Nature Medicine
June 1, 2021
Jennifer Mitchell, Michael P. Bogenschutz, Alia Lilienstein et al.
965 citations
A phase 3 clinical trial tested MDMA-assisted therapy against placebo for severe PTSD. Participants received manualized therapy with either MDMA or placebo alongside preparatory and integrative sessions. At two months after the last session, the MDMA group showed a significantly greater reduction in PTSD symptoms (average 24.4-point drop on the CAPS-5 scale) compared to the placebo group (13.9-point drop), with a large effect size. Functional impairment also improved more with MDMA. No serious safety issues such as abuse potential, suicidality, or heart rhythm problems were observed. The findings suggest MDMA-assisted therapy is highly effective and safe for severe PTSD, including in people with common co-occurring conditions.
Nature Medicine
October 1, 2023
Jennifer Mitchell, Marcela Ot’alora G., Bessel Van der Kolk et al.
400 citations
In a phase 3 trial, MDMA-assisted therapy reduced PTSD symptoms and functional impairment more than placebo with therapy in 104 participants with moderate to severe PTSD. The average decrease in PTSD symptom severity was 23.7 points with MDMA-assisted therapy versus 14.8 points with placebo, and functional disability improved by 3.3 versus 2.1 points. Participants were ethnoracially diverse, with 27% identifying as Hispanic/Latino and 34% as other than White. Severe side effects occurred in 9.4% of the MDMA group and 3.9% of the placebo group; no deaths or serious adverse events were reported. The treatment was generally well tolerated.
EClinicalMedicine
September 24, 2020
B. Anderson, Alicia Danforth, Prof Robert Daroff et al.
271 citations
Psilocybin-assisted group therapy is feasible, relatively safe, and potentially effective for reducing demoralization in older long-term AIDS survivor (OLTAS) gay men, a population with high levels of demoralization and traumatic loss. In an open-label study, participants with moderate-to-severe demoralization received 8-10 group therapy visits and one psilocybin administration (0.3-0.36 mg/kg). The primary clinical outcome showed a reduction in demoralization from baseline to end-of-treatment and to 3-month follow-up, with a moderate effect size (partial eta-squared = 0.47, 90% CI 0.21-0.60). Groups may offer an efficient model for delivering psychotherapy alongside psilocybin to patients with complex needs.
Journal of Neuroscience
November 30, 2020
Danilo de Gregorio, Argel Aguilar-Valles, Katrin H. Preller et al.
258 citations
A renewed interest in hallucinogens for treating psychiatric disorders has emerged. Preclinical and clinical studies have confirmed ketamine's efficacy for depression. Emerging evidence points to psilocybin and LSD's therapeutic properties and their ability to modulate functional brain connectivity. MDMA, an entactogen, has shown usefulness for post-traumatic stress disorder. This review summarizes the pharmacology of hallucinogenic compounds, highlighting differences between psychedelic and nonpsychedelic hallucinogens and entactogens, and describes their behavioral effects in animals and humans. Together, these data substantiate the potential of these compounds for treating mental diseases.
Focus (American Psychiatric Publishing)
July 1, 2023
Jennifer Mitchell, Michael P. Bogenschutz, Alia Lilienstein et al.
97 citations
A phase 3 clinical trial tested MDMA-assisted therapy for severe PTSD. In 90 participants randomized to receive either MDMA or placebo alongside therapy, those receiving MDMA showed a significantly larger reduction in PTSD symptoms, with an average decrease of 24.4 points on the CAPS-5 scale compared to 13.9 points in the placebo group. Functional impairment also improved more with MDMA. No serious safety issues like abuse potential or suicidality were observed. The treatment was effective even for patients with common co-occurring conditions such as depression or substance use history. The authors conclude MDMA-assisted therapy is a safe and highly effective treatment for severe PTSD.
Drug and Alcohol Dependence
February 1, 2022
Christopher R. Nicholas, Julie B. Wang, A. Coker et al.
67 citations
MDMA-assisted therapy for severe PTSD may also reduce hazardous alcohol use without increasing illicit drug use. In a randomized trial, 90 adults with severe PTSD received either MDMA-assisted therapy or placebo plus therapy. Those in the MDMA group showed a greater reduction in alcohol use scores (average decrease of 1.02 points) compared to a slight increase in the placebo group (average increase of 0.40 points). Changes in drug use scores did not differ between groups. The findings suggest MDMA-assisted therapy could serve as an integrated treatment for co-occurring PTSD and alcohol or substance use disorders.
PLoS One
February 25, 2022
Elliot Marseille, Jennifer Mitchell, James G. Kahn
49 citations
For patients with severe or extreme chronic PTSD, MDMA-assisted therapy (MDMA-AT) costs $11,537 per patient and generates net health care savings of $132.9 million over 30 years per 1,000 patients, while accruing 4,856 quality-adjusted life-years (QALYs) and averting 61.4 premature deaths compared with standard care. The therapy breaks even on cost at 3.8 years. A three-session MDMA regimen yields greater medical savings and health benefits than a two-session regimen. Even if no health care cost savings are assumed, the incremental cost-effectiveness ratio is $2,384 per QALY gained. MDMA-AT is cost-saving from a payer's perspective and delivers substantial clinical benefit.
Neuropsychopharmacology
July 21, 2023
Jennifer Mitchell, Brian T Anderson
47 citations
Over the last five years, clinical research into psychedelic medicines has expanded rapidly, with data from a Phase 3 industry trial, a multicenter Phase 2 industry trial, and multiple early-phase trials now published in peer-reviewed journals. This narrative review summarizes recent findings and ongoing clinical trials involving various classes of psyche-manifesting substances that may help treat a broad range of conditions. The review also discusses methodological considerations, unique challenges, and next steps for research, emphasizing the experiential nature of these therapies.
European Journal of Psychotraumatology
December 1, 2025
Gabrielle Agin-Liebes, Richard J. Zeifman, Jennifer Mitchell
11 citations
MDMA-assisted therapy (MDMA-AT) for severe posttraumatic stress disorder (PTSD) improves self-compassion, which may explain its therapeutic benefits. In a double-blind trial with 82 adults, MDMA-AT significantly increased compassionate self-responding (self-kindness, common humanity, mindfulness) and decreased uncompassionate self-responding (self-judgment, isolation, over-identification) compared to placebo plus therapy, with large effect sizes on most subscales. Changes in self-compassion fully mediated the reduction in PTSD severity and depressive symptoms, but not in alcohol or substance use. Self-compassion appears to be a key psychological mechanism in MDMA-AT, suggesting that targeting it could refine treatments for PTSD with co-occurring depression.
Nature Mental Health
May 1, 2025
Daniel H. Grossman, Kevin R. Madden, Nicky J. Mehtani et al.
10 citations
Socioeconomic status (SES) strongly affects mental health outcomes and treatment access, but its reporting in psychedelic-assisted therapy trials is inadequate. A systematic review of 98 articles (49 primary trials and 49 secondary analyses) from 2006 to 2024 found that only 12% of primary trials reported participant income data, and 31% reported educational attainment. In US-based trials, participants had markedly higher SES than the general population: 93% had some college education (versus 62% nationally), and median incomes in major trials substantially exceeded the national median for all workers. Non-US trials showed variable patterns. This underreporting and evidence of socioeconomic disparities highlights an urgent need for standardized SES reporting and strategies to improve socioeconomic diversity in psychedelic-assisted therapy research.
Scientific Reports
August 2, 2024
Jennifer Mitchell, Nicky J. Mehtani, Mallory O. Johnson et al.
9 citations
HIV-related shame predicts substance use and poor antiretroviral adherence among people with HIV, hindering national epidemic-ending goals. In a pilot clinical trial with 12 participants, psilocybin-assisted group therapy produced a large decrease in HIV-related shame, with a median reduction of 5.5 points on the HIV and Abuse Related Shame Inventory from baseline to 3-month follow-up. However, two participants experienced a paradoxical worsening of sexual abuse-related shame after psilocybin, raising concerns about its use in patients with trauma. These preliminary results suggest potential for addressing HIV-related shame but highlight cautions.
Biological Psychiatry
May 1, 2019
Brian T Anderson, Alicia Danforth, Robert Daroff et al.
5 citations
No Summary
bioRxiv (Cold Spring Harbor Laboratory)
November 7, 2024
Lorenzo Pasquini, Jakub Vohryzek, Anira Escrichs et al.
4 citations
preprint
Psilocybin induces fast and sustained improvements in mental well-being, yet its long-term mechanisms are not fully understood. Four weeks after a full dose, fronto-striatal-thalamic (FST) circuitry—involved in goal-directed behavior and motivation—shows increased dynamic activity and flexibility in healthy volunteers. Computational modeling indicates that reduced structural constraints on functional dynamics cause this increased flexibility. Long-term changes include increased bottom-up and reduced top-down information flow, mediated by serotonergic (5-HT2A) and dopaminergic (D2) receptor systems. This functional re-organization of FST circuits may represent a common mechanism underlying clinical improvements across neuropsychiatric disorders such as substance abuse, major depression, and anorexia.
Nat Med
November 1, 2024
Jennifer Mitchell, Marcela Ot’alora G., Bessel Van der Kolk et al.
4 citations
No Summary
Journal of Psychoactive Drugs
January 1, 2024
Kelan Thomas, Robert L. Jesse, Nicky J. Mehtani et al.
4 citations
Policymakers are increasingly using clinical trial data to justify deprioritizing, decriminalizing, or legalizing psychedelic substances, but personal possession limits written into law often lack scientific grounding. This commentary argues that allowable amounts should be based on moderate-high doses shown safe and effective in clinical trials, common naturalistic use, and dose-equivalence studies. The authors provide a table of evidence-informed moderate-high doses for seven psychedelics to guide consistent and equitable policy limits, aiming to replace arbitrary thresholds with scientifically justified ones.
Psychedelics
August 5, 2025
Elliot Marseille, Jennifer Mitchell
2 citations
A commentary on a cost-effectiveness analysis of MDMA-assisted therapy for PTSD, published after the FDA declined to approve the treatment in 2024, identifies two key limitations that reduce its relevance for healthcare decision-makers. The analysis compared MDMA therapy to placebo-based therapy instead of standard-of-care treatments, and it used a pricing strategy of $36,000 for the three MDMA doses that threatens accessibility. Alternative modeling indicates that at a price of approximately $10,500, MDMA therapy could be extremely cost-effective, around $160 per quality-adjusted life year (QALY), or even cost-saving. Future research should incorporate realistic treatment comparators, comprehensive healthcare utilization data, and pricing models balancing economic viability with public health goals.
J Psychoactive Drugs
November 10, 2025
Nicky J. Mehtani, Maha N. Mian, Gabrielle Agin-Liebes et al.
1 citation
A novel approach combines psychedelic therapy with 12-step programs to improve engagement in community-based recovery from substance use disorders. The authors argue that psychedelics may enhance openness, spiritual experiences, and social bonding, which could increase participation in 12-step meetings and practices. This accessible strategy aims to leverage existing recovery communities, potentially broadening treatment options without requiring extensive clinical infrastructure. The paper presents a theoretical framework for integrating these modalities, suggesting that such augmentation could improve outcomes for individuals with substance use disorders, though empirical evidence is not provided.
Hum Brain Mapp
July 1, 2026
Lorenzo Pasquini, Jakub Vohryzek, Anira Escrichs et al.
A computational model predicts that a single dose of psilocybin can produce lasting changes in the dynamic activity and effective connectivity of fronto-striatal-thalamic brain circuits. The modeling suggests that psilocybin may strengthen connectivity between the prefrontal cortex and striatum while altering thalamic gating, effects that persist beyond the acute drug experience. These changes could underlie the sustained therapeutic benefits observed in clinical settings, such as reduced depressive symptoms and increased psychological flexibility. The findings provide a mechanistic framework for understanding how psilocybin induces long-term neural plasticity and highlight potential circuit targets for treating psychiatric disorders.
Philosophical Psychology
April 10, 2026
Eric Rundquist, Diego Nicolás Monasterio López, Juan Jonathan Oyarzo Alvarado et al.
A cognitive-linguistic analysis of interviews with a healthy volunteer after moderate-to-high psilocybin doses reveals that the participant consistently used metaphors framing abstract introspective events in terms of concrete, visible, and interpersonal events, instantiating a cognitive frame called the Observer's Model. These metaphors imply cognitive defusion and heightened metacognitive awareness during the sessions. Literal descriptions of hallucinatory visual experiences correlated semantically with metaphorical expressions, suggesting metaphorical thinking plays a role in motivating those experiences. The findings are linked to neuroscientific research on psychedelics and have psychological and therapeutic implications.
Current Topics in Behavioral Neurosciences
November 22, 2025
Maha N. Mian, Allison R. Coker, Grace Kretzer et al.
Communities that use psychedelics as religious sacraments have developed their own frameworks for safety and hold distinct views on risk and harm. To better understand their lived realities, researchers can collaborate closely with these communities using community-based participatory research (CBPR) practices, which center communities in co-creating research, improve engagement, build trust, and highlight local priorities. This paper presents preliminary findings from a CBPR study with entheogenic communities, sharing lessons learned from forming a community advisory board and initial pilot data gathering. Lessons include consulting community engagement experts, considerations for compensation and confidentiality, using multimodal recruitment strategies, and recognizing the unique historical context of these communities. These lessons aim to develop best practices for psychedelic research, policy, and public education.
BMJ Open
August 1, 2025
Nicky J. Mehtani, B. Anderson, Irina Alexander et al.
Methamphetamine use disorder (MeUD) has no FDA-approved pharmacotherapies and is linked to poor neurological, psychiatric, and cardiovascular outcomes, especially among low-income populations, while also increasing risks for sexually transmitted infections. The Ketamine-Assisted Recovery (KARE) trial is an open-label pilot study enrolling 12 to 24 Medicaid- or Medicare-insured adults with moderate-to-severe MeUD and HIV risk factors. Participants will receive three intramuscular ketamine sessions (0.50-0.75 mg/kg) combined with seven motivational enhancement therapy sessions over five weeks. The study will assess feasibility, acceptability, tolerability, safety, and potential mechanisms such as psychological flexibility, laying groundwork for future randomized trials.