders and glutamatergic drugs such as ketamine or esketamine are likewise attracting attention as another novel approach to treating depression and other psychiatric conditions.^4,23 Recent evidence suggests that 5-HT2_A and mGlu 2/3 receptors form a heterodimer that has a role in cognitive function and the pathophysiology of neuropsychiatric disorders.²⁴ This explanation ties together two groups of controlled drugs—ketamine-like drugs and psychedelics—as novel psychiatric therapies.

PSYCHEDELIC DRUGS AS MEDICINES

"Of course, the drug does not produce the transcendent experience. It merely acts as a chemical key—it opens the mind, frees the nervous system of its ordinary patterns and structures." Psychologist and Psychedelic Guru, Timothy Leary

Interest in the potential therapeutic activity of psychedelic substances has existed for many years.² The classical psychedelic drug, lysergic acid diethylamide (LSD), synthesized in 1938 by Albert Hofmann, underwent clinical testing in 1943 after Hoffman’s accidental discovery of its potent central nervous system (CNS) effects.² The first clinical study of LSD was a European report published in 1947 and a few years later, studies began in the U.S.²⁵ LSD was touted in both the medical literature and the lay press as showing great promise for the treatment of serious mental health disorders including anxiety, depression, schizophrenia, PTSD in military personnel, alcoholism, and other substance abuse disorders.²⁵ Patients with treatment-resistant schizophrenia demonstrated fewer psychological effects than control subjects and it was thought that LSD could also induce psychotic states experimentally.² Early clinical studies in the 1950s found that psilocybin also produced an altered state of consciousness with subjective symptoms such as a marked alteration in perception. Researchers speculated that it could have clinical activity in psychiatric disorders 

Psychedelic drugs were believed to be useful as an aid in psychotherapy.^16,26 Early advocates recommended them for problems including alcoholism, substance abuse, obsessional neurosis, criminal psychopathology, sexual deviancy, and childhood autism.^10,27 Clinical reports suggested that psychedelics, principally LSD which was the most frequently studied drug of this class, could shorten the time required for psychotherapy and could successfully treat psychiatric patients with poor prognoses or who were unresponsive to more conventional therapy.¹⁰ One explanation offered for psychedelics’ effect was that they increased empathy and understanding between patient and therapist and improved recall of past memories and experiences, thereby facilitating psychotherapy.^26,28

Early studies strongly suggested that psychedelic drugs were inappropriate for patients with well-established psychotic disorders or in those with risk of developing them.²⁹ Although patients occasionally recovered from schizophrenia after psychedelic treatment, little evidence indicated the drugs were responsible for the improvement. Most patients with schizophrenia worsened when given psychedelics. Much more encouraging were reports on patients suffering from anxious, obsessive, or depressed states.²⁹

Interest in medical applications of psychedelic drugs surged between 1950 and the mid-1960s.²⁷ More than 1000 clinical papers involving 40,000 patients and dozens of books were published on psychedelic drug therapy during the period and 6 International conferences highlighted ongoing research.²⁷ Some prominent leaders in the mental health community and the pharmaceutical industry considered psychedelics as potential breakthrough therapies for psychiatric disorders due to their powerful clinical effects and relatively safety.²⁵ The rising therapeutic interest also coincided with the rapid advances in the understanding of brain chemistry and function.^4,25 However, clinical improvement was usually based on subjective judgments. Controlled studies with validated endpoints were rare and could be considered equivalent to modern early phase 2 clinical studies.^4,25,29 As a result, conclusions regarding efficacy and safety were incomplete. Interest waned in the 1970s due to legal sanctions placed on the psychedelic drugs (see below) and the concerns over their increasing recreational use.^4,25

NEW INTEREST IN CLINICAL USE

“It does not seem to be an exaggeration to say that psychedelics, used responsibly and with proper caution, would be for psychiatry what the microscope is for biology and medicine or the telescope is for astronomy. These tools make it possible to study important processes that under normal circumstances are not available for direct observation” Czech Psychiatrist Stanislav Grof¹⁰

Psilocybin and other psychedelics have attracted renewed attention for their potential therapeutic use in psychiatric disorders. Recent clinical trials have provided evidence that psilocybin could effectively treat anxiety disorders, depression, obsessive compulsive disorders (OCD), post-traumatic stress disorders (PTSD), substance use disorders (tobacco, alcohol), and end-of-life suffering, often in patients who are poorly responsive to more conventional treatments.^30-33 Potential efficacy against inflammatory diseases has also been noted.³⁰

More research has been conducted on the potential clinical activity of LSD than on psilocybin. However, psilocybin has some advantages when compared with LSD which makes it a more attractive option for clinical use.^16,27 It has a shorter duration of action (an LSD trip may last 8 to 14 hours⁴), and it produces less anxiety, fewer panicking and affective disturbances, and milder systemic adverse effects. In addition, psilocybin has a weaker association with the 1960s counterculture movement and therefore is less stigmatized than LSD.²⁷ Some representative information on clinical studies with psilocybin is reviewed below.

Currently, psilocybin therapy for psychiatric disorders is given within a structured psychotherapeutic setting with considerable therapist input. Patient always engage in a preparatory session before medical staff administers the drug and at least 1 therapist is present during the psychedelic session. A session may last up to 6 hours and usually, the recipient has follow up sessions with therapists.^4,22 It is generally recognized that the therapeutic experience’s effectiveness is dependent on the patient’s mindset and physical and social environment or setting.²⁶

Obsessive Compulsive Disorder

One of the earliest “modern” evaluations of psilocybin was a small (9 subject) pilot study in subjects with OCD published in 2006.³⁴ The subjects, who had no other major psychiatric disorder, received up to 4 double-blind doses of psilocybin (100, 200, or 300 mcg/kg or a sub-hallucinogenic 25 mcg/kg). The investigators conducted each session over an 8-hour period in a controlled environment in an outpatient clinic. They evaluated the subjects using the Yale-Brown Obsessive-Compulsive Scale (YBOCS) and a visual scale measuring overall obsessive-compulsive symptom severity at 0, 4, 8, and 24 hours post-ingestion. All subjects demonstrated a marked decrease in core OCD symptoms of variable degrees (23%-100% decrease in YBOCS score) during 1 or more of the testing sessions and this effect lasted more than 24 hours. There was no consistent effect of dose. Two single case reports in 2014³⁵ and 2020³⁶ also described patients who successfully used psilocybin to reduce OCD’s core symptoms for an extended period of time. In both of these case reports, patients self-medicated on mushrooms and reported that their OCD symptoms subsided for at least 6 months.^35,36 Further studies are needed to adequately understand the activity of psilocybin in OCD, including the possibility that sub-hallucinogenic doses may be effective.

Depression and Anxiety

Some of the most promising results with psilocybin have been in treating anxiety and depression. A recent meta-analysis of 4 studies (3 placebo controlled, 1 open; total of 117 patients) of psilocybin in combination with behavioral interventions reported a large effect on depression and anxiety which persisted at 6 months.³⁷ No serious adverse drug events were reported.

An open-label feasibility trial in 2106 examined psilocybin’s effects of 12 patients with moderate-to-severe, unipolar, treatment-resistant major depression.³⁸ Patients received 2 doses: an initial dose of 10 mg and a second dose of 25 mg one week later. All patients exhibited some reduction in depression severity at 1 week that was sustained in the majority for 3 months after the second dose, along with marked and sustained improvements in anxiety and anhedonia. Using standard criteria, as measured by the Beck Depression Inventory and clinician ratings, 8 of the 12 patients showed evidence of having achieved complete remission.³⁸

In a randomized clinical trial of psilocybin, 24 patients with major depressive disorder who were not currently using antidepressants received two doses of psilocybin (20 mg/70kg [285 mcg/kg], then 30 mg/70kg [428 mcg/kg]) an average of 1.6 weeks apart, along with therapy.³⁹ The study reported that 2/3 of participants had a clinically significant response to the treatment at week 1 as measured by the GRIV-HAMD score and 71% had a clinically significant response at week 4. More than half of participants met the criterion for remission at week 4. Currently, a double-blind clinical trial of psilocybin versus the selective serotonin reuptake inhibitor, escitalopram, in depression is ongoing.⁴

Cancer-Related Anxiety and Depression

Patients with terminal illnesses commonly develop emotional disruptions and this has been a promising area with psilocybin. In 1 study, 12 subjects with different types of advanced-stage cancer and a diagnosis of anxiety disorder secondary to cancer participated in a within-subject, double-blind, placebo-controlled study of psilocybin.⁴⁰ All experimental sessions took place in a hospital clinical research unit in a pleasing, comfortable environment. Each subject received 200 mcg/kg psilocybin or a niacin placebo and were evaluated using multiple assessment tools for depression, mood, and anxiety. The pilot study gave some indication of therapeutic benefit in quantitative psychological evaluations. In particular, a sustained reduction in anxiety reached significance at the 1- and 3-month points after treatment and mood improved for 2 weeks after psilocybin treatment. These improvements were sustained at 6-month follow-up. The authors concluded that the study demonstrated 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.”⁴⁰ 

In another study, 29 patients with cancer-related anxiety and depression received psilocybin (300 mcg/kg) or a niacin control in conjunction with psychotherapy in a double-blind, placebo-controlled, crossover trial. ⁴¹ A single dose of psilocybin produced rapid, robust anxiolytic and anti-depressant effects characterized by decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. The effects were still present at a 6.5-month follow-up. No significant adverse drug events were observed.

A randomized, double-blind cross-over trial investigated the effects of a very low 1 or 3 mg/70 kg) or high (22 or 30 mg/70 kg) dose of psilocybin in 51 cancer patients with a life-threatening diagnosis and symptoms of depression and/or anxiety.⁴² The psilocybin was administered in a counterbalanced sequence with 5 weeks between sessions and included a 6-month follow up. (Counterbalancing removes confounding variables by administering slightly different treatments to different participant groups. In this study, psilocybin doses were constant, but the sequence varied.) Participants, staff, and community observers rated mood, attitudes, and behavior throughout the study. The high dose of psilocybin produced large decreases in depressed mood and anxiety as measured by both participants and clinicians. High-dose psilocybin also increased quality of life, life meaning, and optimism, and decreased in death anxiety. The changes were still present at the 6-month follow-up. The authors noted an association of improved therapeutic outcomes with the presence of “mystical experiences” produced by the drug.⁴² Previous findings had shown that such experiences on session days could predict long-term positive changes in attitude, mood, behavior, and spirituality.

The authors also noted the risks frequently associated with depression in cancer patients which underscored the potential value of an effective treatment.⁴² Depression in cancer patients is an independent risk factor of early death; depression and anxiety are associated with decreased treatment adherence, decreased quality of life, and increased suicidality. Current therapy normally involves the use of antidepressants or, less commonly, benzodiazepines, although limited evidence supports their efficacy. In addition, benzodiazepines are only recommended for short-term use due to their adverse effects and can increase risk of opioid overdose.

AIDS-Related Depression

Psilocybin’s effects on depression have been observed in other life-threatening diseases. A single-arm, open-label, pilot study of psilocybin-assisted group therapy was conducted measuring demoralization in 18 older, gay men.⁴³ Patients received a dose of 300 to 360 mcg/kg. Measure of demoralization improved robustly over baseline by the end of treatment and improvement persisted in a 3-month follow-up. The authors likened these results to similar studies measuring psilocybin’s effect on distress in other life-threatening illnesses. Hypertension and anxiety were noted as adverse effects, with 7 patients experiencing severe, but self-limiting, reactions during the trial. In a few cases, these adverse effects could be attributed to something other than the drug. In all, 14 of the 18 participants experienced moderate-to-severe adverse events that the authors attributed, at least in part, to the study population’s clinical complexity.⁴³

Substance Use

Studies between the 1950s to 1970s provided evidence that serotonergic psychedelics might reduce alcohol and opioid dependence.^44,45 In a more recent trial, 10 volunteers meeting the DSM criteria for alcohol dependence received a dose of psilocybin at weeks 4 (0.3 mg/kg) and 8 (0.4 mg/kg) of a 12-week intervention.⁴⁴ A reduction in heavy drinking days and percent drinking days was observed during weeks 5 through 12 relative to baseline and also relative to weeks 1 to 4 (during the psychosocial treatment but before any psilocybin exposure). Measures of acute intensity of psilocybin effects (“mystical quality”) correlated closely with change in drinking behavior and decreases in craving.⁴⁴

In a recent open-label pilot study, 15 nicotine-dependent smokers received a 20 or 30 mg/70 kg dose of psilocybin as part of a structured smoking cessation treatment protocol.⁴⁵ The investigators administered psilocybin on weeks 5, 7, and 13 of the 15-week protocol. The participants had a mean of 31 years of smoking and averaged 6 previous attempts to quit. Eighty percent of participants demonstrated abstinence from smoking 6 months after the treatment. No difference was observed between the two doses.⁴⁵

Post-Traumatic Stress Disorder

Another possible indication for psilocybin is PTSD. However, more attention has been paid to another psychoactive drug, 3,4-methylenedioxymethamphetamine (MDMA [“Ecstasy”]), an amphetamine-like drug with a different mechanism of action), for this condition.⁴⁶

REGULATORY ISSUES

“America's public enemy number one in the United States is drug abuse. In order to fight and defeat this enemy, it is necessary to wage a new, all-out offensive.” President Richard Nixon. June 17, 1971⁴⁷

As noted earlier, research into the therapeutic applications of psychedelic drugs peaked in the 1950s and 1960s and ground to a virtual halt when Congress passed the Controlled Substances Act (CSA) in 1970. Under the new CSA, psychedelic drugs occupied Schedule I, the most restrictive category, where they remain today.

The U.S. legislated many regulations to control the use of abused drugs during the 20^th Century.⁴⁸ In 1970, President Richard Nixon signed the CSA which consolidated more than 200 separate laws into a comprehensive, unified legal framework to regulate drugs deemed as posing a risk of abuse and dependence.^23,48 A new federal agency, the Drug Enforcement Administration (DEA), was created in 1973 to enforce the new law. Pharmacists are aware that the CSA categorizes drugs into 5 schedules based upon their medical risks, therapeutic use, and potential for abuse and addiction.⁴⁸

Inclusion of psychedelics as Schedule I drugs is often attributed to many factors including a general societal and politicized disapproval of drug abuse (“The War on Drugs”), association of psychedelics with the counterculture movement in the 1960s, and concerns over reports of long-lasting psychotic responses (e.g., “bad trips” and “flashbacks”) and other purported adverse effects (e.g., chromosomal damage, cancer) during recreational use.^9,24,26 The criteria for a Schedule I drug are⁴⁹

• The drug or other substance has a high potential for abuse.
• The drug or other substance has no currently accepted medical use in treatment in the U.S.
• There is a lack of accepted safety for use of the drug or other substance under medical supervision.

Schedule I drugs may only be used in the context of approved scientific studies.⁴⁸ However, the heavy regulatory and costly administrative barriers make conducting clinical research with these drugs more difficult.^4,23,25

Other Schedule I Drugs

The psychedelic agents are not the first Schedule I drugs to demonstrate promising therapeutic profiles while facing regulatory barriers. A relevant case is marijuana, which remains a Schedule I drug at the federal level, although that may not be the case for long. California became the first state to enact a state law permitting the use of marijuana for medical purposes in 1996. Currently, 36 states (plus the District of Columbia) have medical marijuana programs, and 15 states (plus the District of Columbia) have legalized recreational marijuana despite the conflict with the federal law.⁵⁰ FDA approved a form of the non-intoxicating cannabinoid, cannabidiol (CBD; Epidiolex) for treating pediatric seizures. FDA recently de-scheduled finished dosage formulations that contain CBD derived from cannabis and no more than 0.1% tetrahydrocannabinols (and Epidiolex is the only drug that meets this definition currently) since the criterion of “no currently accepted medical use in treatment in the United States” no longer applies.⁵¹ The experience with marijuana provides a potential pathway to quasi-legal status for the psychedelics.

State/Local Initiatives

Recent actions taken at state and municipal levels suggest that such a pathway is at least plausible. In May 2019, Denver, Colorado became the first city to decriminalize psilocybin-containing mushrooms. This came about as the result of a ballot initiative (Initiative 301) which passed narrowly with 50.6% of the vote.⁵²

Specifically, the Act “deprioritizes” the imposition of criminal penalties on persons 21 years of age or older for their possession and personal use of psilocybin-containing mushrooms and prohibits the City of Denver from spending resources to impose criminal penalties on adult mushroom users.⁵² The measure, however, stops short of making psilocybin “legal” in the city. The State Attorney General has indicated that the sale or possession of psychedelic mushrooms is still illegal, and no psilocybin dispensaries or other retail sale will be permitted. Regardless, enforcement of possession and use will take a very low priority.⁵³ While it may be considered symbolically important, the practical impact of the new law is small; between 2016 and 2018, law enforcement officials filed 9,267 drug cases of which only 11 involved psilocybin. Of those 11 cases, 3 were for possession with intent to manufacture or distribute psilocybin.⁵³ However, Colorado decriminalized marijuana in 2005 and supporters believe that the lax enforcement helped pave the way for the state to legalize recreational sales.⁵³ It is possible that the new act may provide the same framework for psilocybin.⁵³

Following in Denver’s footsteps, Oakland and Santa Cruz, California also decriminalized psilocybin in 2019 and 2020, respectively. In both cases, the action was taken by their respective City Councils rather than by referendum.⁵⁴ The Santa Cruz ordinance is very similar to Denver’s, preventing resources from being used to investigate or arrest persons 21 years of age and older solely for the personal use and possession of “entheogenic plants and fungi.” Community testimony from persons sharing mental health struggles and treatment likely contributed to the Council’s decision.⁵⁴ Oakland not only decriminalized mushrooms but also mescaline cacti, ayahuasca, and ibogaine. Voters in Washington D.C. also approved similar measures to decriminalize psychedelic mushrooms in 2020 but, due to Washington’s unique status, implementation awaits Congressional approval. ⁵⁶ The City Council in Ann Arbor, Michigan also unanimously approved mushroom decriminalization in 2020.⁵⁶

In 2020, Oregon became the first state to provide legal access to psilocybin, establishing a therapy program whereby patients could buy and possess psilocybin from a State-licensed health care facility while undergoing treatment in a supervised setting.⁵⁷ The measure was passed by referendum in the 2020 election. Note that Oregon’s law has more of a medical focus as opposed to the recreational thrust in the actions taken by the cities.⁵⁵ An additional law was passed the same day in Oregon to decriminalize possession of small quantities of Schedule I through IV drugs including heroin and cocaine; violators would be subject to a $100 fine which could be waived if the person receives a health assessment from a certified counselor. California’s legislature is also considering decriminalizing mushrooms. It is reasonable to believe that other states (e.g., NY, Vermont, Iowa) could follow. The sponsor of New York’s proposed bill noted the drug’s potential to affect mental health and addiction issues as a rationale.

SUMMARY AND FINAL COMMENTS

Research into the use of psychedelic drugs held out the promise of revolutionary treatment of psychiatric disorders in 1950s and 60’s, but the inclusion of these agents as Schedule I drugs in the new CSA in 1970 dampened the enthusiasm. However, interest recently in both the therapeutic use and relaxing legal restrictions on these compounds has resurged.

Administration of psilocybin to patients with psychotherapy under controlled environments has been associated with improvements in several types of psychiatric conditions. Psilocybin reduces anxiety and depression especially in terminally ill patients (e.g., cancer), and reduces symptoms of alcohol and tobacco dependence.⁵⁸ These effects have been reported in studies generally using doses of approximately 300 mcg/kg. Most studies report either a single dose or two widely spaced doses, with long-lasting effects (6 months in some studies). A striking feature of psilocybin is the demonstration of efficacy with 1 or 2 doses to treat depression, which ordinarily requires a long course of therapy with conventional drugs.⁵⁸ It is noteworthy that psychedelic drugs have a unique mechanism of action unlike existing antidepressant and anti-anxiety drugs. Clinical studies generally report no serious adverse effects, the most common concerns being sympathomimetic symptoms and anxiety which tend to self-limiting.⁶⁰

A review prepared by an expert advisory board that included pharmacists for the Minister of Health of the Netherlands in 2011 concluded that recreational use of mushrooms is relatively safe with relatively mild adverse effects.¹⁷ They determined that acute toxicity was moderate, chronic toxicity was low, and mushroom use produced negligible public health and criminal consequences. Moreover, they concluded that the risk of physical and psychological dependence due to magic mushrooms was low.¹⁷ In fact, some reports indicate that the lifetime recreational use of psychedelics is associated with better measures of psychological well-being (psychological distress and suicidality).⁶⁰ The Dutch advisory committee raised some concerns including combining mushrooms with alcohol and unpredictable provocation of panic attacks and “flash-backs” but these were believed to have a low prevalence.¹⁷ Likewise, the emergence of prolonged psychotic symptoms, while serious, are believed to be rare events with mushrooms and are influenced by the setting and vulnerability of a subset of individuals.⁵⁹

It is significant that FDA has granted breakthrough therapy designation to psilocybin in recognition of its clinical potential; 2 companies are currently conducting psylocibin clinical trials. A breakthrough therapy designation is a process designed to expedite the review and development of new drugs. Eligible therapies must be intended to treat serious conditions where preliminary evidence on a clinically significant endpoint indicates that the therapy may demonstrate substantial improvement over currently available therapy. It must also show a clear advantage over available therapy.⁶¹ In the case of psilocybin, the breakthrough designation is for its potential to improve treatment-resistant depression. Depression is a major public health issue and is a leading factor in disability. It is responsible for producing an economic cost of more than $100 billion per year in the U.S.²³ On average, there are more than 100 suicide deaths per day in the U.S, presumably many due to depression. Patients who fail to respond to antidepressant treatment have few options remaining, and none are very appealing or effective,²³ so the need for alternatives is pressing.

Although clinical research is promising, some shortcomings need to be considered. Few clinical reports are randomized clinical trials.⁵⁸ Many are open label trials with small sample sizes. The studies typically only used 1 or 2 doses, and 6-month follow-up periods, so information on optimal dosing and long-term adverse effects is lacking.⁵⁸ In addition, the standard protocol of intensive psychotherapy and controlled environments raises obstacles for routine applications, including high costs.^4,55 Some patients may also find the treatments to be less convenient than just taking a pill without the need for concurrent psychotherapy intervention.⁵⁵

Nevertheless, the encouraging research results for psilocybin in a variety of psychiatric conditions has generated calls to loosen the regulatory constraints on its use. Four cities and 1 state have decriminalized personal use of mushrooms or psilocybin and there is every reason to believe that the numbers will grow. Pharmacists need to stay abreast of developments in their towns or states. As acceptance of psilocybin escalates, pharmacist will encounter patients with questions about these substances. They should also be on the lookout for unexpected adverse effects and drug interactions, especially since some patients may self-medicate. Pharmacists should keep in mind that mushrooms contain other substances in addition to psilocybin. Conversely, a regulation that specifically modifies the regulation of psilocybin will not necessarily generally apply to mushrooms.

Psilocybin could follow a route similar to that used for medical marijuana and gain quasi-legal status state-by-state. Oregon has already opened the door to legitimizing the medical use of mushrooms by adults and other states are expected to follow. Whether it will be distributed through pharmacies or take another track, such as psychedelic dispensaries as has often occurred with medical marijuana, is unknown. Of course, the drug could also become FDA-approved and be dispensed on prescription, but its availability may be restricted to specialty pharmacies.

With the FDA granting breakthrough therapy designation to psilocybin, it is reasonable to expect that some form of psilocybin could be approved for use under certain circumstances. A similar path led to the approval of esketamine, an enantiomer of the Schedule II anesthetic ketamine, as an adjunct for treatment-resistant depression. However, in psilocybin’s current classification as a Schedule I drug, it is unclear how it may be made available.

What might a future prescription for psilocybin look like? A group of researchers at Johns Hopkins evaluated the current research on the safety and abuse liability of psilocybin and commented that it has therapeutic benefits that could support an application for FDA approval.⁶² They propose that a supportable outcome could be placement in Schedule IV along with a legally binding Research Evaluation and Mitigation Strategies (REMS) plan. A REMS would incorporate dosing limits for individual patients, administration in a clinic setting with psychological support by specially trained staff, restrictions on distribution, and post marketing surveillance.⁶²

Regardless, pharmacists should become familiar with the characteristics of psilocybin in preparation for its expanded use. Forward thinking pharmacists may also begin contemplating that other highly restricted drugs such as DMT, ayahuasca, ibogaine, and LSD may follow. Psilocybin, one of the oldest drugs known to mankind just may become the newest approach to treating psychiatric disorders.

REFERENCES

1. This day in history: April 16. History. Accessed April 6, 2021. https://www.history.com/this-day-in-history/hallucinogenic-effects-of-lsd-discovered#:~:text=Hofmann%20was%20disturbed%20by%20unusual,combined%20with%20a%20slight%20dizziness
2. Nichols DE. Psychedelics. Pharmacol Rev. 2016;68(2):264-355.
3. Nichols DE. Psilocybin: from ancient magic to modern medicine. J Antibiot(Tokyo). 2020; 73(10):679-686.
4. Nutt D, Erritoze D, Carhart-Harris R. Psychedelic Psychiatry’s Brave New World. Cell. 2020; 181:21-28.
5. Tylš F, Páleníček T, Horáček J. Psilocybin--summary of knowledge and new perspectives. Eur Neuropsychopharmacol. 2014; 24(3):342-356.
6. Brusco R. Tripping through time: the fascinating history of the magic mushroom. Ancient Origins. February 1, 2017. Accessed April, 6, 2021. https://www.ancient-origins.net/history-ancient-traditions/tripping-through-time-fascinating-history-magic-mushroom-007474
7. Kinzer S.A CIA Chemist, Mind Control – and the Return of Psychedelic Drugs. Boston Globe. Updated January 9, 2020. Accessed April, 6, 2021. https://www.bostonglobe.com/2020/01/09/opinion/cia-chemist-mind-control-return-psychedelic-drugs/
8. Hofmann A, Frey A, Ott H, et al. Elucidation of the structure and the synthesis of psilocybin. Experientia. 1958; 14(11):397-399.
9. Jaffe JH. Drug addiction and drug abuse. IN: Goodman AG, Rall TW, Nies AS, Taylor P. eds. Goodman and Gilman’s the Pharmacological Basis of Therapeutics. 8th ed. McGraw Hill; 1990:522–573,.
10. Grof S. Realms of the Human Unconscious: Observations from LSD Research. Viking Press;1975. Accessed April, 6, 2021. http://cista.net/Grof/Stanislav%20Grof%20-%20Realms%20Of%20The%20Human%20Unconscious%20-%20Observations%20from%20LSD%20Research.pdf
11. Passie T, Seifert J, Schneider U, Emrich HM. The Pharmacology of Psilocybin. Addict Biology. 2002; 7(4):357- 364. 
12. Yakowicz W. Pharmaceutical startup developing sublingual psilocybin raises $34 million to fund clinical trials. Forbes. October 22, 2020. Accessed April, 6, 2021. https://www.forbes.com/sites/willyakowicz/2020/10/22/pharmaceutical-startup-developing-sublingual-psilocybin-raises-34-million-to-fund-clinical-trials/?sh=76f3577b9046
13. Dinis-Oliveira RJ. Metabolism of psilocybin and psilocin: clinical and forensic toxicological relevance. Drug Metab Rev. 2017; 49(1):84-91.
14. Rickli A, Moning OD, Hoerner MC, Liechti ME. Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. Eur Neuropsychopharmacol. 2016; 26(8):1327-1337.
15. Drug Facts: Psilocybin. Drug Enforcement Administration. Accessed April, 6, 2021. https://www.dea.gov/factsheets/psilocybin
16. Geiger HA, Wurst MG, Daniels RN. DARK classics in chemical neuroscience: psilocybin. ACS Chem Neurosci. 2018:9(10), 2438-2447.
17. Van Amsterdam J, Opperhuizen A, van den Brink W. Harm potential of magic mushroom use: a review. Regul Toxicol Pharmacol. 2011; 59(3):423-429.
18. Blei F, Dorner S, Baldeweg F, et al. Simultaneous production of psilocybin and a cocktail of β‐carboline monoamine oxidase inhibitors in “magic” mushrooms. Chemistry – Europe. 2020; 26(3):729-734.
19. López-Giménez JF, González-Maeso J. Hallucinogens and Serotonin 5-HT_2Areceptor-mediated signaling pathways. Curr Top Behav Neurosci. 2018; 36:45-73.
20. Madsen MK, Fisher PM, Burmester D, et al. Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology. 2019; 44(7):1328-1334.
21. Guzman F. Mechanism of action of anti-psychotic agents. Psychopharmacology Institute. June 27, 2019. Accessed April, 6, 2021.https://psychopharmacologyinstitute.com/publication/mechanism-of-action-of-antipsychotic-agents-2094
22. Gill H, Gill B, El-Halabi S, et al. The emerging role of psilocybin and MDMA in the treatment of mental illness. Exp Rev Neurotherap. 2020; 20(12):1263-1273.
23. Marks M. Psychedelic medicine for mental illness and substance use disorders: overcoming social and legal obstacles. NYU J Legislation Pub Policy. 2017; 21:69-140.
24. Wischhof L, Koch M. 5-HT2A and mGlu2/3 receptor interactions: on their relevance to cognitive function and psychosis. Behav Pharmacol. 2016; 27(1):1-11.
25. Belouin S, Henningfield JE. Psychedelics: Where we are now, why we got here, what we must Neuropharmacology. 2018; 142:7-19.
26. Sessa B. From sacred plants to psychotherapy: The history and re-emergence of psychedelics in Accessed April, 6, 2021. https://www.rcpsych.ac.uk/docs/default-source/members/sigs/spirituality-spsig/ben-sessa-from-sacred-plants-to-psychotherapy.pdf?sfvrsn=d1bd0269_2
27. Marlan D. Beyond cannabis: Psychedelic decriminalization and social justice. Lewis & Clark Law Rev. 2019; 23(3):851-892.
28. Cole JO, Katz MM. The psychotomimetic drugs: An overview. 1964;187(10):758–761.
29. Rucker JJ, Jelen LA, Flynn S, et al. Psychedelics in the treatment of unipolar mood disorders: a systematic review. J Psychopharmacol. 2016; 30(12):1220-1229.
30. Nichols DE, Johnson MW, Nichols CD. Psychedelics as medicines: An emerging new paradigm. Clin Pharmacol Ther. 2017;101(2):209-219.
31. Reiff CM, Richman EE, Nemeroff CB, et al. Psychedelics and psychedelic-assisted psychotherapy. Am J Psychiat. 2020; 177(5):391-410.
32. Carhart-Harris R, Goodwin GM. The therapeutic potential of psychedelic drugs: Past, present, and future. Neuropsychopharmacology. 2017; 42(11):2105-2113.
33. Daniel J, Haberman M. Clinical potential of psilocybin as a treatment for mental health conditions. Ment Health Clin. 2017; 7(1):24-28.
34. Moreno FA, Wiegand CB, Taitano EK, et al. Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive-compulsive disorder J Clin Psychiatry. 2006; 67(11):1735-1740.
35. Wilcox JA. Psilocybin and obsessive compulsive disorder. J Psychoactive Drugs. 2014; 46(5):393-395.
36. Lugo-Radillo A MD, PhD, Cortes-Lopez JL MD. Long-term amelioration of OCD symptoms in a patient with chronic consumption of psilocybin-containing mushrooms. J Psychoactive Drugs. 2020; 22:1-3.
37. Goldberg SB, Pace BT, Nicholas CR, et al. The experimental effects of psilocybin on symptoms of anxiety and depression: A meta-analysis. Psychiatry Res. 2020; 284:112749.
38. Carhart-Harris RL, Bolstridge M, Day CMJ, et al. Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology (Berl). 2018;235(2):399-408.
39. Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2020;e203285.
40. Grob CS, Danforth AL, Chopra GS, et al. Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer. Arch Gen Psychiatry. 2011;68(1):71-78.
41. Ross S, Bossis A, Guss J, et al. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. J Psychopharmacology. 2016; 30(12):1165-1180.
42. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacology. 2016; 30(12):1181-1197.
43. Anderson BT, Danforth A, Daroff PR, et al. Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study. EClinicalMedicine. 2020;27:100538.
44. Bogenschutz MP, Forcehimes AA, Pommy JA, et al. Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol.2015; 29(3):289-299.
45. Johnson MW, Garcia-Romeu A, Cosimano MP, Griffiths RR. Pilot study of the 5-HT2AR agonist psilocybin in the treatment of tobacco addiction. J Psychopharmacol.2014; 28(11):983-992.
46. Krediet E, Bostoen T, Breeksema, et al. Reviewing the potential of psychedelics for the treatment of PTSD. Int J Neuropsychopharmacol. 2020;23(6):385-400.
47. Nixon R. Remarks about an intensified program for drug abuse prevention and control. June 17, 1971. Accessed April, 6, 2021. https://prhome.defense.gov/Portals/52/Documents/RFM/Readiness/DDRP/docs/41%20Nixon%20Remarks%20Intensified%20Program%20for%20Drug%20Abuse.pdf
48. Sacco LN. Drug Enforcement in the United States: History, Policy, and Trends. Congressional Research Service. October 2, 2014. Accessed April, 6, 2021. https://fas.org/sgp/crs/misc/R43749.pdf
49. Drugs of Abuse: A DEA Resource Guide. 2017 Edition. Drug Enforcement Administration. Accessed April, 6, 2021. https://www.dea.gov/sites/default/files/drug_of_abuse.pdf
50. Legal medical marijuana states and D.C. ProCon.Org. Updated December 3, 2020. Accessed April, 6, 2021. https://medicalmarijuana.procon.org/legal-medical-marijuana-states-and-dc/
51. GW Pharmaceuticals PLC and its U.S. subsidiary Greenwich Biosciences, Inc. announce that EPIDIOLEX® (cannabidiol) Oral Solution has been descheduled and is no longer a controlled substance. Accessed April, 6, 2021. https://www.globenewswire.com/news-release/2020/04/06/2012160/0/en/GW-Pharmaceuticals-plc-and-Its-U-S-Subsidiary-Greenwich-Biosciences-Inc-Announce-That-EPIDIOLEX-cannabidiol-Oral-Solution-Has-Been-Descheduled-And-Is-No-Longer-A-Controlled-Substan.html
52. Denver, Colorado, initiated Ordinance 301, psilocybin mushroom initiative (May 2019). BallotPedia. Accessed April, 6, 2021. https://ballotpedia.org/Denver,_Colorado,_Initiated_Ordinance_301,_Psilocybin_Mushroom_Initiative_(May_2019)
53. Wingerter J. Questions about Denver’s decriminalization of magic mushrooms? We have your answers. Denver Post. May 19, 2019. Accessed April, 6, 2021. https://www.denverpost.com/2019/05/09/denver-magic-mushrooms-questions-answers/
54. York JA. Santa Cruz Decriminalizes Natural Psychedelics. Santa Cruz Sentinel. January 29, 2020. Accessed April, 6, 2021. https://www.santacruzsentinel.com/2020/01/29/santa-cruz-decriminalizes-natural-psychedelics/
55. Cormier Z. Psilocybin Treatment for Mental Health Gets Legal Framework. Scientific American. December 1, 2020. Accessed April, 6, 2021. https://www.scientificamerican.com/article/psilocybin-treatment-for-mental-health-gets-legal-framework/
56. Meloni R, Hutchinson D. ClickonDetroit. September 22, 2020. Accessed April, 6, 2021. https://www.clickondetroit.com/all-about-ann-arbor/2020/09/22/city-council-votes-to-make-psychedelic-mushrooms-legal-in-ann-arbor/
57. Oregon Measure 109, Psilocybin Mushroom Services Program Initiative (2020). Accessed April, 6, 2021. https://ballotpedia.org/Oregon_Measure_109,_Psilocybin_Mushroom_Services_Program_Initiative_(2020)
58. Dos Santos, RG, Bouso, JC, Alcázar-Córcoles, M, Hallak, JE. Efficacy, tolerability, and safety of serotonergic psychedelics for the management of mood, anxiety, and substance-use disorders: a systematic review of systematic reviews. Expert Rev Clin Pharmacol. 2018; 11(9):889-902.
59. Lieberman JA, Shalev D. Back to the future: Research renewed on the clinical utility of psychedelic drugs. J Psychopharmacology. 2016; 30(12):1198-1200.
60. Hendricks, PS, Johnson MW, Griffiths RR. Psilocybin, psychological distress and suicidality. J Psychopharmacol. 2015; 29(9):1041-1043.
61. Breakthrough Therapy. U.S. Food and Drug Administration January 4, 2018. Accessed April, 6, 2021. https://www.fda.gov/patients/fast-track-breakthrough-therapy-accelerated-approval-priority-review/breakthrough-therapy
62. Johnson MW, Griffiths RR, Hendricks PS, Henningfield JE. The Abuse Potential of Medical Psilocybin According to the 8 Factors of the Controlled Substances Act. Neuropharmacology. 2018;142:143-166.

Back to Top