This review (2020) presents modern human studies into psychedelic drugs, including psilocybin, LSD, MDMA, and ayahuasca in treating various psychiatric illnesses, including treatment-resistant depression, post-traumatic stress disorder, end-of-life anxiety, and substance use disorders. Safety and efficacy data are also presented from both human and animal studies.
Though there was initial interest in the use of psychedelic drugs for psychiatric treatment, bad outcomes and subsequent passage of the Substance Act of 1970, which placed psychedelic drugs in the Schedule I category, significantly limited potential progress. More recently, however, there has been renewal in interest and promise of psychedelic research. The purpose of this review is to highlight contemporary human studies on the use of select psychedelic drugs, such as psilocybin, LSD, MDMA and ayahuasca, in the treatment of various psychiatric illnesses, including but not limited to treatment-resistant depression, post-traumatic stress disorder, end-of-life anxiety, and substance use disorders. The safety and efficacy as reported from human and animal studies will also be discussed. Accumulated research to date has suggested the potential for psychedelics to emerge as breakthrough therapies for psychiatric conditions refractory to conventional treatments. However, given the unique history and high potential for misuse with popular distribution, special care and considerations must be undertaken to safeguard their use as viable medical treatments rather than drugs of abuse.
Chi and Gold frame psychedelics as a class of compounds with a long anthropological and early clinical history, noting renewed scientific interest after decades of prohibition. Modern interest follows the initial discovery and distribution of LSD and psilocybin in the mid-20th century, a period of enthusiastic but methodologically inconsistent research that ended after widespread recreational use prompted political backlash and the US Controlled Substances Act of 1970. The authors distinguish classic psychedelics (LSD, psilocybin, DMT) that act primarily as 5-HT2A agonists from entactogens such as MDMA, which primarily modulate monoamine transporters, and they note overlapping but distinct neurobiological hypotheses for therapeutic action, including changes in neuroplasticity, altered amygdala responsivity, and engagement of signalling pathways such as mTOR.
Papers cited by this study that are also in Blossom
Strassman, R. J. · Journal of Nervous and Mental Disease (1995)
Belouin, S. J., Henningfield, J. E. · Neuropharmacology (2018)
Strassman, R. J. · Journal of Nervous and Mental Disease (1984)
Bogenschutz, M. P., Johnson, M. W. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2016)
This paper is an expert narrative review rather than a systematic review or meta-analysis. The study team reviewed major peer-reviewed human studies and NIH-registered clinical trials concerning selected psychedelic drugs: psilocybin, LSD, DMT (ayahuasca-related literature is mentioned), and MDMA. The authors synthesised safety data, controlled trials, open-label studies, small pilot investigations, and historical randomized trials, citing pooled analyses where available. The extracted text does not report a formal search strategy, inclusion/exclusion criteria, database list, dates searched, or a formal risk-of-bias assessment; consequently, this review appears to be selective and interpretive rather than adhering to systematic-review methodology.
Psilocybin: Safety data pooled by Studerus et al. from eight double-blind, placebo-controlled studies (1999–2008) covered 277 psilocybin sessions in 110 healthy subjects and indicated generally good short- and long-term tolerability, with common transient adverse effects such as fatigue and headaches and rare prolonged emotional disturbance that resolved with psychotherapy. A Hopkins study of 18 volunteers examined headache specifically and judged psilocybin-associated headaches to be neither severe nor disabling. In clinical populations, early pilot and randomized studies targeted end-of-life anxiety and depression and treatment-resistant depression. A 2010 Harbor‑UCLA double-blind pilot in 12 advanced-cancer patients found no statistically significant change in mood or anxiety but demonstrated feasibility and no serious adverse events. A 2016 Johns Hopkins randomized, double-blind, crossover trial in 51 cancer patients compared very low versus high psilocybin doses and reported strong benefit: 92% of participants showed either clinical remission or a ≥50% reduction in depressive symptoms on GRID-HAMD-17, and >75% improved on HAM-A, with benefits persisting at 5 weeks and no medically serious adverse events. A contemporaneous NYU blinded crossover study using niacin as active control (29 patients) found >80% antidepressant response with psilocybin versus 14% with niacin, and 58% versus 14% for anxiety; many subjects maintained improvement at 6.5 months. Limitations noted across trials included selection bias, incomplete blinding (staff correctly guessed assignment in 97% of cases in one study), and possible expectancy effects. For treatment-resistant depression, an open-label London study of 12 patients reported 67% clinical remission after two psilocybin sessions, with 58% maintaining response at three months and only transient, non-serious adverse events. In obsessive-compulsive disorder, a small University of Arizona proof-of-concept study in nine subjects who had prior psychedelic exposure reported acute YBOCS reductions of 23–100% at 24 hours, but effects largely reverted within a week. A 15-person open pilot for tobacco cessation that combined three psilocybin sessions with structured behavioural therapy found 80% seven-day point-prevalence abstinence at six months and 67% abstinence at 12 months, substantially higher than typical cessation aids; the cohort was self-selected and motivated, limiting generalisability. LSD: Contemporary placebo-controlled studies in about 100 healthy volunteers (doses 40–200 μg) found that LSD produces acute psychotomimetic effects (delusional thinking, perceptual distortion) that are transient, alongside reported increases in positive mood and openness. Physiological effects were transient increases in blood pressure, heart rate and temperature; common post-experiment symptoms included headache, exhaustion and anxiety that resolved. A double-blind, active placebo-controlled trial in 12 patients with life‑threatening illness (two 200 μg sessions versus 20 μg active placebo) showed a non-significant primary outcome but a trend toward reduced anxiety and no enduring LSD-attributed harms. A meta-analysis of six randomized trials from 1966–1970 (536 adults with alcoholism) found that a single LSD dose (200–800 μg) was associated with reduced problematic drinking at 2–6 months, with a number needed to treat (NNT) of 6 for improvement; studies varied in preparatory and psychotherapeutic support. MDMA: Historical and prospective data on MDMA have been more mixed, with concerns raised from animal studies about serotonergic neurotoxicity and from observational studies of recreational users about impaired cortical auditory responses. Prospective human laboratory data pooled from nine placebo-controlled crossover studies in Basel (166 healthy subjects) confirmed dose‑dependent cardiovascular and thermoregulatory effects, with maximal recorded systolic/diastolic blood pressures of 196/130 mmHg and maximal temperature 39.1 °C in the pooled sample. Acute adverse effects recorded more frequently in MDMA recipients versus placebo included lack of appetite (59% v 1%), dry mouth (55% v 1%), difficulty concentrating (46% v 4%), and bruxism (40% v 2%); no hypertensive emergencies or hyperpyrexia >40 °C were reported in these trials, and no serious long-term organ toxicity was observed in the short follow-up. MDMA for PTSD: Early MDMA-assisted psychotherapy trials have shown promising effects. A 2010 MAPS randomized, double‑blind, placebo‑controlled pilot (20 participants) used two 8‑hour MDMA (125 mg) or placebo sessions plus manualised psychotherapy; at two months after the second session the clinical response (>30% CAPS reduction) was 83% (10/12) in the MDMA group versus 25% (2/8) in placebo, and 10 MDMA recipients no longer met DSM‑IV PTSD criteria compared with two in placebo. Long-term follow-up (mean 45 months) in 16/20 participants indicated sustained improvement; no persistent medical or psychiatric adverse effects were observed. A New Zealand replication did not find a statistically significant benefit of MDMA-assisted psychotherapy over psychotherapy alone, and the MAPS programme subsequently ran six Phase II trials across five sites enrolling 105 patients in total (31 control, 74 active) with active doses from 75–125 mg. The text reports heterogeneity in outcomes across studies and calls for larger trials; the MAPS programme advanced to later‑phase testing after these encouraging Phase II data. Across studies, authors consistently report small samples, incomplete blinding, selection bias (often predominantly white, sometimes with prior psychedelic exposure), and limited long-term safety data as important constraints on interpreting efficacy and safety.
Chi and colleagues interpret the assembled literature as indicating that selected psychedelic medicines show therapeutic promise for psychiatric disorders that are refractory to conventional treatments, including end-of-life anxiety, treatment-resistant depression, PTSD and substance use disorders. They emphasise that contemporary studies, unlike many early trials, use careful protocols with psychotherapeutic support and institutional oversight, and that reported adverse effects have generally been transient and non-life-threatening when substances are administered in controlled settings. The authors highlight mechanistic leads—changes in neuroplasticity, amygdala responsivity, and mTOR-related signalling—that may help explain therapeutic effects, but they note that biological mechanisms remain incompletely understood. Key limitations acknowledged by the authors include small sample sizes, selection biases (for example, prior psychedelic exposure and predominantly Caucasian samples), and difficulty maintaining blinding because of the characteristic subjective effects of these drugs, which may introduce expectancy effects. They also note that much of the MDMA safety literature is heterogeneous and that long-term safety and the possibility of dose-dependent harms remain incompletely characterised. Historical, regulatory and societal factors—most notably the Schedule I classification—have constrained large-scale government-funded research and complicated public discourse. In terms of implications, the authors argue for continued controlled clinical research and careful translation into practice, stressing the need for strategies to mitigate diversion, abuse and misinformation. They caution against premature or uncontrolled dissemination, pointing to emerging public trends such as unsupported microdosing practices. At the same time, the review suggests that, if ongoing trials continue to demonstrate favourable benefit–risk profiles, psychedelics could become important adjuncts or alternatives in select, treatment‑refractory psychiatric populations. The authors call for larger, methodologically rigorous trials, longer follow-up for safety outcomes, and thoughtful policy planning to balance access with safeguards.
Psychedelic medicines have a long, vibrant history in human civilization; they have been used on all continents by both highly advanced and preliterate cultures for centuries, if not millennia, for ritual, recreational and healing purposes. In fact, per Oxford Dictionary, the word "psychedelic" derives from ancient Greek and roughly means to make manifest or reveal the mind, soul or spirit. Modern history of psychedelics, however, began in 1943 when the renowned chemist Albert Hoffman at Sandoz, now a division of Novartis, accidentally discovered Lysergic acid diethylamide (LSD) while
Journal Pre-proof testing alkaloids from rye ergot fungus. Interestingly, the same chemist also isolated psilocybin, another psychedelic drug, in 1958. Sandoz marketed LSD and psilocybin under the trade names of Delysid and Indocybin, respectively, and widely distributed them to experts in fields of neurology and psychiatry for basic investigative and therapeutic research. This led to a quarter century of enthusiastic psychedelic research during an era of rapid advancement in psychopharmacology, where medications such as chlorpromazine and imipramine were first discovered and manufactured. Early psychedelic research explored two treatment paradigms: the psycholytic and the psychedelic model. The psycholytic model focuses on administrating low doses of psychedelics during multiple sessions as an adjunct to enhance psychoanalytic therapy. It was used to treat disorders such as personality disorders, anxiety, and somatization disorders. The psychedelic model, on the other hand, utilizes higher doses of psychedelic drugs administered in one or few sessions to induce a "mystical", "peak" or "psychedelic" experience. The goal of this method is to evoke lasting changes in habitual patterns of thoughts and behaviors. This model, which has no parallel in modern psychiatric practice, was studied predominantly among patients with substance use disorders. With clinically favorable profile and potency, these agents were lauded by many prominent leaders in behavioral sciences as a breakthrough therapy for intractable psychiatric disorders, such as anxiety in patients suffering from terminal cancer. These research endeavors were widely supported by institutions such as the United States National Institute of Mental Health, pharmaceutical companies, the military, and intelligence agencies. For example, in the 50s and 60s, it was estimated that about 5,000 human subjects in the United Kingdom received LSD in more than 40,000 LSD sessions; during that era, hundreds of papers were published on psychedelic research worldwide. In the 1960s, however, the promise of psychedelics for treatment and therapy quickly turned sour as illicit manufacturing and distribution led to their widespread black-market use in uncontrolled settings, often by individuals with significant premorbid psychiatric conditions. Reports of "bad trips", characterized by hallucinations, overwhelming anxiety to the point of panic, aggression, and depression with suicidal ideation, raised serious concern about the safety of these substances. The infrequent but often highly publicized homicide cases after "LSD experiences" further incensed the public. Powerful social and political backlash ultimately led to the passing of Substances Act of 1970 in the United States (US). LSD, psilocybin and several other psychedelic substances were J o u r n a l P r e -p r o o f placed in Schedule I by the Drug Enforcement Administration (DEA), the most restrictive drug category. Per the DEA, these substances "have no currently accepted medical use in the US, a lack of accepted safety for use under medical supervision, and a high potential for abuse". As a result of this classification, psychedelic research on humans came to an abrupt halt; it became practically impossible to secure any government funding for new projects. However, support for psychedelic medicines remained strong among some prominent scientists and even politicians, notably Dr. Albert Hoffman and Senator Robert Kennedy. In the 1980s, rigorous research combining new techniques in molecular biology and neuroimaging began anew in a few laboratories. The decade saw the rise of multiple non-profit organizations promoting psychedelic research, including the Multidisciplinary Association for Psychedelic Studies (MAPS), the Heffter Research Institute, and the Beckley Foundation, all funded by private donors and organizations outside of government structure. Unlike clinical trials conducted in the 1960s that were often uncontrolled and unblinded with inconsistent methods, contemporary psychedelic studies are carefully designed and subjected to strict approval process by Institutional Review Boards. Proponents of psychedelic research have argued that the basis of DEA's Schedule I designation was politically driven instead of scientifically informed. For example, prior research has not demonstrated that 5-HT2A agonists, which included the classic psychedelic drugs such as LSD, psilocybin and mescaline, reliably induce tolerance, withdrawal, and compulsive drug-seeking behaviors like known addictive substances such as cocaine and heroin. In fact, some of these drugs may have anti-addictive properties, as will be reviewed below. Secondly, marijuana, despite its classification as a Scheduled I Substance, has been safely administered in medical settings and is currently legalized in several states. Finally, while administration of psychedelic medications does pose some physiological risks (transient elevation in blood pressure and heart rate) and unique psychological risk (overwhelming distress during drug reaction), these risks can usually be effectively minimized with close medical supervision. As such, proponents argue that these substances warrant further allowance for scientific study given their potential promise for psychiatric treatment. This review will focus on the potential psychiatric benefit of psychedelic drugs. Today, the term "psychedelics" encompass a range of substances that elicit a multifaceted clinical syndrome that may involve changes across several cognitive and emotional domains. While there is no widely accepted definition, generally psychedelic substances can be classified into "classic psychedelics" J o u r n a l P r e -p r o o f and entactogens. The classic psychedelics include LSD, psilocybin, dimethyltryptamine (DMT), and mescaline. These drugs all act pharmacologically as agonists at the 5-HT2A receptor. The entactogens include methylenedioxymethamphetamine (MDMA), which acts as a serotonin, dopamine and noradrenaline agonist and has a significantly distinct mechanism of action than the classic psychedelics. Multiple recent studies have found promising clinical benefits of psychedelic substances for a wide range of mental illnesses, including end-of-life anxiety, treatment resistant depression, post-traumatic stress disorder (PTSD), and substance use disorders. While the pharmacodynamic and neurological underpinning of how these psychedelic drugs exert their therapeutic effects remains unclear, current evidence suggests their possible role in changing neuronal transcription, inducing entropic brain activities, and activating cellular pathways distinct from those activated by traditional psychotropic medications. Specifically, one study showed that psychedelic compounds representing all three classes of psychedelics, namely tryptamines (DMT, psilocybin), amphetamines (MDMA), and ergolines (LSD), were capable of promoting neurite growth in vitro and in fruit fly (Drosophila) larvae; additional experiments further demonstrated mTOR (mammalian target of rapamycin) as a possible downstream mediator for the positive neurotropic effect. Interestingly, mTOR has also been theorized to be an important downstream mediator for ketamine, despite the difference in target (NMDA versus 5-HT2A). Another study has shown possible association of reduced amygdala activity with administration of both psilocybin and LSD, which could partly explain the euphoric effect these substances often have on mood. Of note, drugs such as ketamine, scopolamine, and ibogaine are sometimes also classified as psychedelic. However, they will not be discussed in this review. Instead, this review would focus on the recent advancements and potential for use of selected classic psychedelics (psilocybin, LSD, and DMT) and MDMA. It will highlight important modern studies in the psychiatric literature for each drug, describing its safety and efficacy in the treatment of psychiatric illnesses.
This is an expert review of major peer-reviewed studies and NIH-registered clinical trials where the use of selected psychedelic drugs was reported.
Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine), known colloquially as "magic mushrooms" or "shrooms", is a tryptamine-related plant alkaloid that can be found in many species of J o u r n a l P r e -p r o o f mushrooms belonging to the genus Psilocybe. After ingestion, it is immediately dephosphorylated to psilocin (4-hydroxy-N,N-dimethyl-tryptamine), which is structurally similar to serotonin, or 5hydroxytryptamine. It is considered a "classic psychedelic" as it exerts its effect mainly through 5-HT2A agonism. In humans, it may induce a transient state of altered consciousness characterized by marked perceptual alterations, affective disturbance, and thought disorder that is rarely experienced except in dreams and religious exaltation. As previously mentioned, psilocybin is currently a Scheduled I substance. However, multiple recent studies in both healthy volunteers and specific populations of patients have demonstrated generally good tolerability and minimal adverse effects. Inspired by prior research in the 60s, several contemporary research groups have conducted efficacy and feasibility studies on use in specific psychiatric illnesses, including end-life anxiety, treatment-resistant depression, obsessive-compulsive disorder, and tobacco use disorder.
Pulling raw data from eight double-blind, placebo-controlled studies from 1999-2008 in Switzerland, Studerus et al. concluded that psilocybin is generally well tolerated by healthy volunteers both in the short-and long-term. The studies include a total of 277 individual psilocybin sessions and 110 subjects evaluated with validated instruments to assess a myriad of physical and psychological symptoms. Some common short-term adverse effects include fatigue, headaches, and lack of energy. The group found that most of these adverse effects tend to resolve within the first few weeks subsequent to drug administration, and that they are generally not life-interfering. Furthermore, they found no change in drug-seeking behavior, persisting perception disorders, prolonged psychosis, or other long-term impairment in function in all subjects. Of note, the authors did find one subject who had required professional help for emotional instability, depression, and anxiety that persisted several weeks post-experiment; this subject did recover after few sessions of psychotherapy and had not relapsed on follow-up. Another group, from Hopkins, specifically explored the relationship between psilocybin and headache. Psilocybin, as a serotonin receptor modulator, has many structural similarities with several migraine medications; furthermore, headache is one of the most common adverse effects of psilocybin. However, after administering a broad range of psilocybin doses to 18 healthy volunteers, the group concluded that these headaches are "neither severe nor disabling". The same study also does not mention other significant adverse effects.
Journal Pre-proof Clinically significant and disabling depressive and anxiety disorders are common in patients with cancer. They are often missed due to significant overlap between medical and psychiatric symptoms, and the difficulty in differentiating pathological from normative reactions to severe illness. Nonetheless, these psychiatric disorders have been associated with multiple predictors of poor outcome, such as decreased treatment adherence, decreased quality of life, prolonged hospital stays, and poor prognosis. Despite the costs to individuals and the society, there are currently few effective pharmacological treatments for these patients. Conventional antidepressants have shown limited efficacy compared to placebo, and benzodiazepines are generally not recommended for chronic treatment given side effects and risks of withdrawal. In 2010, a group from Harbor-UCLA Medical Center conducted the first double-blind, placebocontrolled pilot study to investigate the safety and efficacy of psilocybin in treating anxiety and depression in patients with advanced-stage cancer. Twelve subjects received two experimental treatment sessions spaced several weeks apart and served as their own control. Though the study found no statistically significant reduction in anxiety and mood, it demonstrated that psilocybin can be safely administered in this medically ill population with no reported clinically significant adverse effects. In 2016, two more studies that involved larger number of subjects were published. A group from Johns Hopkins conducted a randomized, double-blind, cross-over trial comparing the effects of a very low (placebo-like, 1-3 mg/kg) dose versus high dose (22-30 mg/kg) of psilocybin on 51 patients afflicted with advanced-stage cancer. The drug sessions lasted 8-hours and were conducted in an aesthetic living room-like environment with two monitors present the entire time. The group found a clinically significant response for two of the primary outcome measures. Specifically, 92% of the participants demonstrated either clinical remission or a 50% reduction of depressive symptoms compared to baseline, as measured by GRID-HAMD-17. More than 75% of the subjects also demonstrated similar response in anxiety as measured by HAM-A. Furthermore, a large number of these subjects continued to exhibit reduced symptom severity or remission at 5-week follow-up. Importantly, all adverse events were medically non-serious. In the same year, another group from New York University conducted a randomized, blinded, crossover study using niacin as the active control; study subjects in both the experimental and control groups also received psychotherapy. In this study, 29 patients were followed for 9 months. The results showed significant improvement in both depression and anxiety; specifically, more than 80% of study subjects receiving psilocybin met criteria for antidepressant response, compared with 14% in the group that received niacin (for anxiety, it was 58% for psilocybin and 14% for niacin). J o u r n a l P r e -p r o o f At 6.5-month follow-up, after all subjects received psilocybin from the crossover leg, the antidepressant or anxiolytic response rate were about 60-80%. While it is unclear from the data whether the beneficial outcome was secondary to psilocybin alone or some interactive effect of psilocybin plus targeted psychotherapy, the improvement was vast and significant and, similar to the study conducted by the group from Johns Hopkins, there were no serious adverse effects. The authors did, however, recommended further research to elucidate the contribution of each component alone. All three of these studies share similar limitations in terms of patient selection bias and suboptimal blinding. The study from Johns Hopkins, for example, was conducted on subjects who are predominantly Caucasian, with almost half of the subjects having past exposure to psychedelic substances. In other words, expectancy effect, where subjects' expectations of certain result (e.g. taking psilocybin) could unconsciously affect the outcome and could be an important contributor to study results. However, some authors argue that psychological expectations can be therapeutic and should be considered as an active part of treatment rather than a confounder. As expected, there is an inherent difficulty with blinding given the unique effect of psychedelic substances. Even when using an active placebo such as niacin, which produces effect of warmth, arousal, and tingling sensation, post-experiment analysis by the group from New York showed that the staff had guessed the assignment correctly in 97% of the cases. Regardless of these limitations, these studies have demonstrated not only feasibility and safety, but potentially paradigm-altering benefits of psilocybin on a refractory psychiatric disorder in a particularly ill population in need of potential treatments.
A group from London conducted an open-label, non-controlled study investigating possible benefits of administrating psilocybin to twelve patients with treatment resistant depression. At the time of participation, all twelve patients were in an active depressive episode and had demonstrated no improvement after two adequate trials of antidepressants from different pharmacological classes lasting more than six weeks within the current episode. All patients were clinically assessed to have moderate to severe depression at the time of enrollment. After receiving two treatment sessions of psilocybin, 67% of the patients achieved clinical remission and 58% continued to meet criteria for response after three months. No serious adverse events were found other than transient confusion, anxiety, mild thought disorder, headache, and mild nausea. This side effect profile J o u r n a l P r e -p r o o f compares extremely favorably to currently available treatments such as electroconvulsive therapy and vagal nerve stimulation. If further research continues to reliably demonstrate safety and efficacy, psilocybin could potentially become an invaluable treatment option for treatment resistant depression.
Obsessive-compulsive disorder (OCD) is a chronic illness with few patients achieving true remission in their lifetime. Though selective serotonin reuptake inhibitors (SSRIs) are potent and effective first-line treatments, about 40-60% of patients do not respond to SSRI therapy. Other options for treatment refractory patients include switching to another SSRI, augmenting with other agents, and adding Cognitive Behavioral Therapy (CBT). However, a significant percentage of these patients would remain treatment refractory; at that point, novel or experimental drug treatments such as electroconvulsive therapy, neurosurgery, or repetitive transcranial magnetic stimulation may be considered. Yet these neurosurgical techniques are often invasive, highlighting the need for other novel therapeutic options in this population. A group from University of Arizona recently conducted a small proof-of-concept study on nine subjects with OCD who had failed at least one first-line treatment. All of these subjects must have had prior exposure to psychedelics and must abstain from antidepressants for at least two weeks prior to treatment. They then received four escalating doses of psilocybin in random order, from very low dose to high dose (25 to 300 μg/kg body weight), in four sessions separated by at least one week. Aggregate results from all dosing, even the very low dose, showed a 23-100% reduction in symptoms as measured by the Yale-Brown Obsessive-Compulsive Score (YBOCS) 24 hours postexposure. The improvement, however, did not appear to persist beyond one week as most subjects returned to baseline symptoms by the next session. This preliminary study demonstrates acute, transient benefit of psilocybin in patients with refractory OCD. While results from one small pilot study is unlikely to be generalizable, the overall positive results do at least warrant further research.
There is one open-label pilot study exploring the effect of psilocybin on patients with Tobacco Use Disorder. In this study, fifteen psychiatrically healthy subjects received three sessions of moderate or high doses of psilocybin within a structured 15-week smoking cessation treatment protocol
Journal Pre-proof consisting of four weekly meetings integrating CBT, elements of mindfulness training, and guided imagery. Abstinence from tobacco was monitored and confirmed by exhaled CO and urinary cotinine level. At 6-month follow-up, twelve out of fifteen (80%) of the participants showed sevenday point prevalence abstinence. The cessation rate was significantly higher than commonly reported rate for other available behavioral or pharmacology therapies, such as bupropion, varenicline, and CBT (<35%). Notably, ten out of fifteen (67%) participants continued to be abstinent at 12-month follow-up, at a rate that also exceeded what was typically found with other smoking cession aids (around 30%). Similar to other trials, there were no clinically significant adverse events. One possible limitation of the study, however, was that it included a self-selected population that was motivated to quit. Head-to-head trials comparing psilocybin and popular smoking cessation aids are needed to contextualize these findings, yet these results show promise for use in tobacco cessation.
Lysergic acid diethylamide (LSD), often referred to by the street name "acid", is one of the most potent known hallucinogens. Similar to psilocybin, it is a classic psychedelic as it exerts its effect through 5-HT2A agonism. However, unlike psilocybin, it has also been shown to indirectly affect dopaminergic neurotransmission without direct D2 receptor stimulation. As mentioned during introduction, LSD was first synthesized by Albert Hofmann in 1938 from lysergic acid, a chemical derived from ergot fungus (Claviceps purpurea) and several other fungal species. In 1947, the clinical similarity between the effect of LSD and schizophrenia was noted, leading to its experimental use as a model for psychosis. It has been found that animals chronically treated with low-dose LSD (0.16mg/kg every other day for more than three months) exhibited symptoms of hyperactivity, irritability, anhedonia and impaired social interaction that persisted months after cessation of LSD treatment; these symptoms mimic closely the negative symptoms of chronic schizophrenia. Interestingly, these symptoms could be transiently reversed by antipsychotics such as haloperidol and olanzapine. In humans, however, judicious ingestions of LSD had not been shown to cause persistent psychosis, at least not in people without pre-existing psychotic condition. In fact, Albert Hofmann, who intentionally ingested the substance at high dose as part of selfexperiment, described a sense of profound wellbeing after surviving the initial, transient symptoms of unpleasant "altered perception, fear and paranoia". It is not surprising then that when LSD was first distributed by Sandoz pharmaceuticals in 1948, the product guidelines had stipulated "analytical psychotherapy" and "experiment studies on psychosis" as two main applications.
While most early clinical trials used LSD, contemporary trials tend to use psilocybin due to its shorter duration of action and less controversial history. For this reason, there are not as many studies with LSD compared to those on psilocybin. Nonetheless, over the last decade, multiple placebo-controlled studies on healthy volunteers and one study on the effect of LSD on anxiety among patients with terminal cancer have been conducted. This section will summarize findings from these studies, in addition to provide one recent meta-analysis that pools several well-designed studies conducted from 1966-1970 on the efficacy of LSD in patients with alcohol use disorder.
Over the last five years, several placebo-controlled studies of LSD have been conducted in Basel, London, and Zurich on about one hundred healthy subjects. The dose ranges from low moderate (40-80 μg) to relatively high dose (200 μg). These studies have provided several insights into the psychological and medical effects of LSD. First, LSD produces profound acute psychosis-like symptoms such as delusional thinking, perceptual distortion, cognitive distortion, and paranoia. One study found that LSD produces a mean Psychotomimetic States Inventory (PSI) score that is much higher than what was found after ketamine infusion, post-THC, and post cannabis use; fortunately, these effects were found to be only transient. The same study also noted that for majority of the subjects, even those who experienced unpleasant psychotic symptoms, endorsed positive mood and other positive effects such as significant increases in optimism and personality trait openness. The finding that LSD could cause "blissful state" is also found in another study. These results could explain why LSD was found to be efficacious in treating anxiety and mood disorders and as a psychotherapy adjunct in the 1960-1970s. Secondly, no serious adverse physiological effect was observed other than transient increase in systolic blood pressure, heart rate, and temperature. Common post-experiment psychological adverse effects included headache, exhaustion, difficulty concentrating, and anxiety; these symptoms tended to resolve by the end of experiment and were not life-impairing.
To date, there has been only one double-blind, active placebo-controlled, randomized clinical trial exploring the feasibility of LSD on patients with life-threatening illnesses. In this study, 12 subjects with terminal cancer, autoimmune, and neurological diagnoses underwent a 3-month experiment that included 6-8 psychotherapy sessions combined with two LSD experiences at 4 to 6-week J o u r n a l P r e -p r o o f intervals. The participants were randomized to full-dose group (200 μg) or active placebo (20 μg). At baseline, all participants exhibited significant anxiety as measured by the Spielberger State-Trait Anxiety Inventory, and all but one subject had a history of being treated for major depressive disorder, panic disorder, or generalized anxiety. On days of LSD administration, subjects stayed overnight at the physician's office with attendant nearby. 9 out of 12 subjects completed follow-ups at 1 week, 2 months, and 12 months. Though the primary outcome measure was not statistically significant (no clinical improvement in anxiety scores), there was a positive trend towards improvement of anxiety. Perhaps more importantly, the study found no patients experienced adverse effects that are often attributed to LSD, such as prolonged anxiety ("bad trip"), lasting psychotic or perceptual disorders, or clinically significant changes in heart rate and blood pressure.
A recent meta-analysis of six double-blind, randomized control trials from 1966 to 1970 yielded promising efficacy of LSD on reducing problematic drinking behavior and total abstinence. The meta-analyses included a total of 536 adults, where about 60% were randomized to receive experimental dose of LSD. All subjects had listed "alcoholism" as their primary problem and had been admitted to alcohol-focused treatment programs prior to participation. All trials excluded patients with known personal psychiatric conditions. Active LSD doses ranged from 200-800 μg, while placebos included low-dose LSD, d-amphetamine, inactive drug, or ephedrine. All subjects received one LSD dose and were monitored during the active treatment phase. Though the preparation and follow-up before and after the experimental session varied between the studies (from very brief orientation and no debriefing to multiple clinical interviews plus psychotherapy), all trials used clearly defined, standardized questionnaire to assess outcomes on alcohol abuse. The outcomes were then dichotomized into "improved" or "not improved"; improvement encompassed both abstinence and reduction in binge drinking behaviors. The results showed a statistically significant of improvement in problematic alcohol use. Specifically, at 2-6 months follow-up, LSD was associated with a reduction in problematic drinking behavior with a number needed to treat (NNT) of 6. This compares favorably with naltrexone, which has an NNT of 9 at similar perimeters. LSD is also shown to have positive effect on abstinence that is significant at least in short follow-up (1-3 months). Ultimately, it is interesting to consider that a single dose of LSD may provide similar effect as oral naltrexone, which requires daily dosing. However, one could argue that, for possibly comparable benefit, Vivitrol injections are more convenient and less controversial to administer on J o u r n a l P r e -p r o o f an outpatient basis. Of course, there are no studies that compare LSD with monthly Vivitrol injection. Even still, the study found no lasting harmful adverse effects of LSD even in this large population. This suggests that the risk as compared to vivitrol might be comparable. Regardless, the result of this study points to potential benefits of LSD on an important, prevalent substance use disorder.
MDMA, known commonly by the street name "Molly" or "ecstasy", was first synthesized in 1912 by pharmaceutical company Merck as a precursor to a new potential hemostatic compound. It is a ring-substituted methamphetamine derivative but, unlike methamphetamine or amphetamine, it exerts its effect mainly on the serotonin transporter. MDMA remained virtually unknown, however, till the mid-1970s when its therapeutic potentials were explored by a small group of therapists and researchers. MDMA was described at the time as a relatively mild, short-acting drug that promoted introspection, reduced fear response to perceived emotional threats, and encouraged friendliness with others without the troublesome perceptual alternation or emotional lability observed with LSD. About 500,000 doses of MDMA had been consumed between early 1970s to 1980s with little to no negative publicity; side effects were perceived to minimal at the time, presumably with judicious use as prescribed by the therapists. However, the drug became increasingly popular through word of mouth; by 1980s, aggressive marketing led to a dramatic increase in recreational use. Interestingly, MDMA was almost marketed as "empathy"; however, the distribution network thought that "ecstasy" would sell better even though "empathy" was more appropriate. Today, MDMA remained popular among young people, especially in dance clubs and rave parties. There is ongoing controversy regarding the safety of MDMA, as will be discussed below. While historically MDMA was used to treat a variety of disorders including alcohol use disorder, OCD, end-of-life anxiety, and sequalae to psychological trauma, contemporary MDMA research over the last decade has been focusing on its potential as a novel therapy for post-traumatic stress disorder (PTSD).
Over the last several decades, more than a thousand papers examining the potential short and longterm effect of MDMA use have been published; however, results were inconsistent and at times contradictory given wide variability in the type, quality, participant selection criteria and methodologies utilized, generating considerable controversy. For example, there has long J o u r n a l P r e -p r o o f been concern about MDMA-induced neurotoxicity based on prior studies on rodents and primates. A group from Johns Hopkins has demonstrated that administrating squirrel monkeys at 2.5, 3.5, and 5.0mg/kg of MDMA twice daily for four days could result in significant serotonin depletion and loss of serotonin-immunoreactive nerve fibers in dose-dependent manner when the animal brains were removed and studied two weeks post-exposure. Similar studies are obviously impossible to conduct in humans. However, it turns out that serotonin plays an important role in regulating the sensitivity of auditory neurons; in response to loud serotonin helps attenuating cortical response to protect neurons from being damaged from overstimulation. Using electroencephalogram (EEG), a group from London was able to compare cortical responses to loud auditory stimuli in the primary auditory cortex between long-term MDMA users, long-term cannabis users, and controls. The result showed impaired cortical responses in long-term MDMA users, indirectly suggesting MDMA-induced neurotoxicity. However, proponents of therapeutic MDMA research argued that retrospective data on long-term users lacked validity, citing reasons such as that the doses consumed are often much higher in naturalistic settings, that street MDMA pills often contain other impurities, that self-report of past usage is inherently subject to bias, and that many of the subjects are multi-drug users. Ideally, the effect of MDMA should be evaluated in prospective, placebo-controlled trials with strict inclusion criteria, validated instruments for outcome measures, and standardized dosages. In 2006, Dumont et al. screened over 1400 articles and found 29 studies (for a total of around 300 subjects) from 1998-2004 that met the aforementioned criteria. Physiologically, the authors found that MDMA most often causes increase in cardiovascular markers (SBP, DBP, HR), pupil size, and temperature. Notably, among the included studies there was not enough reported evidence on the side effect of memory changes. The authors had expressed surprise and disappointment over this finding given the fact that retrospective studies have consistently cited memory problem as one of the most concerning side effects. Since 2006, about a dozen similarly-designed studies on healthy subjects have been performed; however, they were small and not all of them had specifically measured adverse side effects. In 2017, a group from University of Basel in Switzerland pooled data from 9 placebo-controlled, crossover studies performed in the same laboratory on a total of 166 health subjects. Among them, 30 participants received a single 75 mg dose of MDMA. Among the remaining 136 participants, MDMA was administered as a single dose in 24 subjects and as two single-doses of 125 mg in 112 subjects, resulting in total exposure of 250 mg of MDMA (time interval between the two doses was about 26 days). The study again confirmed the dose-dependent J o u r n a l P r e -p r o o f effect on vital signs. Among all subjects, no hypertensive urgencies or hyperpyrexia (> 40 degree Celsius) was reported; however, maximal systolic and diastolic blood pressure values were 196 and 130 mmHg, and maximal temperature was 39.1 degree Celsius. Frequent acute adverse effects included lack of appetite (59% of MDMA group versus 1% in placebo), mouth (55% vs. 1%), difficulty concentrating (46% vs. 4%), and bruxism (40% vs. 2%). Subacute (up to 24 hours) effects were similar. Chronic (around 30 days) effects on kidney and liver functions were nonexistent, though there was a statistically significant decrease in hemoglobin and red blood cells in women. Most side effects were found more commonly in volunteers receiving higher doses of MDMA. No serious adverse effect was reported. Unfortunately, memory-related side effects were not investigated in this study, presumably due to the short follow-up. Overall, it would appear that prospective participants in any MDMA trial will need to be carefully screened, especially for existing cardiovascular conditions, and that there are more regularly occurring, dose dependent, side effects of MDMA than have been found for some other psychedelics. Again, more high-quality long-term data is needed to evaluate possible permanent adverse effects and to determine whether there is a "safe" exposure dose for humans.
Current guidelines for PTSD suggest psychotherapy as first-line treatment over pharmacological monotherapies, namely the SSRIs sertraline and paroxetine, the only two Federal Drug Administration (FDA)-approved medications for PTSD. The effect size for both exposure therapy and CBT, two popular psychotherapeutic options, was about 8.0 when compared to waitlist or supportive counseling. This is similar to the effect size of sumatriptan for temporary migraine relief and levodopa for reduction of Parkinson's symptoms. However, while effective, the response rate for participants who completed the entire course of active psychotherapy treatment (usually 10-12 weeks) falls between 60-95%. In other words, while psychotherapy is an effective treatment for PTSD, studies indicate that about 25 to 50% of participants who enrolled in clinical trials remained refractory. This emphasized the need for further research into more effective options for this chronic, debilitating illness. The first modern pilot study of MDMA-assisted psychotherapy was conducted in Spain in 2008; however, the study was prematurely terminated due to political reasons. Two years later, in 2010, the MAPS completed the first clinical trial investigating the effect of MDMA as psychotherapy adjunct. The study was a randomized, double-blind, placebo-controlled pilot study with 20 J o u r n a l P r e -p r o o f participants, among whom the majority had failed either multiple adequate medication trials or at least one course of psychotherapy. Of note, all subjects were required to taper and abstain from all psychotropic medications except sedative hypnotics or anxiolytics given as needed between MDMA or placebo sessions. participants received manualized psychotherapy based on prior LSDassisted psychotherapy conducted during 1970s with PTSD-specific modifications. MDMA (125 mg) or a placebo was administered in two 8-hour experimental psychotherapy sessions followed by overnight stay in the clinic with nurse on duty. The two sessions were about four weeks apart, with three weekly psychotherapy sessions in between. Primary outcome was measured by Clinician-Administered PTSD Scale (CAPS), considered the gold standard in PTSD assessment, and was obtained at baseline, 4 days after each experimental session, and 2 months after the second session. Clinical response was defined as >30% reduction from baseline of CAPS total severity score. Significant reduction was shown after 4 days post first experimental session; at 2-month follow-up after the second experiment session, the clinical response rate was 83% (10/12) in the MDMA group versus 25% (2/8) in the placebo group. Ten participants in the MDMA group no longer met DSM-IV criteria for PTSD compared to two in the placebo group. Finally, the study offered an openlabel arm where the participants randomized to the placebo group could cross-over. After crossing over, the clinical response rate was found to be 100%. Moreover, the improvement in symptoms appeared to be sustained when 16/20 of the subjects were reassessed with CAPS at long-term follow up (between 17-74 months post study, with mean of 45 months). No lasting medical or psychiatric adverse effects were observed in both studies. Interestingly, a group from New Zealand replicated the study by MAPS but did not find a statistically significance in MDMA-assisted psychotherapy versus psychotherapy alone. The study did, however, concur the overall tolerability of MDMA; there was no serious drug-related adverse events. The authors cited baseline differences in subjects (participants at the earlier study had higher baseline CAPS), chance (given smaller number of subjects), and cross-cultural differences as possible reasons for the discrepancy. Nonetheless, the MAPS group proceeded to conduct six phase two trials at five study sites: three in the US, one in Canada, one in Switzerland, and one in Israel, from 2004 to 2017. All six trials used a randomized, double-blind design but with active doses varying between 75-125 mg and placebo or control doses from 0-40 mg. The six studies enrolled a total of 105 patients, with 31 in the control group and 74 in the active treatment group. The patients had baseline CAPS score similar to those J o u r n a l P r e -p r o o f treatments require multiple regular administrations over prolonged period of time to achieve maximal benefit. Future research into psychedelic medicines, as with any other emergent novel therapies, will require balancing between foreseeable benefits, adverse effects, and feasibility. Despite concern about side effects, particularly the fear of addiction and abuse, psychedelics appear to be generally well-tolerated. Physiological changes, such as elevation in cardiovascular perimeters, were found to be transient and mostly non-medically serious except in patients with pre-existing heart condition. Other side effects, both physical and psychological, were usually mild and not functionally impairing. Serious adverse events, such as persistent psychosis and suicidality, have not been demonstrated. Some psychedelics, such as psilocybin and LSD, have even been shown to have anti-addictive property in patients with substance use disorders. One could argue that it is still simpler, safer, and perhaps more cost-effective to take a pill every day than to receive one dose of controlled substance, given the extensive amount of time, monitoring, and preparation required. However, if taking a pill is ineffective, the promise of these medications may outweigh the fear of potential risk. Additionally, psychedelic research is still at its preliminary stage; in the future, it is possible that these substances may be administered in less and less restrictive settings as more information about their safety, pharmacology and mechanism of action comes to light. The recent renewed interest in psychedelics has already begun to capture public imagination, inspiring anecdotal reports, popular general-audience books, and dedicated psychedelic research centers in major academic institutions. Given the unique history of psychedelics, special precaution must be taken in the dissemination of these findings to the general population and their subsequent implementation as therapies. The history of psychedelic research has demonstrated unequivocally that rampant, uncontrolled usage of these powerful substances can lead to harm and also hindrance to bona fide scientific research. We also know that the opinions of the public, politicians, and medical professionals do not always align as we saw with the reclassification of psychedelics as Schedule I drugs. As such, care must be taken to conduct controlled studies on these medications, and as new data continue to emerge and treatments are being evaluated by the FDA, consideration must be given to safety, diversion, and abuse strategies for medication dissemination. We live in an time where access to information is easier and faster than ever; however, it is also becoming increasingly more difficult for lay public to distinguish evidence-based knowledge from misinformation. Currently, there is already a struggle between physicians and the public regarding the use of marijuana, a Schedule I Substance that has been legalized in many states. The public J o u r n a l P r e -p r o o f Journal Pre-proof misinformation about psychedelics is no different. This is best illustrated by the recent emergence of the concept "micro-dosing", which has garnered enthusiastic public interest even with very limited scientific support. As physicians, we must continue to critically appraise available data and discuss its meaning to our patients and the public. From panacea to drugs of abuse, psychedelics have played an important role in our culture since the dawn of civilization. With the help from modern technology, we may be able to successfully and safely harness their powerful effect to alleviate suffering from specific psychiatric illnesses while minimizing the known risks and negative social repercussions. Psychedelics such as LSD, psilocybin, and MDMA have a long, complex history in psychiatry The passage of Substance Act of 1970 made all psychedelic drugs illegal in response to widespread black-market use and "bad trips"; as a result, research on their use for treatment effectively stopped There has been a recent renewed interest in psychedelic research for psychiatric treatment Multiple contemporary studies have demonstrated safety and possible benefit of psychedelic drugs in multiple psychiatric illnesses refractory to conventional treatments Caution must be taken to safeguard the distribution and utilization of these psychedelic substances; education is needed for the public to prevent misunderstanding and misuse J o u r n a l P r e -p r o o f
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