Registered clinical studies investigating psychedelic drugs for psychiatric disorders

Psychedelics, often described as serotonergic hallucinogens, produce profound alterations in perception, mood and cognition via multiple serotonin-related mechanisms. The authors frame psychedelics as a heterogeneous group that includes classic 5-HT2A agonists (for example LSD, psilocybin, ayahuasca, DMT), empathogens/entactogens (MDMA), dissociative agents (NMDA antagonists, excluded here) and atypical hallucinogens (for example salvia divinorum, ibogaine). Interest in their therapeutic potential dates back to mid-20th century trials, but regulatory scheduling curtailed research until a recent resurgence. Contemporary studies have emphasised the use of psychedelics alongside psychotherapy, and early reports suggest promising efficacy and tolerability across conditions such as PTSD, major depressive disorder (MDD) and substance use disorders. Siegel and colleagues set out to systematically identify and describe all clinical studies registered on ClinicalTrials.gov that investigate psychedelic drugs (excluding ketamine) for psychiatric disorders. Rather than summarising published results, the analysis focused on registered trials—including ongoing and not-yet-completed studies—in order to map the research landscape, identify likely near-term evidence generation, and highlight gaps that warrant future attention.

ClinicalTrials.gov was searched on December 3, 2020, with an additional search on March 13, 2021. The inclusion criteria encompassed interventional and observational clinical studies that evaluate psychedelic drugs as treatments to improve psychiatric symptoms, as well as mechanistic studies in human participants. Studies of ketamine were deliberately excluded because of its distinct NMDA antagonist mechanism. The original search used the terms “psychedelics” and “psychiatric disorders” and was cross-referenced with specific drug terms: MDMA, psilocybin, DMT, 5-MeO-DMT, ibogaine hydrochloride, ayahuasca, LSD and salvia divinorum. All completed, active and upcoming clinical studies were considered; suspended, withdrawn or terminated studies were catalogued in a brief analysis but excluded from the main descriptive synthesis. For each eligible registration the investigators extracted study characteristics including study type, Phase, allocation and masking, intervention model, primary outcome, dates, administration route and dosing, number of doses, drug, control condition, concurrent behavioural interventions, location, sponsor and sample characteristics. Extracted data were analysed descriptively using IBM SPSS (Version 25). The authors modelled their approach on prior reviews of registered ketamine trials and analogous review methods used in fields with large numbers of ongoing trials.

Seventy registered clinical studies met the inclusion criteria. At the time of extraction, 21 of the 70 registered studies had published findings, and an additional four studies were terminated, suspended or withdrawn (these four were not included in the primary analyses). Across the 70 studies, the drug distribution was: MDMA 32 studies (45.7%), psilocybin 29 (41.4%), ayahuasca 1 (1.4%), LSD 3 (4.2%), ibogaine hydrochloride 2 (2.8%), salvia divinorum 1 (1.4%), 5-MeO-DMT 1 (1.4%) and DMT fumarate 1 (1.4%). Study status and purposes: 28 studies were marked as completed (40%), six were active but not recruiting (8.5%), 24 were recruiting (34%) and 11 were not yet recruiting (15.7%). Of the registrations, 55 studies (78.5%) were treatment trials, 10 (14.2%) were mechanistic studies and one (1.4%) was a prevention study. Most studies enrolled all genders (95.8%); 41 studies (58.5%) limited enrolment to adults aged 18–65 years while 29 studies (41.4%) accepted any adult aged 18 or older. Clinical indications targeted included PTSD (24.2%), MDD (18.5%), substance-related disorders (8.5%), mood disorders broadly (8.5%), alcohol use disorder (10%), anxiety disorders (7.1%), treatment-resistant depression (8.5%) and smaller proportions for conditions such as anorexia nervosa, obsessive–compulsive disorder and autism spectrum disorder. The authors report variable PTSD entry criteria across trials, ranging from specified severity thresholds to requirements for prior treatment failures. MDMA-focused studies: Of 32 MDMA trials, 23 (71.9%) were completed, two (6.3%) active but not recruiting, four (12.5%) recruiting, two (6.3%) not yet recruiting and one had unavailable status. Across these MDMA studies 1,014 participants were recruited. Primary aims were treatment in 19 studies (59.4%), mechanistic investigation in 10 (31.3%) and prevention in one (3.1%). Regarding Phase distribution, 34.3% were Phase I, 1.4% Phase I/II, 46.8% Phase II and 6.2% Phase III. MDMA trials most commonly targeted PTSD (53.1%), with other indications including mood disorders, substance-related disorders and anxiety. Approximately half of MDMA trials included MDMA-assisted psychotherapy; a single 125 mg dose was the most common dosing regimen, with some studies using ranges of 120–180 mg or multiple doses. Psilocybin-focused studies: Among 29 psilocybin trials, three (10.3%) were completed, four (13.8%) active and not recruiting, 14 (48.3%) recruiting and eight (27.6%) not yet recruiting. These trials plan to recruit a total of 1,587 participants. Nearly all (96.6%) had treatment as the primary purpose. Phase distribution included eight studies (27.5%) in Phase I, one (3.4%) in Phase I/II and 17 (58.6%) in Phase II. Indications included MDD (10 studies, 34.5%), treatment-resistant depression (five, 17.2%), alcohol use disorder (five, 17.2%), substance-related disorders (three, 10.3%), anxiety (two, 6.9%) and anorexia nervosa (three, 10.3%). Most studies administered psilocybin orally (69%); single doses of 25 mg and weight-based doses of 0.1–0.3 mg/kg were common. Seven trials incorporated microdosing protocols. Other agents: One randomized oral ayahuasca study for MDD in South America enrolled 35 participants and is completed but without posted results. Two randomized ibogaine hydrochloride trials (one placebo-controlled) enrolled 32 participants in total to study alcohol use disorder and drug addiction; dosing schemes varied, including one study with three fixed doses (240, 320 and 400 mg) and another with six ascending doses for half the sample and repeated 100 mg doses for the other half. A single open-label cohort study of salvia divinorum (Phase I/II) was recruiting and had enrolled one participant. Three registered LSD trials—reported as Phase III randomized clinical studies—targeted MDD, anxiety disorders and severe somatic disorders, enrolling 112 participants in total. One Phase I/II interventional, non-randomised, open-label 5-MeO-DMT study for treatment-resistant depression had 16 participants enrolled. Finally, one Phase I/II randomised, parallel, quadruple-masked intravenous DMT fumarate study for MDD had enrolled 68 participants.

Siegel and colleagues interpret their findings as evidence of a clear resurgence in clinical research on psychedelics: the number of registered studies rose substantially after 2000 and peaked in 2020. The United States accounted for the largest number of trial sites, followed by Switzerland, and most studies were clustered in Phase II. Oral administration was the most common route and many trials used randomised, parallel designs with quadruple masking. Typical sample sizes were modest, often between 10 and 30 participants. MDMA and psilocybin dominate the registered landscape. MDMA was the single most-studied compound, with PTSD as the leading indication; the authors link this focus to MDMA's pharmacology (monoamine release, transporter effects, partial serotonin receptor agonism and increased oxytocin), which may render it a suitable adjunct to trauma-focused psychotherapy. Psilocybin trials were predominantly directed at MDD and treatment-resistant depression, a pattern the authors ascribe to psilocybin's combined serotonergic and glutamatergic effects and to encouraging preliminary antidepressant signals reported elsewhere. Ibogaine registrations targeted substance and alcohol use disorders, reflecting its putative anti-addictive properties. By contrast, ayahuasca, salvia divinorum, 5-MeO-DMT and DMT fumarate were each represented by only a single registered study, all typically for MDD or treatment-resistant depression. The authors note that more registered trials exist for ketamine (n = 119) than for all other non-ketamine psychedelics combined in their sample (n = 70). They acknowledge several limitations of the current review: restricting the search to ClinicalTrials.gov likely omitted trials registered on other platforms or not registered at all, and some registry entries lacked key information such as route of administration, dosing schedules or details of adjunct psychotherapy, reducing the completeness of the descriptive synthesis. To strengthen future registration quality the authors recommend that investigators provide fuller protocol details in registry entries. Identified gaps include the need for trials that directly compare psychotherapeutic approaches delivered alongside psychedelics and studies that systematically vary dosing frequency to define optimal dose ranges. Finally, the authors advise that researchers, funders and reviewers consider the large body of ongoing registered projects before initiating new trials—particularly in the areas of MDMA and psilocybin research—so as to prioritise research questions that are not already being addressed.