This review (2020) finds that randomized clinical trials (RCTs) support the efficacy of various psychedelic-assisted therapies for mental health disorders.

Abstract

“Objective: The authors provide an evidenced-based summary of the literature on the clinical application of psychedelic drugs in psychiatric disorders.

Methods: Searches of PubMed and PsycINFO via Ovid were conducted for articles in English, in peer-reviewed journals, reporting on “psilocybin,” “lysergic acid diethylamide,” “LSD,” “ayahuasca,” “3,4-methylenedioxymethamphetamine,” and “MDMA,” in human subjects, published between 2007 and July 1, 2019. A total of 1,603 articles were identified and screened. Articles that did not contain the terms “clinical trial,” “therapy,” or “imaging” in the title or abstract were filtered out. The 161 remaining articles were reviewed by two or more authors. The authors identified 14 articles reporting on well-designed clinical trials investigating the efficacy of lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), psilocybin, and ayahuasca for the treatment of mood and anxiety disorders, trauma and stress-related disorders, and substance-related and addictive disorders as well as in end-of-life care.

Results: The most significant database exists for MDMA and psilocybin, which have been designated by the U.S. Food and Drug Administration (FDA) as “breakthrough therapies” for posttraumatic stress disorder (PTSD) and treatment-resistant depression, respectively. The research on LSD and ayahuasca is observational, but available evidence suggests that these agents may have therapeutic effects in specific psychiatric disorders.

Conclusions: Randomized clinical trials support the efficacy of MDMA in the treatment of PTSD and psilocybin in the treatment of depression and cancer-related anxiety. The research to support the use of LSD and ayahuasca in the treatment of psychiatric disorders is preliminary, although promising. Overall, the database is insufficient for FDA approval of any psychedelic compound for routine clinical use in psychiatric disorders at this time, but continued research on the efficacy of psychedelics for the treatment of psychiatric disorders is warranted.”

Authors: Collin M. Reiff, Elon E. Richman, Charles B. Nemeroff, Linda L. Carpenter, Alik S. Widge, Carolyn I. Rodriguez, Ned H. Kalin & William M. McDonald

Summary

—The Moody Blues, 1968

In 1938, Albert Hofmann synthesized the first synthetic hallucinogen, LSD, while working with the pharmaceutical company Sandoz. In 1943, Hofmann came into physical contact with LSD and began marketing it as Delysid.

Timothy Leary began experiments with psilocybin and LSD in 1960, but was dismissed from Harvard in 1963. Governments raised concerns about the general public’s use of psychedelics in 1965, and the FDA forced researchers to relinquish their supplies of psychedelics.

Timothy Leary died in 1996, but the lyrics by Ray Thomas were prescient: psychedelic research was indeed dead after the passage of the Controlled Substances Act.

Over the past decade, there has been a resurgence of research on the potential therapeutic benefits of psychedelic compounds, with several organizations funding pivotal trials and working with regulatory agencies to ensure that studies conform to regulatory guidelines for eventual approval of clinical use.

The U.S. Drug Enforcement Administration (DEA) currently classifies LSD, ayahuasca, psilocybin, and MDMA as Schedule I substances because they lack accepted medical use or safety data.

Methods

We searched PubMed and PsycINFO via Ovid for articles on psilocybin, LSD, ayahuasca, 3,4-methylenedioxymethamphetamine, and MDMA in human subjects, and identified 14 articles reporting on well-designed clinical trials investigating the efficacy of these drugs for the treatment of mood and anxiety disorders, trauma- and stress-related disorders, and substance use disorders.

Psychedelic Compounds

The psychedelics are divided into four classes: classic psychedelics, empathogens or entactogens, dissociative anesthetic agents, and atypical hallucinogens. In this review, we discuss three classic psychedelics and one entactogen in detail.

Psilocybin

Psilocybin is a plant alkaloid derived from tryptamine precursors and found in a variety of mushroom species. It was first isolated from the mushroom species Psilocybe mexicana by Roger Heim and Albert Hofmann and his colleagues at Sandoz Laboratories.

Psilocybin is active metabolized to psilocin, a serotonin transporter inhibitor and 5-HT2A receptor partial agonist. It can cause mild to profound changes in sensory perception, including synesthesia, euphoria, sensory illusions, and auditory and visual hallucinations.

Systematic investigation into psilocybin began in 1962 with the Marsh Chapel Experiment, in which Protestant divinity student volunteers received psilocybin or a placebo. The experiment confirmed the potential entheogenic properties of psilocybin.

Leary and colleagues conducted an open-label study of psilocybin-assisted group psychotherapy in prisons to determine whether it could reduce rates of recidivism.

Psilocybin has been used to treat depression, obsessive-compulsive disorder, end-of-life anxiety, and tobacco and alcohol use disorders. A pilot study has shown that psilocybin may be effective in treating moderate to severe depression and treatment-refractory depression. The mean change in QIDS depression scores was significantly decreased from baseline to 1 week and 3 months after treatment. Eight patients achieved categorical remission at 1 week and seven patients achieved categorical response at 3 months.

fMRI scans were performed at baseline and the morning after a high-dose psilocybin-assisted psychotherapy session. Patients who received psilocybin showed increased amygdalar responses to fearful compared with neutral faces 1 day after treatment, and this response predicted positive clinical outcome 1 week later.

A randomized clinical trial of psilocybin for the treatment of anxiety in patients with advanced-stage breast, colon, ovarian, peritoneal, or salivary gland cancers or multiple myeloma found that STAI trait scores were significantly decreased at follow-up assessments 1 month and 3 months after the second treatment session.

A double-blind randomized crossover study by Griffiths et al. (18) investigated the effects of psilocybin on depression and anxiety syndromes in patients with terminal cancer who also had a DSM-IV diagnosis of an anxiety or mood disorder.

Participants received high-dose psilocybin for 5 weeks, and the effects persisted through 6-month follow-up. A clinically significant response was defined as a decrease of $50% in score on the GRID-HAM-D-17 or the HAM-A relative to baseline.

A double-blind placebo-controlled randomized controlled crossover study evaluated the efficacy of a single high dose of psilocybin in patients with cancer-related anxiety and depressive symptoms. The study included preparatory psychotherapy, medication dosing sessions, and postdosing integrative psychotherapy.

The psilocybin group had significant reductions in all primary measures immediately after the experimental session, and these reductions persisted until crossover of the control group at week 7. The placebo group had no sustained significant reductions in depression or anxiety symptoms.

A pilot study of 15 participants who wanted to quit smoking used psilocybin in combination with cognitive-behavioral therapy and assigned a target quit date. All participants remained smoke-free at 6 months, 12 months, and 2.5 years.

Bogenschutz et al. (31) evaluated open-label psilocybin for the treatment of alcohol dependence in individuals who had at least two heavy drinking days in the previous 30 days.

The researchers found that after the first psilocybin session, abstinence increased and was sustained through 36 weeks. A randomized clinical trial is currently being conducted to investigate the efficacy of psilocybin for treating alcohol dependence.

Psilocybin-assisted therapy is based on the notion that participant response correlates with a psilocybin-induced “mystical” or “spiritual” experience. The Mystical Experience Questionnaire (MEQ-30) is a validated measure of mystical experience that assesses seven domains of mystical experiences.

In a prospective study, individuals with no prior use of psilocybin had healthy psychological functioning at 6-month follow-up. The intensity of the psilocybin-induced mystical experience made the most significant contribution to the effect.

Despite the acute presentation of psilocybin-intoxicated individuals closely resembling psychosis, researchers have found no evidence of hallucinogen persisting perception disorder, prolonged psychosis, or other long-term impairment of functioning in any subjects.

In an online survey of almost 2,000 people, 39% reported having a psychologically difficult or challenging experience after taking psilocybin mushrooms. Twenty-four percent reported psychological symptoms lasting 1 week or longer, and 10% reported persistent symptoms for more than 1 year.

Psilocybin was designated a “breakthrough therapy” by the FDA in 2018 for treatment-resistant depression, and several phase 2 and 3 clinical trials are currently underway to investigate psilocybin’s effects in patients with a diagnosis of obsessive-compulsive disorder, cocaine use disorder, opioid use disorder, anorexia nervosa, and depression in early Alzheimer’s disease.

Lysergic Acid Diethylamide (LSD)

LSD is an ergot derivative that induces powerful psychedelic, spiritual, and mystical experiences. It can also induce feelings of closeness to others, enhance emotional empathy, enhance sociality, and acutely impair fear recognition.

LSD causes hallucinations by binding to several receptors, including the 5-HT2A receptor and the 5-HT1A receptor, and also causes increased functional connectivity and excitability in thalamic and cortical structures.

Several studies have shown that LSD may cause psychotic symptoms in healthy volunteers, but a large epidemiologic study has not found a link between psychedelic use and mental health problems or suicidal behavior.

LSD has been recognized as a potential treatment for alcohol use disorder, mood disorders, and pain syndromes associated with end-of-life care. However, clinical research on the therapeutic use of LSD was cut short in 1968 when the Drug Abuse Control Amendments were modified. Gasser et al. (48) conducted a randomized controlled trial in which 12 patients with anxiety associated with medical disease received LSD-assisted psychedelic psychotherapy.

At the 2-month follow-up, mean trait anxiety and mean state anxiety were significantly decreased in the high-dose LSD group compared with the low-dose (placebo) group, respectively.

Swiss researchers reported on short-term and long-term follow-ups after healthy volunteers were given a single moderate dose of LSD as part of a randomized double-blind placebo-controlled crossover study with two experimental sessions.

One and 12 months after LSD administration, participants showed significant increases in positive attitudes, positive mood changes, altruistic/positive social effects, positive behavioral changes, and well-being/life satisfaction. They also rated their LSD experience as among the 10 most meaningful experiences in their lives.

Researchers found that LSD decreased amygdalar activity during processing of fearful stimuli, and impaired recognition of fearful faces. They suggested that LSD might be useful for reducing perceptions of negative emotions, ameliorating social cognitive deficits, and facilitating therapeutic alliance.

Recently, there has been emerging interest in microdosing LSD, but there is no available scientific evidence to support the practice. Furthermore, low-dose LSD (20 mg) received by the active placebo group was associated with worsening anxiety in people with comorbid medical illness.

There are several new clinical investigations into LSD in Switzerland, including LSD-assisted psychotherapy for patients with illness-related anxiety and LSD-induced altered states of consciousness.

Ayahuasca

Ayahuasca is a decoction made from Banisteriopsis caapi and Psychotria viridis that works synergistically to induce effects by inhibiting monoamine oxidase A and releasing 5-HT.

Ayahuasca is associated with a wide range of subjective effects, including auditory and visual hallucinations, altered sensorium, altered spatial perceptions, euphoria, and psychotic episodes. These psychotic episodes are not generally prolonged.

Ayahuasca consumption is associated with traditional practices among indigenous groups of the northwestern Amazon region, but clinical trials are non-existent in the United States because DMT is a Schedule I controlled substance.

Brazilian researchers conducted a small open-label clinical trial with ayahuasca in patients with depression who had not responded to at least one trial of an antidepressant medication. The mean HAM-D score was reduced by 62% 1 day after drug administration and by 72% 7 days after drug administration.

The same research team conducted a replication study with a larger sample (N=17), and found that symptoms decreased acutely, starting 80 minutes after drug administration, and decreased significantly at 21-day follow-up.

Currently, the data are insufficient to support the use of ayahuasca in the clinical setting. Further studies using standardized compounds are necessary to advance our knowledge about the therapeutic potential of ayahuasca.

3,4-Methylenedioxymethamphetamine (MDMA)

MDMA, a ring-substituted phenethylamine with structural similarities to amphetamine and mescaline, was synthesized by Merck & Co. in 1912 as a potential therapeutic agent to decrease clotting time and to prevent hemorrhaging. Its psychoactive properties encouraged its use as a recreational drug.

MDMA and other 3,4-methylenedioxy-substituted phenethylamines have been postulated to represent a new class of pharmacological agents, termed entactogens, with effects only partially overlapping those of psychostimulants and serotonergic hallucinogens.

MDMA causes transient but tolerable increases in heart rate, blood pressure, and body temperature in healthy subjects, and the processing of contextual information is left intact after MDMA ingestion. A double-blind fMRI study in healthy volunteers demonstrated that MDMA reduces response to threat and enhances response to reward.

Mithoefer et al. (106) conducted a phase 2 randomized controlled trial on 23 adults with chronic PTSD. The participants received either manualized MDMA-assisted psychotherapy with active drug (125 mg orally with an optional supplemental dose of 62.5 mg) or placebo.

A significant proportion of participants in the MDMA group met criteria for categorical response compared to the placebo group, and 7 of 8 placebo-treated participants crossed over to the MDMA group and had a clinical response 4 – 6 weeks after two MDMA sessions.

A prospective long-term follow-up study examined CAPS scores obtained 17 – 74 months after the two MDMA-assisted psychotherapy sessions. No significant change was observed in mean CAPS scores among completers. Mithoefer et al. (105) completed a phase 2 double-blind randomized controlled trial in which 26 service personnel, firefighters, police officers, and veterans received MDMA in two blinded psychotherapy sessions spaced 1 month apart. The moderate- and high-dose groups had greater reductions in PTSD symptom severity from baseline than the low-dose group, and more participants in the moderate- and high-dose groups met criteria for clinical response.

The FDA approved MDMA for two phase 3 clinical trials in 2016 and designated it as a breakthrough therapy in 2017.

Comparison of the Psychological Effect and Neurobiology of the Psychedelic Compounds

The classic psychedelics are subdivided into phenethylamines and tryptamines, which include LSD, psilocybin, DMT, ayahuasca, and ketamine. These drugs affect multiple brain areas and can cause dissociation, alterations in the perception of sight and sound, derealization, “mystical-type” effects, paranoia, and transient confusion.

While the structures and pharmacological profiles of the classic psychedelic compounds are distinct, the psychological effects overlap. These psychological effects can be used to treat psychiatric disorders.

LSD has the greatest affinity for the 5-HT2A receptor, and also has affinity for the a1 adrenergic and D1 – 3 dopaminergic receptors. Its effects on consciousness are correlated with decreased connectivity between the parahippocampus and retrosplenial cortex.

MDMA, an entactogen, has the psychological effects of a serotonergic hallucinogen, including positive emotions and euphoria, and the autonomic and cardiovascular effects of a methamphetamine, including increased energy, tachycardia, increased systolic and diaphragmatic blood pressure, and tachypnea.

Ketamine, phencyclidine, and nitrous oxide are dissociative anesthetics that have psychological properties in common with the classic psychedelics. Ketamine-assisted psychotherapy is not currently well defined, and there is limited objective evidence to support its use.

Ketamine is an NMDA antagonist that causes increased activation of AMPA receptors and indirectly enhances dopaminergic and serotonergic activity. Its acute antidepressant effect is primarily attributed to its NMDA receptor antagonism.

Psilocybin and ketamine are potent modulators of glutaminergic activity in prefrontal circuits that produce overlapping psychological effects on the five-dimension Altered States of Consciousness Scale. These effects are due to a common mechanism of action that modulates glutaminergic transmission in the prefrontal-limbic circuit.

There remains debate about how psychedelics alter consciousness and mood. Vollenweider suggests that psilocybin induces metabolic changes, including hyper-frontality, and that the disruption of thalamic gating disables the filtering of sensory and cognitive information, which leads to perceptual alterations during the psychedelic experience.

Vollenweider and Carhart-Harris raise new questions about the role of cerebral perfusion, thalamic gating, connectivity, and serotonin in psychiatric disorders.

Psychedelic-Assisted Psychotherapy

The number of studies using psychedelic-assisted psychotherapy has increased, leading to variable methodologies across studies. Psycholytic therapy and psychedelic therapy are the two most widely utilized psychotherapy paradigms, and MDMA studies have used a hybrid of psycholytic therapy and psychedelic therapy.

Psychedelic-assisted psychotherapy involves three types of sessions: preparatory, medication, and integration. The male-female co-therapy team maintains integrity and safety for the therapeutic relationship, which is important given the history of sexual abuse during psychotherapy with MDMA in the 1980s.

A psychedelic drug is administered in a comfortable room with a reclining chair or bed in an environment that feels familiar and not intimidating. The therapists listen empathically to the patient and maintain a nonthreatening, neutral therapeutic stance.

Little is known about how psychedelic drugs work in facilitating psychotherapy, but it is believed that the drug works with the patient’s mindset, the external conditions, and the therapist.

Currently, it is unclear whether one psychotherapy approach is better than another. It is also unclear whether it is the psychedelic drug itself, the psychedelic-assisted psychotherapy experience, or drug-facilitated enhancements in the therapeutic alliance that promote change.

The Potential for Abuse

All drugs reviewed here, except ketamine, are classified as Schedule I controlled substances under the Controlled Substances Act. This classification was created by the U.S. Congress in 1970 to diminish the availability of drugs of abuse.

In 2010, the United Kingdom’s Independent Scientific Committee on Drugs published a study that directly addressed the prevalence and severity of adverse effects of potential drugs of abuse. Alcohol, heroin, and crack cocaine had the highest overall harm scores, followed by benzodiazepines, ketamine, and methadone.

Hallucinogens are not associated with uncontrollable drug-seeking behavior, and animals cannot be trained to self-administer hallucinogens. Medical administration of hallucinogens should include careful consideration of the appropriate dosage, patient screening, and appropriate preparation of the patient.

MDMA has a lesser abuse potential than cocaine in animals, and a prospective long-term follow-up study of individuals with PTSD who received MDMA reported that no study participants developed a substance abuse problem during the follow-up period.

Researchers at Johns Hopkins University determined that psilocybin would be appropriate for Schedule IV classification if approved as a medication.

The available evidence supports further research into the abuse potential of psychedelic compounds, including measures of drug-seeking behavior over time and urine drug screens to monitor illicit drug use.

Recommendations for Future Research

With the increased interest in psychedelic research and the FDA’s fast-tracking of psychedelic compounds, the National Institutes of Health should conduct a series of international symposia on clinical trial methodology in psychedelic drug research.

Sellers et al. express their concern that many of the dependent variables in these studies are incompletely characterized and do not have established predictive validity or utility. Some scales, however, have been validated in experimental studies with controlled doses of psilocybin.

Future research should focus on the pharmacodynamic and pharmacokinetic profiles of these agents, with close attention paid to the dose-response relationship and side effects, and on the abuse potential of these drugs, particularly in more vulnerable populations.

Conclusions

The published scientific evidence supports continued investigation of psychedelic compounds for treating psychiatric disorders, but more clinical trials using rigorous and validated methodology in controlled settings are needed to address concerns about the potential for substance abuse and significant medical and psychiatric sequelae in vulnerable populations.

The FDA’s breakthrough designation of MDMA for the treatment of PTSD and psilocybin for the treatment of depression reflects the drugs’ potential to treat resistant psychiatric disorders. Several sessions of psilocybin-assisted psychotherapy can lead to antidepressant effects that persist for weeks to months.

Microdosing psychedelics (low doses below the perceptual threshold) has become increasingly popular in the general population, raising additional questions about psychedelics that might be encountered in clinical practice.

Albert Hofmann’s joy at having fathered LSD was tarnished after ten years of uninterrupted scientific research and medicinal use when LSD was swept up in the huge wave of an inebriant mania that began to spread over the Western world. The preliminary data reviewed here supports further research into the therapeutic potential and the abuse potential of psychedelic drugs used as monotherapy, as well as the potential neurobiological processes and therapeutic outcomes achieved by patients with a variety of mood and anxiety spectrum disorders.

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