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.
JAMA
August 31, 2023
Charles L. Raison, Gerard Sanacora, Joshua Woolley et al.
493 citations
A single 25-mg dose of synthetic psilocybin, administered with psychological support, produced a clinically significant and sustained reduction in depressive symptoms and functional disability over 43 days in adults with major depressive disorder. In a phase 2 trial of 104 participants, those receiving psilocybin showed a mean 12.3-point greater improvement on the Montgomery-Asberg Depression Rating Scale at day 43 compared with those receiving a niacin placebo. Psilocybin also improved daily functioning and led to more sustained response, though not remission. No serious adverse events occurred, but psilocybin was associated with more overall and severe adverse events.
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.
Psychiatry Research
January 2, 2020
Simon B. Goldberg, Brian T. Pace, Christopher R. Nicholas et al.
234 citations
A meta-analysis of four studies (three randomized, placebo-controlled; one uncontrolled) with 117 participants found that psilocybin combined with behavioral interventions produced large reductions in anxiety and depression among people with elevated symptoms. Within-group effects from before treatment to after treatment and at follow-up were large (Hedges' g = 1.16 to 1.47) and statistically significant. Across the placebo-controlled studies, the pre-post effects compared to placebo were also large (g = 0.82 to 0.83) and statistically significant. No serious adverse events were reported. The results tentatively support further research on psilocybin for anxiety and depression, though the small number of studies and potential bias limit confidence.
Clinical Pharmacokinetics
March 28, 2017
Randall Brown, Christopher R. Nicholas, Nicholas V. Cozzi et al.
189 citations
Psilocybin is a psychedelic tryptamine being studied for depression and substance use disorders. In an open-label study of 12 healthy adults, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg were given at monthly intervals. No psilocybin was found in plasma or urine; its active metabolite psilocin had an elimination half-life of 3 hours (standard deviation 1.1). Renal clearance of intact psilocin accounted for less than 2% of total clearance, indicating no dose reduction is needed for mild-moderate renal impairment. Body weight did not predict variation in psilocin clearance. No serious adverse events occurred. A fixed 25 mg dose approximates the exposure of a 0.3 mg/kg dose.
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.
Journal of Psychopharmacology
June 27, 2018
Christopher R. Nicholas, Kelsey M. Henriquez, Michele Gassman et al.
85 citations
Healthy participants given escalating doses of psilocybin (0.3, 0.45, and 0.6 mg/kg) showed a significant linear dose-related increase in Mystical Experience Questionnaire total score and the transcendence of time and space subscale, but not in the rate of complete mystical experiences. Dose 3 produced significantly higher transcendence of time and space scores than dose 1, while no dose-related differences emerged for total scores or mystical experience rate. Positive persisting effects 30 days after the last dose were significantly higher than negative ones, and a moderate increase in well-being or life satisfaction was associated with the maximum mystical experience score. Pharmacokinetic measures correlated with dose but not with mystical experience scores or rate, indicating that a complete mystical experience was not necessary for positive outcomes.
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.
Psychological Medicine
November 4, 2020
Simon B. Goldberg, Benjamin Shechet, Christopher R. Nicholas et al.
66 citations
Classical psychedelics such as psilocybin, ayahuasca, and LSD produce significant psychological effects lasting at least 24 hours after administration, according to a systematic review and meta-analysis of 34 experimental studies involving 549 participants. Large effects were observed for reducing targeted symptoms in psychiatric samples, improving negative and positive affect, social outcomes, and existential or spiritual well-being, with between-group effect sizes ranging from Hedges' g = 0.84 to 1.08. Effects may be larger in clinical samples. Evidence for changes in personality traits or mindfulness was weak. No post-acute adverse effects were found, but high risk of bias, heterogeneity, and possible publication bias underscore the need for larger, placebo-controlled trials.
Am J Psychiatry
January 1, 2024
Kelley C. O’donnell, Brian T Anderson, Frederick S. Barrett et al.
31 citations
This critical response addresses misinterpretations and omissions in a commentary by Goodwin and colleagues on psilocybin-assisted therapy, arguing that the commentary misrepresents existing evidence and overlooks key methodological issues. The authors contend that the commentary fails to adequately discuss safety concerns, including adverse events and the potential for psychological distress, and omits important data on long-term outcomes. They emphasize the need for rigorous, balanced evaluation of psilocybin-assisted therapy's risks and benefits, cautioning against overstating positive outcomes while underreporting negative findings. The response calls for more transparent reporting and careful interpretation of clinical trial results.
Am J Psychiatry
January 1, 2024
Michael Alpert, Kelley C. O’donnell, Casey Paleos et al.
22 citations
Psychotherapy is a necessary component of psychedelic treatment, providing safety and evidence-based support. The text argues that integrating structured psychological guidance with psychedelic sessions enhances therapeutic benefits and improves mental health outcomes. This combined approach fosters a supportive journey, leading to transformative mental health care and healing potential.
Frontiers in Psychiatry
March 14, 2023
Jonathan Brett, Elizabeth Knock, Paul Liknaitzky et al.
16 citations
Methamphetamine use disorder is a chronic condition with high relapse rates and limited effective treatments. Contingency management and psychotherapy show modest efficacy, while pharmacological options have little to no benefit. Psilocybin-assisted psychotherapy is emerging as a promising approach for substance use disorders, though no studies have yet examined it for methamphetamine use disorder. This review presents the rationale for using psilocybin-assisted psychotherapy to treat methamphetamine use disorder and describes practical considerations from early experience designing and implementing four clinical trials on this approach.
Translational Psychiatry
September 12, 2024
Christopher R. Nicholas, Matthew I Banks, Richard C Lennertz et al.
10 citations
Psilocybin, a serotonergic psychedelic, can relieve symptoms in several psychiatric disorders and improve well-being, but it was unclear whether these benefits arise during the acute experience or depend on later memory of it. In 8 healthy participants, psilocybin (25 mg) was co-administered with the amnestic benzodiazepine midazolam at a dose that allowed a conscious psychedelic experience while partially impairing memory for it. Higher midazolam doses and greater memory impairment tended to associate with lower salience, insight, and well-being from psilocybin. These results suggest memory plays a role in therapeutically relevant behavioral effects of psilocybin.
Psychedelic Medicine
January 20, 2025
Marianna Graziosi, Gabrielle Agin-Liebes, Mary P Cosimano et al.
9 citations
Psilocybin and other serotonergic psychedelics are used in research settings with safety measures including controlled environments, staff presence, screening, and psychoeducation. An analysis of study materials from psilocybin trials over the past two decades found that psychoeducation documents varied but commonly emphasized biological and physical safety, psychological safety and well-being, aspects of setting, and the potential for expectancies. The materials prioritized biological and psychological safety across all sites. The authors also identified elements unrelated to safety that may contribute to participant expectancies and suggest these extrapharmacological factors be studied systematically to maximize safety while minimizing extraneous expectancies.
Psychedelic Medicine
December 1, 2023
Julia Malicki, Amelia Baltes, Christopher R. Nicholas et al.
7 citations
A clinical trial found that giving psilocybin together with buprenorphine to people with opioid use disorder was safely tolerated and did not interfere with buprenorphine's effectiveness or psilocybin's subjective effects. The study faced feasibility challenges that required changes to the participant pool and eligibility rules, along with strategies to improve accessibility, reduce burden, and increase generalizability.
Nat Med
November 1, 2024
Jennifer Mitchell, Marcela Ot’alora G., Bessel Van der Kolk et al.
4 citations
No Summary
Front Psychiatry
December 9, 2025
Haley Maria Dourron, Heith Copes, Daniel H. Grossman et al.
3 citations
People diagnosed with non-affective psychotic disorders who used psychedelics reported a mix of positive and negative effects. Common challenges during the acute experience included transient anxiety, sometimes leading to brief hospitalizations. Some participants described psychosis-specific experiences such as reduced self-stigma and insight into their hallucinations and delusions. Perceived long-term benefits varied widely, with some reporting lasting positive changes and others noting negative effects or no lasting impact. The findings suggest psychedelics may pose both risks and potential benefits for this population, highlighting the need for careful safety trials.
bioRxiv (Cold Spring Harbor Laboratory)
June 13, 2024
Christopher R. Nicholas, Matthew I. Banks, Richard C Lennertz et al.
3 citations
preprint
Co-administering the amnestic benzodiazepine midazolam with psilocybin in 8 healthy participants partially impaired memory for the psychedelic experience while still allowing a conscious experience to occur. The degree of memory impairment was inversely associated with salience, insight, and well-being induced by psilocybin. These results suggest that memory of the acute psychedelic experience contributes to therapeutically relevant behavioral effects. Because midazolam blocks memory by blocking cortical neural plasticity, it may also help evaluate how the pro-neuroplastic properties of psychedelics contribute to their therapeutic activity.
International Journal of Mental Health and Addiction
March 17, 2026
Haley Maria Dourron, Melissa Bradley, Heith Copes et al.
Interviews with 19 people diagnosed with non-affective psychotic disorders who had used psychedelics revealed that, while some similarities exist in altered thinking and meaning attribution, most participants reported that psychedelic experiences did not closely resemble their psychosis. Sensory alterations, emotional experience, sense of control, and self-experience were points of contrast. When asked which drug most resembled their psychotic symptoms, the majority endorsed cannabis, followed by dissociative anesthetics and stimulants. The findings suggest that psychedelics may not accurately model many symptoms of psychosis and that interpreting psychedelic experiences as broadly psychosis-like may be misleading.
bioRxiv (Cold Spring Harbor Laboratory)
July 29, 2025
May Kung Sutherland, Christopher R. Nicholas, Richard C Lennertz et al.
preprint
Psilocybin, a serotonergic psychedelic, induces neural plasticity and alters consciousness, while midazolam, a benzodiazepine, blunts plasticity and causes sedation and amnesia. In an open-label pilot study, 25 mg of oral psilocybin was given alongside intravenous midazolam at doses that allowed a full psychedelic experience but reduced memory of it. EEG recordings showed that 15-30 minutes after dosing, when midazolam was at its target concentration, beta power increased and the spectral exponent decreased. As psilocybin's effects emerged over the next six hours, Lempel-Ziv complexity and spectral exponent increased while broadband power decreased. These findings suggest psilocybin's effects persist even with midazolam, supporting its use in mechanistic studies.
Drug and Alcohol Dependence
July 1, 2025
Dilara Bahceci, Krista J. Siefried, Maureen Steele et al.
Among 268 people who used methamphetamine, nearly half had a diagnosed mental illness and were at risk of suicide, and most had taken other substances besides methamphetamine and psychedelics. Most psychedelic experiences were unplanned, recreational, and combined with other drugs. After the experience, about 59% reported improved mood, 50% improved social functioning, and 34% reduced methamphetamine use. Planning the experience and having less challenging experiences were linked to better outcomes. The findings suggest that psychedelic use may improve mood and social function and reduce substance use in this population, but highlight the importance of context and setting.
Frontiers in Psychology
January 1, 2024
Kelley C O'Donnell, Lauren Okano, Michael Alpert et al.
A conceptual framework for MDMA-Assisted Therapy for PTSD centers on the participant's inner healing intelligence as the primary agent of change, with the therapeutic relationship as the core facilitative condition. This inner-directed, holistic, self-directed, relational, and trauma-informed approach includes a non-pathologizing stance toward embodied experiences, such as intense emotional expression, multiplicity, suicidal ideation, and transpersonal experiences. Therapists bring psychodynamic, somatic, and transpersonal awareness, empathic attunement, relational skillfulness, and cultural humility. MDMA with this psychotherapy outperformed placebo with psychotherapy in Phase 2 and 3 trials, though significant symptom reduction also occurred in the placebo group, supporting the psychotherapy model itself.
Kelley C O'Donnell, Michael Alpert, Lauren Okano et al.
preprint
MDMA-Assisted Therapy for PTSD uses a short-term, intensive psychotherapy model that includes three sessions facilitated by MDMA along with non-drug therapy sessions. The MDMA helps recall and process traumatic memories and enhances learning in social contexts, integrating top-down and bottom-up trauma care. This paper describes the psychotherapeutic concepts and theories behind this approach, centering on the participant's inner healing intelligence as the main agent of change, with the therapeutic relationship as a core facilitative condition. Phase 2 and 3 trials showed MDMA with therapy outperformed placebo with therapy in reducing PTSD symptoms, though significant symptom reduction also occurred in participants who received only therapy.
Translational Psychiatry
February 14, 2026
Michael H Sutherland, Christopher R. Nicholas, Richard C Lennertz et al.
Psilocybin, a serotonergic psychedelic, induces neural plasticity and alters consciousness, while midazolam, a benzodiazepine, blunts plasticity and induces sedation. In an open-label pilot study, 25 mg of oral psilocybin was given alongside intravenous midazolam at doses that allowed a full psychedelic experience but blunted memory. Electroencephalography (EEG) data showed that 15–30 minutes after dosing, when midazolam was at its target concentration, beta power increased and spectral exponent decreased. As psilocybin's effects emerged over the next six hours, Lempel-Ziv complexity and spectral exponent increased, while broadband power decreased, especially in delta, theta, and alpha bands. The findings suggest psilocybin's effects persist with midazolam, supporting its use in mechanistic studies.