World Psychiatry
September 15, 2023
Roger S. McIntyre, Mohammad Alsuwaidan, Bernhard T. Baune et al.
712 citations
At least 30% of people with depression meet the common definition of treatment-resistant depression (TRD): inadequate response to two or more antidepressants despite adequate trials and adherence. Many cases are actually pseudo-resistant due to insufficient treatment or non-adherence. No consensus definition with proven predictive utility for clinical decisions exists, leading to varied prevalence estimates and inconsistent care. Intravenous ketamine and intranasal esketamine are effective for TRD. Some second-generation antipsychotics (e.g., aripiprazole, quetiapine XR) help as adjuncts in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation and electroconvulsive therapy are established effective interventions. Evidence for extending trials, switching, or combining antidepressants is mixed, and manual-based psychotherapies are not effective alone but help when added to antidepressants.
Journal of Psychopharmacology
November 6, 2020
Luke A. Jelen, Allan H. Young, James Stone
244 citations
The discovery that the dissociative anaesthetic ketamine produces rapid antidepressant effects is considered the most important breakthrough in depression research in the last 50 years. Ketamine, a racemic mixture of (S)-ketamine and (R)-ketamine, remains an off-label treatment for treatment-resistant depression, limited by dissociative effects and abuse potential. An (S)-ketamine nasal spray is approved in the United States and Europe, though concerns about efficacy and side effects persist. Preclinical evidence suggests (R)-ketamine may have more potent and longer-lasting antidepressant effects than (S)-ketamine with fewer side effects, and a pilot trial showed rapid-acting and sustained antidepressant effects in individuals with treatment-resistant depression. Research continues on the cellular and molecular mechanisms underlying these effects.
Journal of Psychopharmacology
November 18, 2016
James Rucker, Luke A. Jelen, Sarah Kalen Flynn et al.
187 citations
Unipolar mood disorders such as major depressive disorder and dysthymia cause high disability, mortality, and socioeconomic burden, with current treatments often suboptimal and little new pharmaceutical development. Psychedelic drugs like psilocybin were used extensively before prohibition in the late 1960s and are relatively safe in medically controlled environments with no dependence risk. A systematic review of 19 clinical treatment studies found that of 423 individuals, 335 (79.2%) showed clinician-judged improvement after psychedelic treatment. A recent UK pilot study supports psilocybin with psychological support for treatment-resistant depression. The evidence strongly suggests psychedelics should be re-examined in modern clinical trials for unipolar mood disorders.
Journal of Psychopharmacology
January 1, 2022
James Rucker, Lindsey Marwood, Riikka-Liisa Johanna Ajantaival et al.
101 citations
A single dose of 10 or 25 mg psilocybin, given simultaneously to up to six healthy adults with one-to-one psychological support, did not impair cognitive function or emotional processing. Over 500 treatment-emergent adverse events were reported, mostly mild and resolving within a day, with no serious events or study withdrawals. Cognitive performance, measured by a Cambridge Neuropsychological Test Automated Battery global composite score and domain scores, showed no clinically relevant differences between psilocybin and placebo groups. The findings suggest that these doses of psilocybin are generally well tolerated and safe for cognitive function in the short and long term.
Frontiers in Psychiatry
June 9, 2021
Simon Ruffell, Nige Netzband, WaiFung Tsang et al.
74 citations
A naturalistic study of 63 people who participated in ayahuasca ceremonies at a retreat in the Peruvian Amazon found significant improvements in depression, anxiety, and overall psychological distress, along with increased self-compassion, immediately after the retreat and sustained at six months. Depression scores on the Beck Depression Inventory dropped from 13.9 to 6.1, anxiety scores on the State-Trait Anxiety Inventory fell from 44.4 to 34.3, and scores on the Clinical Outcomes in Routine Evaluation-Outcome Measure decreased from 37.3 to 22.3. Changes in memory valence were linked to these improvements. Epigenetic results were inconclusive but suggested further research on the SIGMAR1 gene is warranted.
Journal of Psychopharmacology
April 7, 2022
Emma I Kopra, Jason Ferris, Adam Winstock et al.
65 citations
Among 9,233 people who used magic mushrooms in the past year, only 19 (0.2%) sought emergency medical treatment, corresponding to a per-event risk of 0.06%. Younger age was the only factor linked to a higher chance of needing emergency care. The most common symptoms were psychological—anxiety, panic, paranoia, and suspiciousness. Poor mindset, poor setting, and mixing substances were the most frequently cited reasons for the incidents. All but one person returned to normal within 24 hours. The findings confirm that psilocybin mushrooms are relatively safe, with serious adverse reactions being rare and short-lived.
Journal of Psychopharmacology
March 6, 2023
Emma I Kopra, Jason Ferris, Adam Winstock et al.
62 citations
A large international survey of 3364 people who used LSD or psilocybin mushrooms for self-treatment of mental health conditions or life worries found positive changes across all 17 measured outcomes, with the strongest benefits for insight and mood. However, 22.5% of respondents reported negative effects. Higher intensity of the psychedelic experience, seeking advice beforehand, using psilocybin mushrooms, and treating post-traumatic stress disorder were linked to better outcomes. Younger age, high experience intensity, and using LSD were associated with more negative effects. The findings suggest self-treatment outcomes are generally favorable but carry more frequent negative effects than clinical settings.
Brazilian Journal of Psychiatry
July 3, 2020
Simon Ruffell, Nige Netzband, Catherine Bird et al.
43 citations
Ayahuasca, a South American psychoactive plant brew used in traditional spiritual and cultural rituals, has been studied primarily for the prevention of deamination of N,N-dimethyltryptamine (DMT) by monoamine oxidase inhibitors (MAOIs) in the brew. Two constituents, DMT and harmine, have received more research attention than secondary harmala alkaloids. Current evidence suggests that the pharmacological interactions in ayahuasca may act synergistically or additively to produce psychoactive effects, but the understanding of these synergistic mechanisms is limited and more complex processes may be involved. There is not yet enough data to determine any potential synergistic interaction between the known compounds, and increased pharmacological understanding is needed to avoid potential risks.
Journal of Psychopharmacology
June 7, 2022
Emma I Kopra, Jason Ferris, James Rucker et al.
42 citations
Among 10,293 people who used LSD in the past year, 1.0% sought emergency medical treatment, with a per-event risk of 0.2%. Younger age, mental health conditions, and more frequent use increased that risk. Most adverse reactions were psychological—anxiety, panic, confusion—often linked to poor setting or mindset. Symptoms usually resolved within 24 hours, though 11 people had issues lasting beyond 4 weeks. LSD appears relatively safe in recreational settings; adverse effects are typically short-lived and psychological. In clinical contexts, screening, preparation, and supervision should further reduce risks.
Frontiers in Psychiatry
April 21, 2021
James Rucker, Allan H. Young
40 citations
Psilocybin has a history of non-medical use, and some infer therapeutic utility from this. Early phase clinical trials are encouraging but only indicate a need for larger, multicentre trials, which are ongoing but will take years. Retreat centers offering paid psilocybin truffle experiences use early trial data for bold public claims, which is unwise because early trials are not designed for generalization. This risks misleading the public and conflicts with ethical principles from the Nuremberg Code and Kefauver Harris Amendments. Using psilocybin before proper testing may undermine the credibility of retreat centers and the wider field.
Therapeutic Advances in Psychopharmacology
January 1, 2020
Matthew Butler, Mathieu Seynaeve, Timothy R. Nicholson et al.
38 citations
Functional neurological disorder (FND), previously called conversion disorder, is common in neurology clinics and causes substantial disability, but treatment options are limited. Psychedelics like psilocybin and LSD may help by altering brain circuits involved in self-representation, which is thought to be disrupted in FND. A systematic review of nine studies from 1954 to 1967, involving 26 patients, found that most received psychotherapy with variable adjunctive psychedelic use (psycholytic therapy). Of those treated, 69% (18 patients) showed at least some recovery on subjective clinician-rated criteria. Adverse events were mostly mild, though one patient withdrew due to distressing effects. All studies were low quality, lacking controls and valid outcome measures, so no conclusions on efficacy can be drawn.
Addiction
January 30, 2025
Theodore Piper, Francesca Small, Michael Kelleher et al.
27 citations
This first systematic review of psychedelic-assisted treatments for alcohol, tobacco, and other substance use disorders examined 37 studies involving 2,035 participants. The best evidence of efficacy came from a phase 2 randomized controlled trial of psilocybin for alcohol use disorder and a phase 2 trial of ketamine for alcohol use disorder. Psilocybin-assisted treatment for alcohol use disorder appears to have the strongest evidence among all major psychedelic-assisted treatments. No serious adverse events were reported across any study. The review recommends that future research report all safety events, identify contraindications, mitigate participant blinding, use factorial designs, and develop a core outcome set.
BMJ Open
December 1, 2021
James Rucker, Hassan Jafari, Tim Mantingh et al.
23 citations
A randomized, placebo-controlled trial is testing the feasibility of psilocybin-assisted therapy for people with major depressive disorder who have not responded to at least two prior treatments. Up to 60 participants in London, UK receive either 25 mg psilocybin or a placebo in a single dosing session, along with psychological therapy. The primary outcomes are recruitment rates, dropout rates, and variance in depression scores measured by the Montgomery Asberg Depression Rating Scale at 3 and 6 weeks. The trial also collects neuroimaging and omics data and offers an open-label extension dose of psilocybin.
Psychopharmacology
August 22, 2023
Robert F. Dougherty, Patrick Clarke, Merve Atli et al.
21 citations
A machine learning model that analyzes language from therapy sessions can predict which patients with treatment-resistant depression will respond to psilocybin therapy. Researchers used a zero-shot classifier based on the BART large language model to measure sentiment (valence and arousal) in transcripts of therapist-patient conversations one day after COMP360 psilocybin administration. These sentiment scores, combined with the Emotional Breakthrough Index and treatment arm, were fed into multinomial logistic regression models. The models predicted responder status at week 3 and through week 12 with 85% and 88% accuracy, respectively, and AUC values of 88% and 85%. This approach could enable early identification of patients needing alternative treatments.
Pharmacology & Therapeutics
April 6, 2024
Zarah R. Haniff, Mariia Bocharova, Tim Mantingh et al.
16 citations
Major depression increases the risk of later dementia, and late-life depression may be an early sign of dementia. Adult hippocampal neurogenesis (AHN), the lifelong birth of new neurons in the dentate gyrus, supports learning, memory, and mood. Microglia, the brain's immune cells, regulate AHN, and disruptions in AHN and microgliosis are linked to both depression and neurodegenerative diseases. Psychedelics like psilocybin, a serotonergic agonist with rapid antidepressant effects, may promote neuroplasticity and modulate microglial function. This narrative review examines evidence that psilocybin could affect AHN and microglia, potentially altering the progression from major depression to dementia in at-risk individuals.
September 30, 2022
Robert F. Dougherty, Patrick Clarke, Merve Alti et al.
3 citations
preprint
A machine learning model that analyzes language from therapy sessions accurately predicted which patients with treatment-resistant depression would respond to psilocybin treatment. Transcripts of psychological support sessions held one day after COMP360 (a synthetic psilocybin formulation) administration were analyzed using a zero-shot classifier based on the BART large language model to measure sentiment (valence and arousal) for both participant and therapist. These scores, combined with the Emotional Breakthrough Index and treatment arm, were used to predict treatment outcome measured by MADRS scores. Two multinomial logistic regression models predicted responder status at week 3 and through week 12 with 85% and 88% accuracy, and AUC values of 88% and 85%, respectively. The approach enables rapid prognostication of personalized response to psilocybin treatment and insights into therapeutic model optimization.
Journal of Psychopharmacology
January 26, 2026
Jess Kerr-Gaffney, Samuel Myrtle, Famia Askari et al.
2 citations
A single dose of psilocybin, compared to an inert placebo, did not alter personality traits, psychiatric symptoms, or cognitive flexibility in healthy participants. However, both the 10 mg and 25 mg psilocybin groups reported greater changes in personal values at both short-term (day 8) and long-term follow-up (day 85). The acute psychedelic experience, particularly the feeling of oceanic boundlessness, partially explained these value changes, with auditory alterations also playing a role in one subscale. These exploratory findings are tentative and require replication in larger samples.
Psychotherapy and Psychosomatics
June 12, 2026
Thorsten Barnhofer, Maria Niemi, Johannes Michalak et al.
1 citation
For adults with difficult-to-treat depression—those who have not responded to prior treatments, have treatment-resistant depression, or have a chronic course—mindfulness-based cognitive therapy (MBCT) is likely superior to usual care, reducing depressive symptoms by a standardized mean difference of -0.40 at post-treatment and -0.41 at medium-term follow-up. There was a 92% and 85% probability, respectively, that these benefits exceeded a minimal important difference. However, MBCT did not show clear superiority over other active psychosocial interventions, and no robust moderators of outcome were identified across baseline severity, chronicity, or comorbidity.
Research Directions Depression
October 13, 2023
Ian B. Hickie, F. Markus Leweke, Allan H. Young
1 citation
Interest in evaluating the therapeutic value of psychedelic compounds for treatment-resistant depression has grown among research groups and the wider recreational drug-using community. This enthusiasm accompanies advocacy for decriminalization, legalization, and public licensing of these substances for medicinal use.
Biological Psychiatry
April 10, 2023
James Rucker, Mathieu Seynaeve, Allan H. Young et al.
1 citation
Nasal administration of tryptamine psychedelics significantly elevates mood in 70% of participants, based on a sample size of 150 individuals. This method enhances the effects on consciousness and psychological well-being, indicating strong potential in pharmacology and psychiatry. The study highlights how these substances influence neurotransmitter receptors, leading to altered states of awareness. With implications for forensic toxicology and drug analysis, findings suggest that psychedelics may offer new avenues for therapeutic applications in mental health.
BJPsych Open
June 1, 2025
Anna Borissova, Allan H. Young, Mitul A. Mehta et al.
In interviews with seven people who had previously received ketamine for treatment-resistant depression, participants were motivated by hope for symptom improvement and a desire to support depression research. They described feeling more open and involved after ketamine and thought it could enhance therapy sessions. They suggested clearer communication that mood changes may not last, providing audiovisual materials to prepare for the infusion experience, and offering check-ins between sessions plus a final session for referrals and support. These insights informed a planned feasibility randomized controlled trial comparing intravenous ketamine plus behavioral activation (n=20) against midazolam plus behavioral activation (n=20) for major depressive disorder with anhedonia.