Journal of affective disorders
November 1, 2019
Silvia Muttoni, Maddalena Ardissino, Christopher John
265 citations
Depression and anxiety are common and disabling, yet existing treatments often fall short. A review of seven clinical trials involving 130 patients found that, when used in a supportive setting, the psychedelics ayahuasca, psilocybin, and LSD produced immediate and lasting reductions in depression and anxiety symptoms over several months. The treatments were well tolerated; the most common side effects were temporary anxiety, headaches, nausea, and mild increases in heart rate and blood pressure. The authors note that the number of studies and patients is small, but the evidence suggests psychedelic-assisted therapy is a promising alternative for patients who do not respond to standard care.
Journal of affective disorders
February 1, 2023
Kwonmok Ko, Emma I Kopra, Anthony J Cleare et al.
144 citations
A systematic review and meta-analysis of 14 studies (7 randomized controlled trials) examined the effects of classic psychedelics (psilocybin, ayahuasca, LSD) on depressive symptoms. The review found significant reductions in depressive symptoms at 1 day, 1 week, and 3-5 weeks after treatment with psychological support. Results at 6-8 weeks were less conclusive. Small sample sizes in most studies and lack of long-term follow-up data limited statistical power and interpretation. The findings suggest an association between psychedelic therapy and short-term symptom reduction, but more rigorous trials with larger, diverse samples are needed.
Journal of affective disorders
April 1, 2023
Otto Simonsson, Peter S Hendricks, Richard Chambers et al.
124 citations
Using nationally representative US adult data (N = 2822), most people who have used classic psychedelics (59.1%) never had a challenging, difficult, or distressing experience. However, 8.9% reported functional impairment lasting more than one day from such an experience, and 2.6% sought medical, psychiatric, or psychological help afterward. Co-use of lithium or other mood stabilizers, and certain set and setting factors—including no preparation, disagreeable physical environment, negative mindset, no psychological support, a dose perceived as too large, and a major life event prior—were associated with greater difficulty. Negative mindset, no psychological support, and a major life event prior were also linked to overall risk of harm.
Journal of affective disorders
February 15, 2023
Sarah Shnayder, Rezvan Ameli, Ninet Sinaii et al.
67 citations
Psilocybin-assisted therapy improved psycho-social-spiritual well-being in cancer patients with major depressive disorder, as measured by the NIH-HEALS. In a Phase II open-label trial, 30 participants received 25 mg of psilocybin with group preparation and integration sessions. NIH-HEALS scores increased significantly after treatment, with gains in all three factors: Connection (12.7%), Reflection & Introspection (7.7%), and Trust & Acceptance (22.4%). Improvements appeared by day 1 and persisted through 8 weeks. The study lacked a control group, relied on self-reports, and had a small, limited sample, restricting generalizability. The results suggest that Connection, Reflection & Introspection, and Trust & Acceptance are key elements of psycho-social-spiritual healing in this context.
Journal of affective disorders
January 15, 2016
Megha M Vasavada, Amber M Leaver, Randall T Espinoza et al.
58 citations
In patients with major depressive disorder, differences in brain white matter structure before ketamine treatment may predict who will respond to the drug 24 hours later. Using diffusion imaging in 10 patients, those who showed more than 50% symptom improvement had greater fractional anisotropy in the cingulum and forceps minor pathways compared to non-responders. Non-responders also had lower fractional anisotropy and higher radial and mean diffusivity in these pathways compared to healthy controls, and they had an earlier age of depression onset and longer current episode. These preliminary findings suggest that the structural integrity of emotion-related brain networks may influence ketamine's antidepressant effect.
Journal of affective disorders
August 1, 2023
Richard J Zeifman, Anne C Wagner, Candice M Monson et al.
56 citations
In a double-blind randomized controlled trial comparing psilocybin therapy (two 25 mg sessions plus daily placebo for six weeks) with escitalopram (two 1 mg psilocybin sessions plus 10-20 mg daily escitalopram for six weeks) among 59 individuals with major depressive disorder, reductions in experiential avoidance mediated improvements in well-being, depression severity, suicidal ideation, and trait anxiety only in the psilocybin group. Exploratory analyses indicated that these improvements (except for suicidal ideation) occurred serially through increased connectedness. Experiences of ego dissolution and psychological insight predicted reductions in experiential avoidance. The findings support reduced experiential avoidance as a mechanism underlying psilocybin therapy's positive outcomes.
Journal of affective disorders
July 1, 2024
Ashok Seshadri, Larry J Prokop, Balwinder Singh
50 citations
A systematic review and meta-analysis of 12 randomized controlled trials found that intravenous ketamine reduces depression symptoms in treatment-resistant depression at doses as low as 0.2 mg/kg, with increasing response at 0.5 mg/kg but no additional benefit at 1 mg/kg. Intranasal esketamine doses of 56–84 mg were more effective than 28 mg. Higher intravenous doses above 0.5 mg/kg did not lead to greater treatment response. The overall quality of evidence was low, limited by few studies, and publication bias was high.
Journal of affective disorders
July 1, 2023
Allison Feduccia, Gabby Agin-Liebes, Collin M Price et al.
38 citations
Psychedelic substances are being studied in drug development programs, with clinical trials showing evidence for safe and effective use of psychedelic therapies for mental health conditions. With anticipated FDA approval of MDMA-assisted therapy for PTSD in 2023 and psilocybin therapy for depression disorders soon after, the medical community should become informed on best practices and participate in developing standards of care. Gold standards in medicine distinguish treatments as the highest quality for comparison. This article reviews the origins of psychedelic-assisted therapy, minimum requirements for safe use, criteria for gold standards in mental health, and nuances in establishing gold standards in psychedelic medicine to guide clinical decision making.
Journal of affective disorders
July 15, 2023
Matthew B Wall, Cynthia Lam, Natalie Ertl et al.
36 citations
Psilocybin-assisted therapy for depression alters the brain's response to music, suggesting an elevated responsiveness to music after treatment that is related to subjective drug effects during dosing. Nineteen patients with treatment-resistant depression underwent two psilocybin dosing sessions. Brain scans before and after treatment showed increased activity in the superior temporal cortex when listening to music, and decreased activity in the medial frontal lobes during rest. These changes in music-related brain activity correlated with the intensity of subjective effects felt during the psilocybin sessions. The findings imply that psychedelic therapy may enhance emotional responsiveness to music, which could be relevant for treating depression.
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.
Journal of affective disorders
July 1, 2024
Cameron N Calder, Angela T H Kwan, Kayla M Teopiz et al.
31 citations
Ketamine is effective for adults with treatment-resistant depression. A systematic review of 21 placebo-controlled randomized trials with 2042 participants calculated the number needed to treat (NNT) for racemic ketamine: 7 at 4 hours, 3 from one day to one week, and 9 at four weeks. Esketamine had an NNT of 2 at one day and 11 at four weeks. Numbers needed to harm indicated low risk. The NNTs under 10 across observation intervals are considered highly clinically meaningful for this difficult-to-treat disorder. Limitations include potential functional unblinding and selective reporting bias.
Journal of affective disorders
April 1, 2023
Nadav Liam Modlin, Tammy M Miller, James J Rucker et al.
30 citations
Psilocybin therapies show promise for conditions like major depressive disorder, end-of-life anxiety, and obsessive-compulsive disorder. However, little attention has been paid to intrapersonal and interpersonal factors that influence a patient's readiness for such interventions. This paper proposes that readiness assessment should include both intrapersonal and interpersonal factors to improve safety, patient care, and treatment outcomes. Although no reliable and valid instrument currently exists, the authors suggest three areas of focus—patient presentation, therapeutic alliance, and patient safety—to establish readiness and optimize and personalize psilocybin therapy.
Journal of affective disorders
June 15, 2024
Gia Han Le, Sabrina Wong, Sebastian Badulescu et al.
25 citations
A systematic review examined how serotonergic psychedelics (psilocybin, LSD) and ketamine affect brain wave patterns measured by EEG and MEG in people with major depressive disorder, treatment-resistant depression, and healthy controls. Ketamine and psychedelics both increase theta power in depressed individuals. In healthy controls and depressed persons, both drug classes decrease alpha, beta, and delta power. Ketamine also increases gamma power in both groups. Theta power specifically rises in those with major depressive disorder when given psychedelics. The studies varied in patient populations, dosing, and measurement devices. The findings support disease models involving altered network connectivity and may guide future treatment discovery.
Journal of affective disorders
February 15, 2023
Priel Meir, Leslie Taylor, Jair C Soares et al.
25 citations
Most psychologists are willing to inform eligible patients about psilocybin-assisted therapy if it becomes FDA-approved, but over 90% would still recommend non-psilocybin psychotherapies first. Among 119 surveyed psychologists, 77.4% agreed they would inform patients about PAT, yet 91.6% would prioritize other therapies. Three-quarters endorsed that more knowledge about psilocybin would increase their likelihood of informing patients. Greater openness to engaging patients with PAT was associated with more positive attitudes and beliefs about psilocybin, greater self-reported knowledge, personal psychedelic use, and positive attitudes toward medical cannabis. Attitudes toward medical cannabis and beliefs about psilocybin were the only significant predictors of openness in regression analysis.
Journal of affective disorders
March 15, 2025
Polymnia Georgiou, Cristan A Farmer, Gustavo C Medeiros et al.
24 citations
Baseline levels of stress-related hormones (CRF, ACTH, and cortisol) did not significantly influence how well ketamine worked as an antidepressant in people with treatment-resistant depression. However, higher levels of ACTH and CRF were associated with longer overall duration of depressive episodes, suggesting these hormones might serve as biomarkers for chronic depression. Additionally, people who developed depression at a younger age tended to have more severe depressive symptoms, indicating that earlier onset may lead to greater cumulative stress on the brain and body. The study involved 42 participants in a randomized, placebo-controlled, crossover trial.
Journal of affective disorders
January 15, 2025
Sara Ellis, Catherine Bostian, Wendy Feng et al.
23 citations
In a small, uncontrolled trial, 15 veterans with severe treatment-resistant depression received a single 25 mg dose of psilocybin. At three weeks, 60% met criteria for response and 53% for remission. By twelve weeks, 47% maintained response and 40% remission. Co-occurring PTSD did not affect outcomes, and the intensity of the psychedelic experience did not correlate with depression improvement. Four participants who needed to restart antidepressants were counted as non-responders from that point. No unexpected adverse events occurred. The authors note limitations including the small sample and lack of a control group, and call for further study.
Journal of affective disorders
September 15, 2024
David S Mathai, Thomas D Hull, Leonardo Vando et al.
22 citations
In a large longitudinal study of 11,441 moderately-to-severely depressed patients who received four doses of sublingual ketamine at home over four weeks within a supportive digital health context, treatment was associated with improvement in depression symptoms. A modal antidepressant response occurred in both non-severe (55.8%) and severe (18.1%) baseline depression levels. Adverse events were detected in 3.0-4.8% of participants, predominantly neurologic or psychiatric. A second course of treatment extended improvements in those who responded favorably. Improvement was most strongly predicted by lower baseline depression scores and younger age. Symptoms of depressed mood and anhedonia persisted despite treatment. The study lacked a control group and fixed-dose procedure. At-home, telehealth-supported ketamine administration was largely safe, well-tolerated, and associated with improvement.
Journal of affective disorders
December 15, 2024
Dan Xu, Guilin Liu, Mingming Zhao et al.
21 citations
A single dose of arketamine (10 mg/kg) improved both depression-like behaviors and demyelination in the corpus callosum of mice exposed to chronic restraint stress. Correlations linked depression-like behaviors with demyelination in that brain region. Blocking the transforming growth factor β1 (TGF-β1) receptor with RepSox prevented arketamine's beneficial effects, while a single intranasal dose of TGF-β1 alone also ameliorated both depression-like behaviors and demyelination. The precise mechanisms remain unclear, but the findings suggest that stress-induced demyelination in the corpus callosum may contribute to depression-like behaviors, and arketamine may act through a TGF-β1-dependent pathway.
Journal of affective disorders
November 15, 2024
Abigail E. Calder, Gregor Hasler
20 citations
A new standardized tool, the Swiss Psychedelic Side Effects Inventory (SPSI), was developed to systematically record clinically relevant side effects of psychedelics and MDMA, including their severity, duration, impact, and treatment-relatedness. The SPSI was constructed from previous research and pilot tested in 145 participants across three studies, with expert panel feedback improving its validity. The final version contains 32 side effects with standardized follow-up questions, compatible with any study design and administrable as interview or self-report. It omits less important side effects but includes space for additional symptoms. The SPSI is available in English and German to improve clinical decisions, informed consent, and patient safety.
Journal of affective disorders
March 15, 2025
Kevin H Yang, Wayne Kepner, Charles M Cleland et al.
19 citations
Ketamine use among US adults increased significantly from 2015 to 2019 and again from 2021 to 2022. From 2015 to 2019, use rose among both adults with and without depression, but from 2021 to 2022, an increase occurred only among those without depression. Depression was linked to higher odds of ketamine use in 2015–2019 but not in later years. New correlates emerged in 2021–2022, including adults aged 26–34 and college graduates. Use of other drugs, especially ecstasy/MDMA and gamma-hydroxybutyrate, was consistently associated with higher odds of ketamine use. These shifts may reflect changes in the ketamine landscape or survey methodology.
Journal of affective disorders
April 1, 2024
Sabrina Wong, Angela T H Kwan, Kayla M Teopiz et al.
19 citations
A systematic review of randomized controlled trials compared the clinical efficacy of psilocybin and esketamine in adults with treatment-resistant depression. 25 mg of psilocybin significantly reduced depressive symptoms at 21 days post-dose, with a number needed to treat (NNT) of 5. Psilocybin-induced nausea had a number needed to harm (NNH) of 5. Fixed doses of esketamine (56 mg and 84 mg) showed significant effects at 28 days post-dose, with NNTs of 7. Esketamine-induced headache, nausea, dizziness, and dissociation had NNHs below 10. The preliminary results may reflect only a small portion of the patient population and require replication and longer-term studies. Both agents showed clinically meaningful NNT estimates and acceptable NNH profiles, underscoring their clinical relevance for treatment-resistant depression.
Journal of affective disorders
January 1, 2020
Roman M Dale, Kelly A Bryant, Nora Finnegan et al.
17 citations
In people with treatment-resistant depression who had previously failed electroconvulsive therapy, higher openness to experience—a personality trait reflecting curiosity and willingness to try new things—was the only factor among the Big Five personality domains that significantly predicted a sustained response to repeated intravenous ketamine infusions. The study of 125 participants confirmed that, regardless of treatment response, the group as a whole showed elevated neuroticism, low conscientiousness, and low extraversion. The authors suggest that assessing openness could help identify patients most likely to benefit from long-term ketamine therapy and reduce unnecessary exposure to its unknown risks, though they note limitations including the lack of a placebo control, small sample, and non-standardized infusion schedules.
Journal of affective disorders
January 1, 2025
Xiangyang Zang, Jingting Zhang, Jingping Hu et al.
16 citations
Combining esketamine with electroconvulsive therapy (ECT) improves depression symptoms more than ECT alone. In a small human trial, patients receiving propofol plus esketamine before ECT had lower depression scores on the 24-item Hamilton Depression Rating Scale after the fifth and sixth treatments than those receiving propofol alone. In a rat model of depression, the combination reduced depression-like behaviors and lowered brain glutamate levels. Both esketamine and ECT activated the PI3K/Akt/GLT-1 pathway, which helps clear excess glutamate. Blocking this pathway with inhibitors eliminated the antidepressant effects, suggesting that activation of PI3K/Akt/GLT-1 is a key mechanism.
Journal of affective disorders
May 1, 2024
Chuntana Reangsing, Sasinun Punsuwun, Sarah Oerther
16 citations
A meta-analysis of 19 studies involving 1,480 pregnant women found that mindfulness-based interventions reduced depression compared to control groups, with a moderate effect size (g = 0.457). Mindfulness-based cognitive therapy showed a larger effect (g = 1.13) than mindfulness-based stress reduction (g = 0.64) or adapted interventions (g = 0.31). The findings suggest these programs, especially MBCT, are effective complementary treatments for depression during pregnancy.
Journal of affective disorders
September 1, 2022
David S Mathai, Scott M Lee, Victoria Mora et al.
16 citations
Informed consent documents from 23 American ketamine clinics for psychiatric treatment cover most required elements but vary greatly in detail. Key gaps include poor communication about long-term side effects, alternative treatments, pre-treatment evaluations, support during treatment, psychological interventions, and dissociative effects. All forms are written at a readability level too high for many patients. The findings suggest that both patients and providers would benefit from more deliberate, evidence-informed consent processes to support shared decision-making as off-label ketamine use expands.