The Journal of Clinical Psychiatry
May 4, 2023
Sandeep M. Nayak, Melissa Bradley, Bethea A Kleykamp et al.
38 citations
A systematic review of randomized trials of psychedelics in humans found that most studies use inert placebos rather than active comparators, and very few assess whether blinding was successful. Of 86 unique studies, 61.2% used an inert placebo, 20.0% used active comparators, and only 17.3% included any assessment of blinding; when assessed, blinding success was generally poor. Only 3 of 21 therapeutic trials compared psychological support to a minimally supportive condition. The review concludes that randomized psychedelic trials underutilize blind assessment, active drug controls, and adequate control conditions for psychological support, and recommends improvements to trial methods.
Neuropharmacology
April 2, 2023
Farah Z Zia, Michael H. Baumann, Sean J Belouin et al.
28 citations
Chronic pain is a leading cause of disability and opioid overdose in the United States. While many people manage pain with existing medicines and psychosocial treatments, others find these options ineffective or unacceptable due to side effects and risks. Preliminary evidence suggests psychedelics may improve quality of life, functionality, and reduce disability and distress for people whose pain may never be completely relieved. This commentary calls for more basic research and clinical trials to explore psychedelics' potential in chronic pain management, and to determine whether effects stem from direct antinociceptive or anti-inflammatory mechanisms, or from increased tolerability, acceptance, and spirituality that mediate therapeutic effects seen in psychiatric disorders.
JAMA Psychiatry
January 1, 2023
Brian D Kiluk, Bethea A Kleykamp, Sandra D Comer et al.
22 citations
A review sponsored by a public-private partnership addresses clinical trial design for new opioid use disorder (OUD) treatments that target systems other than the μ-opioid receptor. The authors present consensus recommendations for evaluating novel therapies such as cannabinoids, psychedelics, sedative-hypnotics, and immunotherapeutics. Key design elements include specifying the treatment stage (e.g., early abstinence, long-term recovery), defining the treatment's role (adjunctive or independent), selecting patient-informed primary outcomes that assess opioid use patterns, retention, and quality of life, and monitoring adverse events like relapse or overdose, especially when patients are not on maintenance opioid agonist or antagonist medications. Incorporating input from people with lived experience is urged to accelerate development and uptake of effective therapeutics.
The journal of pain
October 1, 2022
Robert H. Dworkin, Brian T Anderson, Nick Andrews et al.
22 citations
Psychedelic substances have been used historically for spiritual and mystical experiences, and recent interest focuses on their potential to treat chronic pain. Clinical trials support psychedelics' effectiveness for psychiatric conditions, but studies on chronic pain—such as cancer pain, phantom limb pain, migraine, and cluster headache—are few and mostly uncontrolled. Risks are relatively rare with careful patient screening and supervision. Key challenges include identifying mechanisms of action, selecting appropriate pain conditions, designing rigorous trials with proper control groups, minimizing unblinding bias, and accounting for patient mindset and setting. Evidence-based recommendations are needed for future research to yield informative results.
Clinical Pharmacology & Therapeutics
October 5, 2023
Robert H. Dworkin, Michael Mcdermott, Sandeep M. Nayak et al.
16 citations
Combining a classic psychedelic (e.g., psilocybin) with psychotherapy may produce benefits that are synergistic—greater than the sum of each treatment alone—but current trials have not tested this directly. Most studies pair the drug with some form of psychological support, yet providing full psychotherapy is more costly and harder to scale than basic harm-reduction support. Factorial designs, in which patients are randomly assigned to drug plus psychotherapy, drug alone, psychotherapy alone, or double placebo, can isolate the separate contributions of each component and detect true synergy. Such trials require large sample sizes but could determine whether the added expense of psychotherapy is worthwhile for improving outcomes in conditions like depression, anxiety, and chronic pain.
Neuroscience and Biobehavioral Reviews
November 1, 2023
Sophia Linguiti, Jacob W Vogel, Valerie J Sydnor et al.
15 citations
A systematic review of 91 fMRI studies on acute psychedelic effects found substantial methodological heterogeneity. Only 51 unique samples were used across the 91 papers, and 54% of studies did not meet current standards for correcting Type I errors or controlling motion artifacts. Psilocybin and LSD consistently modulated connectivity along the sensorimotor-association cortical axis. Ketamine consistently increased activation in the dorsomedial prefrontal cortex. The review calls for future adoption of pre-registration, standardized processing and statistical testing, and data sharing to improve rigor.
Nature Mental Health
May 1, 2026
S. Parker Singleton, Brooke L. Sevchik, Analiese Lahey et al.
2 citations
A living systematic review and meta-analysis of 15 randomized controlled trials (801 participants) found that psilocybin-assisted therapy substantially reduces depressive symptoms compared to control conditions, with a standardized mean difference of −0.90 (Hedges’ g). The analysis included 12 trials (585 participants) in the primary model. Many studies had small sample sizes or risk of bias. The review is maintained as a living resource with an open-data database and online dashboard that will be updated as new evidence emerges.
CNS Drugs
June 15, 2026
Edward P. Hackett, Aditi Chaudhri -, Linda Hasman et al.
Dextromethorphan (DXM), a common over-the-counter cough suppressant, produces psychedelic effects at high doses that may be useful for treating psychiatric disorders resistant to standard therapies. A systematic review of eight studies with 104 total participants found that psychedelic effects begin at 100 mg, with hallucinatory and mystical experiences intensifying at 300 and 400 mg. Adverse effects such as nausea, vomiting, motor impairment, and cognitive slowing become more prominent above 200 mg. The evidence is too limited to establish true dose-response relationships, and the certainty of evidence is low for most outcomes, highlighting the need for larger, well-designed studies.
medRxiv Preprint Server
March 27, 2026
Brooke L. Sevchik, S. Parker Singleton, Analiese Lahey et al.
preprint
A living systematic review and meta-analysis of six randomized controlled trials with 286 participants found that MDMA-assisted therapy reduces PTSD symptoms more than control conditions (Hedges' g = -0.71). More dosing sessions and higher cumulative doses were linked to larger effects. MDMA also led to higher response (risk ratio 1.35) and remission (risk ratio 2.25) rates. Most studies had low risk of bias per Cochrane guidelines, though issues like expectancy and functional unblinding remain. The evidence was rated low certainty using GRADE, and the authors note more trials are needed.
medRxiv
August 16, 2025
S. Parker Singleton, Brooke L. Sevchik, Analiese Lahey et al.
preprint
Psilocybin-assisted therapy produces substantial reductions in depressive symptoms compared to control conditions, according to a systematic review and meta-analysis of 12 randomized controlled trials with 711 participants. The pooled effect size was large (Hedges' g = –0.91), and effects appeared rapidly and remained consistent over several weeks. However, many studies had small sample sizes or risk of bias, and waitlist-controlled or crossover designs contributed heterogeneity. The review provides a living open data resource that will be updated as new evidence emerges.