Recommended readings 3
Top 10 Articles on Psychedelics in 2020

 

This list was made in cooperation, and co-published, with Blossom.

The number of publications in the psychedelic research field has been steadily growing in the year 2020. While the majority of the outside world was dealing with a global pandemic, research on psychedelics continued its march forward. This list of top 10 articles will present some of the most impactful publications of the year.

The papers have been selected from the 2.000 (PubMed) to 39.000 (Google Scholar) articles published last year on psychedelics. Most of the publications listed below have already been featured in Blossom’s monthly round-ups of psychedelic research and the MIND’s ASC Study Monitor. Although the top-cited paper on the list has ‘only’ 27 citations as of early 2021, we expect many of these to become future classics.

Read our list of Top 10 Articles of 2020 to learn about a ground-breaking trial with psilocybin for major depressive disorder, long-term outcomes of MDMA-assisted psychotherapy for PTSD, how psychedelics work in the brain, and how to produce psychedelics at a larger scale.

Psilocybin has been studied, in combination with psychotherapy, for its potential in helping those with treatment-resistant depression (TRD, e.g., Carhart-Harris et al., 2017). Patients suffering from major depressive disorder (with moderate to severe scores on the Hamilton Depression Rating Scale) qualify as treatment-resistant when showing no improvements after two treatments with antidepressants of different classes, each lasting at least 6 weeks.

Those suffering from TRD represent 10 to 30% of patients suffering from depression (Al-Harbi, 2012). Davis and colleagues’ study provided evidence that psilocybin-assisted therapy may be a suitable option for the treatment of major depressive disorder.

This study used two sessions with a high dose of psilocybin and found a clinically significant response (>50% lower score on depression score) in 71% of patients four weeks later. Although the study was open-label and done with no more than 24 participants, it offers hope that psychedelic-assisted therapy will become a viable option to improve symptoms of depression in patients who do not respond to conventional psychiatric treatments.

Davis, A.K., Barrett, F.S., May, D.G., et al. (2020) Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA Psychiatry

Importance: Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression.
Objective: To investigate the effect of psilocybin therapy in patients with MDD.
Design, Setting, and Participants: This randomized, waiting list–controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population).
Interventions: Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay.
Main Outcomes and Measures: The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR).
Results: Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.5; 95% CI, 1.4-3.5; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.5-3.7; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 2.6; 95% CI, 1.8-3.5; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 2.3; 95% CI, 1.5-3.0; P < .001). In the overall sample, 17 participants (71%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score).
Conclusions: and Relevance Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression..

Jerome and colleagues conducted a long-term follow-up study on the results across six phase 2 trials led by Multidisciplinary Association for Psychedelic Studies (MAPS). The trials were all double-blind, open-label, and included a long-term follow-up. At the end of the treatment, 56% of the patients did not meet the criteria for PTSD, and at the long-term follow-up (at least 12 months later), 67%. More than half of the study participants indicated that they experienced considerable benefits that persisted or increased over time.

These results contributed another piece of evidence to the hypothesis that psychedelics and entactogens may become a feasible treatment option for those suffering from mental health disorders. An analysis of the costs of this medical approach by Marseille and colleagues modeled that MDMA-assisted psychotherapy for PTSD can add quality-adjusted life years (QALY) at lower costs than conventional treatments.

Jerome, L., Feduccia, A. A., Wang, J. B., Hamilton, S., Yazar-Klosinski, B., Emerson, A., Mithoefer, M. C., & Doblin, R. (2020). Long-term follow-up outcomes of MDMA-assisted psychotherapy for treatment of PTSD: a longitudinal pooled analysis of six phase 2 trials. Psychopharmacology, 237(8):2485–2497.

Rationale: Posttraumatic stress disorder (PTSD) is a chronic condition that has wide-ranging negative effects on an individual’s health and interpersonal relationships. Treatments with long-term benefits are needed to promote the safety and well-being of those suffering from PTSD.
Objectives: To examine long-term change in PTSD symptoms and additional benefits/harms after 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treatment of PTSD.
Methods: Participants received two to three active doses of MDMA (75–125 mg) during blinded or open-label psychotherapy sessions with additional non-drug therapy sessions. PTSD symptoms were assessed using the Clinician-Administered PTSD Scale for DSM IV (CAPS-IV) at baseline, 1 to 2 months after the last active MDMA session (treatment exit), and at least 12 months post final MDMA session (LTFU). A mixed-effect repeated-measures (MMRM) analysis assessed changes in CAPS-IV total severity scores. The number of participants who met PTSD diagnostic criteria was summarized at each time point. Participants completed a long-term follow-up questionnaire.
Result: There was a significant reduction in CAPS-IV total severity scores from baseline to treatment exit (LS mean (SE) = − 44.8 (2.82), p < .0001), with a Cohen’s d effect size of 1.58 (95% CI = 1.24, 1.91). CAPS-IV scores continued to decrease from treatment exit to LTFU (LS mean (SE) = − 5.2 (2.29), p < .05), with a Cohen’s d effect size of 0.23 (95% CI = 0.04, 0.43). The number of participants who no longer met PTSD criteria increased from treatment exit (56.0%) to LTFU (67.0%). The majority of participants reported benefits, including improved relationships and well-being, and a minority reported harms from study participation.
Conclusion: PTSD symptoms were reduced 1 to 2 months after MDMA-assisted psychotherapy, and symptom improvement continued at least 12 months post-treatment. Phase 3 trials are investigating this novel treatment approach in a larger sample of participants with chronic PTSD.

Psychedelic-assisted therapy sessions are usually done with individual patients. In their pilot study (n=18), Anderson and colleagues showed that psilocybin can be useful in treating demoralization and that it also has the potential to be used in a group setting. Although more data is needed, offering the preparation and follow-up sessions (or in the future, even the session with the administration of psychedelics) in a group setting showcased a potential to improve the therapy’s costs side even further.

Anderson, B.T., Danforth, A., Daroff, R., Stauffer, C., Ekman, E., Agin-Liebes, G., et al. (2020) Psilocybin-assisted group therapy for demoralized older long-term AIDS survivor men: An open-label safety and feasibility pilot study. EClinicalMedicine, 27:100538

Background: Psilocybin therapy has shown promise as a rapid-acting treatment for depression, anxiety, and demoralization in patients with serious medical illness (e.g., cancer) when paired with individual psychotherapy. This study assessed the safety and feasibility of psilocybin-assisted group therapy for demoralization in older long-term AIDS survivor (OLTAS) men, a population with a high degree of demoralization and traumatic loss.
Methods: Self-identified gay men OLTAS with moderate-to-severe demoralization (Demoralization Scale-II ≥8) were recruited from the community of a major US city for a single-site open-label study of psilocybin-assisted group therapy comprising 8–10 group therapy visits and one psilocybin administration visit (0·3–0·36 mg/kg po). Primary outcomes were rate and severity of adverse events, and participant recruitment and retention. The primary clinical outcome was change in mean demoralization from baseline to end-of-treatment and to 3-month follow-up assessed with a two-way repeated measures ANOVA. Trial registration: Clinicaltrials.gov (NCT02950467)
Findings: From 17 July 2017 to 16 January 2019, 18 participants (mean age 59·2 years (SD 4·4)) were enrolled, administered group therapy and psilocybin, and included in intent-to-treat analyses. We detected zero serious adverse reactions and two unexpected adverse reactions to psilocybin; seven participants experienced self-limited, severe expected adverse reactions. We detected a clinically meaningful change in demoralization from baseline to 3-month follow-up (mean difference -5·78 [SD 6·01], ηp2 = 0·47, 90% CI 0·21–0·60).
Interpretation: We demonstrated the feasibility, relative safety, and potential efficacy of psilocybin-assisted group therapy for demoralization in OLTAS. Groups may be an effective and efficient means of delivering psychotherapy pre- and post-psilocybin to patients with complex medical and psychiatric needs.

Psychedelics may offer a novel alternative in the treatment of PTSD, depression (TRD, MDD), addiction, and several other mental disorders. Schindler and colleagues expanded the reach of psychedelics with the first double-blind, placebo-controlled study (n=10) and the use of psilocybin for migraines.

The study used a medium dose of psilocybin and found a significant reduction in migraine frequency up to two weeks later. The exact mechanisms behind this phenomenon are still not fully understood, but a recent review of psychedelics for cluster headaches identified functional connectivity changes as a possible route.

Schindler, E., Sewell, R. A., Gottschalk, C. H., Luddy, C., Flynn, L. T., Lindsey, H., Pittman, B. P., Cozzi, N. V., and D’Souza, D. C. (2020) Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin. Neurotherapeutics

While anecdotal evidence suggests that select 5-hydroxytryptamine 2A (5-HT2A) receptor ligands, including psilocybin, may have long-lasting therapeutic effects after limited dosing in headache disorders, controlled investigations are lacking. In an exploratory double-blind, placebo-controlled, cross-over study, adults with migraine received oral placebo and psilocybin (0.143 mg/kg) in 2 test sessions spaced 2 weeks apart. Subjects maintained headache diaries starting 2 weeks before the first session until 2 weeks after the second session. Physiological and psychological drug effects were monitored during sessions and several follow-up contacts with subjects were carried out to assure safety of study procedures. Ten subjects were included in the final analysis. Over the 2-week period measured after single administration, the reduction in weekly migraine days from baseline was significantly greater after psilocybin (mean, - 1.65 (95% CI: - 2.53 to - 0.77) days/week) than after placebo (- 0.15 (- 1.13 to 0.83) days/week; p = 0.003, t(9) = 4.11). Changes in migraine frequency in the 2 weeks after psilocybin were not correlated with the intensity of acute psychotropic effects during drug administration. Psilocybin was well-tolerated; there were no unexpected or serious adverse events or withdrawals due to adverse events. This exploratory study suggests there is an enduring therapeutic effect in migraine headache after a single administration of psilocybin. The separation of acute psychotropic effects and lasting therapeutic effects is an important finding, urging further investigation into the mechanism underlying the clinical effects of select 5-HT2A receptor compounds in migraine, as well as other neuropsychiatric conditions.

The acute psychedelic experience is often defined as an altered state of consciousness. In the treatment of mental disorders, psychedelic substances can achieve long-term beneficial effects in the patients, but the acute experience may not always be desired. The possibility of eliminating the acute psychedelic effects while preserving long-term outcomes was explored by Cameron et al. In their study, the administration of tabernanthalog, a non-psychoactive analog to ibogaine, led to similar structural neural plasticity (something seen with other psychedelics too, e.g., Ly et al., 2018 or Barrett et al., 2020), reduction in addiction-like behavior, and antidepressant-like effects in mice. This phenomenon still needs to be explored in humans, but it suggested that analogs to psychedelic substances could offer therapeutic value without the acute effect and lower to no toxicity.

Cameron, L.P., Tombari, R.J., Lu, J., Pell, A.J., Hurley, Z.Q., Ehinger, Y., Vargas, M.V., McCarroll, M.N., Taylor, J.C., Myers-Turnbull, D., Liu, T., Yaghoobi, B., Laskowski, L.J., Anderson, E.I., Zhang, G., Viswanathan, J., Brown, B.M., Tjia, M., Dunlap, L.E., Rabow, Z.T., et al. (2021) A non-hallucinogenic psychedelic analogue with therapeutic potential. Nature, 589(7842):474–479

The psychedelic alkaloid ibogaine has anti-addictive properties in both humans and animals1. Unlike most medications for the treatment of substance use disorders, anecdotal reports suggest that ibogaine has the potential to treat addiction to various substances, including opiates, alcohol and psychostimulants. The effects of ibogaine-like those of other psychedelic compounds-are long-lasting2, which has been attributed to its ability to modify addiction-related neural circuitry through the activation of neurotrophic factor signalling3,4. However, several safety concerns have hindered the clinical development of ibogaine, including its toxicity, hallucinogenic potential and tendency to induce cardiac arrhythmias. Here we apply the principles of function-oriented synthesis to identify the key structural elements of the potential therapeutic pharmacophore of ibogaine, and we use this information to engineer tabernanthalog-a water-soluble, non-hallucinogenic, non-toxic analogue of ibogaine that can be prepared in a single step. In rodents, tabernanthalog was found to promote structural neural plasticity, reduce alcohol- and heroin-seeking behaviour, and produce antidepressant-like effects. This work demonstrates that, through careful chemical design, it is possible to modify a psychedelic compound to produce a safer, non-hallucinogenic variant that has therapeutic potential.

Mason and colleagues undertook a closer inspection of brain activity during a psychedelic experience. This study investigated changes in the levels of the neurotransmitter glutamate in different brain areas. The authors concluded that psychedelics might increase neuroplasticity via glutamatergic activity. In the double-blind, placebo-controlled brain imaging study, lower hippocampal glutamate levels were associated with a positively experienced ego dissolution.

Several other studies in 2020 investigated neuronal changes at the peak of a psychedelic experience. Alamia and colleagues provided further evidence of changed cortical waves under DMT, while Varley and colleagues found that psilocybin and LSD increase fractal dimensions in brain areas related to spatial and temporal domains.

Mason, N.L., Kuypers, K.P.C., Müller, F. et al. (2020) Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin. Neuropsychopharmacol. 45:2003–2011

There is growing interest in the therapeutic utility of psychedelic substances, like psilocybin, for disorders characterized by distortions of the self-experience, like depression. Accumulating preclinical evidence emphasizes the role of the glutamate system in the acute action of the drug on brain and behavior; however this has never been tested in humans. Following a double-blind, placebo-controlled, parallel group design, we utilized an ultra-high field multimodal brain imaging approach and demonstrated that psilocybin (0.17 mg/kg) induced region-dependent alterations in glutamate, which predicted distortions in the subjective experience of one’s self (ego dissolution). Whereas higher levels of medial prefrontal cortical glutamate were associated with negatively experienced ego dissolution, lower levels in hippocampal glutamate were associated with positively experienced ego dissolution. Such findings provide further insights into the underlying neurobiological mechanisms of the psychedelic, as well as the baseline, state. Importantly, they may also provide a neurochemical basis for therapeutic effects as witnessed in ongoing clinical trials.

Salvia Divinorum is a sage species found in Mexico with longstanding traditions in religious and healing practices. Salvinorin A is a hallucinogen and a k-opioid receptor agonist found in Salvia Divinorum. In the study by Doss et al., participants were given Salvinorin A, and their brain activity was assessed with fMRI. Interestingly, the data showed a decrease in static functional connectivity of the default mode network (DMN), which is an effect comparable to the action of classic psychedelics. Although the sample size was relatively small (n=12) and the participants were already experienced with psychedelics (on average more than 250 previous experiences!), the results suggested that the k-opioid receptor signaling pathways may elicit effects comparable to those triggered by classic psychedelics, which target serotonin receptors. Müller and colleagues have already observed this phenomenon and found similar neuronal changes induced by MDMA.

Doss, M.K., May, D.G., Johnson, M.W. et al. (2020) The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain. Sci Rep, 10:16392

Salvinorin A (SA) is a κ-opioid receptor agonist and atypical dissociative hallucinogen found in Salvia divinorum. Despite the resurgence of hallucinogen studies, the effects of κ-opioid agonists on human brain function are not well-understood. This placebo-controlled, within-subject study used functional magnetic resonance imaging for the first time to explore the effects of inhaled SA on strength, variability, and entropy of functional connectivity (static, dynamic, and entropic functional connectivity, respectively, or sFC, dFC, and eFC). SA tended to decrease within-network sFC but increase between-network sFC, with the most prominent effect being attenuation of the default mode network (DMN) during the first half of a 20-min scan (i.e., during peak effects). SA reduced brainwide dFC but increased brainwide eFC, though only the former effect survived multiple comparison corrections. Finally, using connectome-based classification, most models trained on dFC network interactions could accurately classify the first half of SA scans. In contrast, few models trained on within- or between-network sFC and eFC performed above chance. Notably, models trained on within-DMN sFC and eFC performed better than models trained on other network interactions. This pattern of SA effects on human brain function is strikingly similar to that of other hallucinogens, necessitating studies of direct comparisons.

The mechanisms of action of psychedelics can be studied at various levels. The studies above mostly looked at changes in and between networks of brain areas. This study, published by Roth and colleagues, investigated the molecular properties of the 5-HT2A serotonin receptor.

This article, just like the one on tabernanthalog, contributes to our understanding of how to separate the brain-plasticity (therapeutic) effects from the acute effects of psychedelics. It also aimed at explaining how psychedelics bind to the serotonin receptor and subsequently trigger its conformational change.

To get a better overview of the recent research on 5HT2A receptors, visit our list of recommended readings in the Psychedelic Compendium.

Kim, K., Che, T., Panova, O., DiBerto, J. F., Lyu, J., Krumm, B. E., Wacker, D., Robertson, M. J., Seven, A. B., Nichols, D. E., Shoichet, B. K., Skiniotis, G., and Roth, B. L. (2020). Structure of a Hallucinogen-Activated Gq-Coupled 5-HT2A Serotonin Receptor. Cell, 182(6):1574–1588.e19.

Hallucinogens like lysergic acid diethylamide (LSD), psilocybin, and substituted N-benzyl phenylalkylamines are widely used recreationally with psilocybin being considered as a therapeutic for many neuropsychiatric disorders including depression, anxiety, and substance abuse. How psychedelics mediate their actions-both therapeutic and hallucinogenic-are not understood, although activation of the 5-HT2A serotonin receptor (HTR2A) is key. To gain molecular insights into psychedelic actions, we determined the active-state structure of HTR2A bound to 25-CN-NBOH-a prototypical hallucinogen-in complex with an engineered Gαq heterotrimer by cryoelectron microscopy (cryo-EM). We also obtained the X-ray crystal structures of HTR2A complexed with the arrestin-biased ligand LSD or the inverse agonist methiothepin. Comparisons of these structures reveal determinants responsible for HTR2A-Gαq protein interactions as well as the conformational rearrangements involved in active-state transitions. Given the potential therapeutic actions of hallucinogens, these findings could accelerate the discovery of more selective drugs for the treatment of a variety of neuropsychiatric disorders.

One large area of research on psychedelics in the year 2020 was the manufacturing of psychedelic substances. In order to make psychedelics available for therapy in patients, the production (and administration) of psychedelics needs to be realized at an industrial scale and at lower costs. Kargbo and colleagues (primarily at Usona Institute) published a method to produce psilocybin on a large scale (1kg, or >33.000 high dosages).

This study is just one among many to investigate novel ways of producing psychedelics. Milne and colleagues were able to use brewer’s yeast to produce not only psilocybin but also norbaeocystin, baeocystin, and aeruginascin. And co-authors on the paper of this section, Cozzi and Daley also synthesized DMT for clinical trials.

To dive deeper into the psilocybin production in microorganisms, read the interview that Nick Milne gave in the MIND Blog.

Kargbo, R.B., Sherwood, A., Walker, A., Cozzi, N.V., Dagger, R.E., Sable, J., O’Hern, K., Kaylo, K., Patterson, T., Tarpley, G., and Meisenheimer, P. (2020) Direct Phosphorylation of Psilocin Enables Optimized cGMP Kilogram-Scale Manufacture of Psilocybin. ACS Omega, 5(27):16959-16966

A second-generation kilogram-scale synthesis of the psychedelic tryptamine psilocybin has been developed. The synthesis was designed to address several challenges first encountered with the scale-up of previously described literature procedures, which were not optimized for providing consistent yield and purity of products, atom economy, or being run in pilot plant-scale reactors. These challenges were addressed and circumvented with the design of the second-generation route, which featured an optimized cGMP large-scale Speeter–Anthony tryptamine synthesis to the intermediate psilocin with improved in-process control and impurity removal over the three steps. Psilocin was subsequently phosphorylated directly with phosphorous oxychloride for the first time, avoiding a tedious and poor atom economy benzyl-protecting group strategy common to all previously described methods for producing psilocybin. In this report, the challenges encountered in a 100 g scale first-generation literature-based synthesis are highlighted, followed by a detailed description of the newly developed second-generation synthesis to provide over one kilogram of high-purity psilocybin under cGMP.

The studies above provided a glimpse into the future of psychedelics research. They showcased ways in which psychedelics can be beneficial, how they work in the brain, and even how they can be produced on a large scale. Looking back at the research and publications between the years 2007 and 2019, Reiff and colleagues reviewed the current state of insights on psychedelics for psychedelic-assisted psychotherapy.

They identified and discussed studies with MDMA for PTSD and the psilocybin trials for depression and cancer-related anxiety, and that studies like the ones above have offered more evidence for psychedelics as therapeutics. Another review by Goldberg and colleagues comes to a similar conclusion, finding significant positive effects on various mental diseases symptoms in their across 24 unique samples with almost 550 subjects total.

Reiff, C.M., Richman, E.E., Nemeroff, C.B., Carpenter, L.L., Widge, A.S., Rodriguez, C.I., Kalin, N.H., and McDonald, W.M. (2020) Psychedelics and Psychedelic-Assisted Psychotherapy. The American Journal of Psychiatry, 177(5):391-410

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.