The New England journal of medicine
November 3, 2022
Guy M. Goodwin, Scott T Aaronson, Oscar Alvarez et al.
1,095 citations
A single 25 mg dose of psilocybin, but not 10 mg, reduced depression scores more than a 1 mg control dose over three weeks in adults with treatment-resistant depression. In this phase 2 trial, 233 participants were randomly assigned to 25 mg, 10 mg, or 1 mg of synthetic psilocybin with psychological support. The 25 mg group showed an average 12-point drop on the MADRS depression scale versus a 5.4-point drop in the 1 mg group, a significant difference. The 10 mg group did not differ significantly from control. Response and remission rates at three weeks supported the primary result, but sustained response at 12 weeks was not significantly different.
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.
The Journal of Clinical Psychiatry
April 20, 2020
Ewa Wajs, Leah Aluisio, Richard Holder et al.
288 citations
In a year-long open-label study of 802 adults with treatment-resistant depression, esketamine nasal spray combined with a new oral antidepressant showed a manageable safety profile and sustained improvement in depressive symptoms. Common side effects included dizziness, dissociation, nausea, and headache, mostly mild or moderate and resolving the same day. Two deaths occurred, neither linked to the drug. Cognitive performance remained stable or improved. Depression scores dropped during the first four weeks and stayed lower through the maintenance phase.
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.
New England Journal of Medicine
October 4, 2023
Andreas Reif, Istvan Bitter, Jozefien Buyze et al.
197 citations
In treatment-resistant depression, esketamine nasal spray combined with an SSRI or SNRI led to remission in 27.1% of patients at week 8, compared to 17.6% for extended-release quetiapine plus an SSRI or SNRI. Over 32 weeks, 21.7% of patients on esketamine had no relapse after remission versus 14.1% on quetiapine. The open-label, single-blind, randomized trial included 676 patients. Adverse events matched known safety profiles. Esketamine was superior to quetiapine for achieving remission and preventing relapse.
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 Affective Disorders
February 3, 2023
Guy M. Goodwin, Scott T Aaronson, Oscar Alvarez et al.
168 citations
Three weeks after a single dose, 25 mg of psilocybin, and to a lesser extent 10 mg, improved patient-reported measures of depression severity, anxiety, affect, and functioning in people with treatment-resistant depression. These findings extend the primary results from the largest randomized clinical trial of psilocybin for TRD, highlighting outcomes that matter to patients.
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.
The World Journal of Biological Psychiatry
November 3, 2020
Siegfried Kasper, Wiesław Jerzy Cubała, Andrea Fagiolini et al.
84 citations
Esketamine nasal spray, an NMDA glutamate receptor antagonist, offers a fast-acting treatment option for patients with treatment-resistant depression (TRD) who have not responded to several prior therapies. A group of six European experts with clinical experience using esketamine nasal spray developed consensus statements on practical considerations before, during, and after administration. The guidance is based on their experience and available literature, aiming to help clinicians unfamiliar with the treatment. Further real-world use is expected to expand existing knowledge.
Neuroscience & Biobehavioral Reviews
May 10, 2021
Laith Alexander, Luke A. Jelen, Mitul A. Mehta et al.
79 citations
The anterior cingulate cortex (ACC), including its subgenual, perigenual, and dorsal zones, plays a key role in major depression and its treatment. Ketamine, a rapidly acting antidepressant, induces acute (over minutes) and post-acute (over hours to days) changes in subgenual and perigenual ACC activity, and these changes can correlate with antidepressant efficacy. The subgenual and dorsal ACC zones are specifically linked to ketamine's anti-anhedonic effects. The review emphasizes combining human neuroimaging with animal brain manipulations to understand causal relationships between brain activity and therapeutic outcomes. Circuit-based perspectives highlight ACC function in a central network mediating affective pain and its role as the anterior node of the default mode network.
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.
Psychological Medicine
May 24, 2013
James Stone, Helen L. Fisher, Barnaby Major et al.
69 citations
Cannabis use is linked to an earlier onset of psychosis and more severe manic symptoms and conceptual disorganization, but not to delusions, hallucinations, negative symptoms, or daily functioning. In a naturalistic cohort of 502 patients with first-episode psychosis assessed at entry to services and after one year, those who reduced or stopped cannabis use showed the greatest improvement in symptoms, while continued users remained more symptomatic than non-users. Effective interventions to reduce cannabis use could yield significant health benefits for this population.
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.
Nature Medicine
July 1, 2024
Paul Glue, Colleen Loo, Johnson Fam et al.
60 citations
An extended-release oral tablet form of ketamine (R-107) was effective, safe, and well tolerated for treatment-resistant depression. In a phase 2 trial, 231 adults with severe depression took 120 mg of R-107 daily for 5 days; 168 who responded were then randomly assigned to receive 30, 60, 120, or 180 mg of R-107 or placebo twice weekly for 12 weeks. The 180 mg dose produced a significantly greater reduction in depression scores than placebo, with a mean difference of 6.1 points on the MADRS scale. Relapse rates dropped from 70.6% with placebo to 42.9% with 180 mg. No blood pressure changes occurred, and sedation or dissociation were minimal. Most dosing took place at home.
International Review of Psychiatry
June 5, 2020
Ben Carter, Rebecca Strawbridge, Muhammad Ishrat Husain et al.
45 citations
A network meta-analysis of 27 randomized trials found that NMDA-targeting medications (e.g., ketamine) are markedly more effective than placebo for augmenting treatment-resistant depression (effect size 0.91). Antipsychotics, mood stabilizers, and other pharmacological augmenters were also compared, but NMDA therapies had the highest probability of being effective. No psychological augmentation trials could be included due to the lack of a common comparator. The evidence is limited by few trials, heterogeneity, and inconsistent safety reporting.
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.
Depression and Anxiety
July 5, 2020
N. Weston, Damian Gibbs, Catherine Bird et al.
38 citations
A systematic review of literature from 1940 to 2000 examined the combined use of psychological therapies and psychedelic drugs for treating ICD-10 anxiety disorders. Twenty studies were included in the final analysis. Three studies reported improvements in anxiety on standardized measures, with two finding a dose-related effect. Among 145 cases of psychoneurotic anxiety reaction, 94 (65%) showed improvement ranging from moderate to full recovery. The majority of studies indicated that combining psychedelic drug administration with psychological therapy was most beneficial; no study suggested that the drug alone was sufficient.
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.
Journal of Affective Disorders
March 1, 2025
Guy M. Goodwin, Scott T Aaronson, Oscar Alvarez et al.
35 citations
In treatment-resistant depression, a single dose of 25 mg of psilocybin produced stronger correlations between certain psychedelic experiences and depression improvement three weeks later than lower doses. The intensity of psychedelic effects was dose-related, but scores for different doses overlapped considerably. At the 25 mg dose, dimensions of oceanic boundlessness and visual restructuralization, along with emotional breakthrough, showed the strongest correlations with reduced depression scores. The study does not establish causation and requires replication. The overlap in experience intensity across doses suggests unblinding to dose is less likely. Correlations between psychedelic experience and outcome indicate specificity in psilocybin's mechanism of action.
The International Journal of Neuropsychopharmacology
June 6, 2025
Naim Zaki, Li Nancy Chen, Rosanne Lane et al.
32 citations
In a long-term extension study (SUSTAIN-3) involving 1,148 adults with treatment-resistant depression, esketamine nasal spray combined with an oral antidepressant was evaluated for safety and efficacy over up to 79 months (median 45.8 months). Common adverse events included headache (36.9%), dizziness (33.9%), and nausea (33.6%). Nine participants died, with causes including COVID-19 and suicide. Depressive symptoms, measured by the MADRS, improved during the initial induction phase (average reduction of 12.8 points) and this improvement was maintained during the optimization/maintenance phase. At the end of maintenance, 49.6% of participants were in remission. No new safety concerns emerged, and depression improvement generally persisted for those continuing treatment.
Journal of psychopharmacology (Oxford, England)
August 1, 2024
James Jonathan Rucker, Claire T. Roberts, Mathieu Seynaeve et al.
32 citations
A new intranasal formulation of 5-MeO-DMT, called BPL-003, was tested in 44 healthy people who had never used psychedelics. Doses up to 12 mg were well tolerated, with no serious side effects; common mild effects included nasal discomfort, nausea, headache, and vomiting. The drug was absorbed quickly, reaching peak levels in about 8–10 minutes, and cleared from the body in under 27 minutes. Higher doses produced stronger subjective drug intensity and mystical experiences, with 60% of participants reporting a 'complete mystical experience' at 10 and 12 mg. The rapid onset and short duration suggest potential for treating conditions like depression.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
August 1, 2024
Roger S McIntyre, Istvan Bitter, Jozefien Buyze et al.
30 citations
In the ESCAPE-TRD trial, esketamine nasal spray caused treatment-emergent adverse events more often than quetiapine extended release (91.9% versus 78.0%), but these events were typically mild or moderate and transient: 92.0% resolved the same day, and only 4.2% of patients discontinued esketamine due to adverse events compared with 11.0% for quetiapine. The median proportion of days with adverse events was lower with esketamine (11.9% versus 21.3%). Along with greater efficacy, esketamine's tolerability profile supports its use for treatment-resistant depression.