This meta-analysis of 12 randomised controlled trials (n = 257) found that classic serotonergic psychedelics (mainly psilocybin, with LSD and ayahuasca) produced moderate, significant improvements in acute mood in healthy volunteers and patients and significant reductions in depressive symptoms in patients at acute, medium (2–7 days) and longer-term (16–60 days) follow-ups. Despite concerns about unblinding and expectancy, the robust effect sizes, rapid onset and enduring effects support further double-blind, placebo-controlled clinical trials of these agents for negative mood and depression.
Rationale
Major depressive disorder is one of the leading global causes of disability, for which the classic serotonergic psychedelics have recently reemerged as a potential therapeutic treatment option.
Objective
We present the first meta-analytic review evaluating the clinical effects of classic serotonergic psychedelics vs placebo for mood state and symptoms of depression in both healthy and clinical populations (separately).
Results
Our search revealed 12 eligible studies (n = 257; 124 healthy participants, and 133 patients with mood disorders), with data from randomized controlled trials involving psilocybin (n = 8), lysergic acid diethylamide ([LSD]; n = 3), and ayahuasca (n = 1). The meta-analyses of acute mood outcomes (3 h to 1 day after treatment) for healthy volunteers and patients revealed improvements with moderate significant effect sizes in favor of psychedelics, as well as for the longer-term (16 to 60 days after treatments) mood state of patients. For patients with mood disorder, significant effect sizes were detected on the acute, medium (2–7 days after treatment), and longer-term outcomes favoring psychedelics on the reduction of depressive symptoms.
Conclusion
Despite the concerns over unblinding and expectancy, the strength of the effect sizes, fast onset, and enduring therapeutic effects of these psychotherapeutic agents encourage further double-blind, placebo-controlled clinical trials assessing them for management of negative mood and depressive symptoms.
Papers cited by this study that are also in Blossom
Araújo, A. M., Carvalho, F. M., Carvalho, M. et al. · Archives of Toxicology (2015)
Moreno, F. A., Wiegand, C. B., Taitano, E. K. et al. · Journal of Clinical Psychiatry (2006)
Tracy, D., Baumeister, D., Barnes, G. et al. · Therapeutic Advances in Psychopharmacology (2014)
Bershad, A. K., Schepers, S. T., Bremmer, M. P. et al. · Biological Psychiatry (2019)
Earlier research has seen a resurgence of interest in classic serotonergic psychedelics — principally psilocybin, DMT (often via ayahuasca), LSD and mescaline — as potential treatments for depressive disorders. The background presented by Galvão-Coelho and colleagues notes limitations of conventional antidepressants (delayed onset, side-effects, and a high proportion of treatment-resistant cases) and highlights preclinical and clinical evidence that psychedelics act primarily via serotonin 2A receptor agonism and may produce rapid and enduring mood effects. The authors also outline safety considerations and prior trial activity, including open‑label studies and double‑blind trials in populations such as patients with life‑threatening cancer, and note regulatory interest (for example, FDA "breakthrough therapy" designation for psilocybin in 2019).
This work is a systematic review and meta-analysis of double‑blind, randomised, placebo‑controlled trials comparing classic serotonergic psychedelics with inactive comparators. The systematic search followed a registered PROSPERO protocol and PRISMA guidance, and screened Cochrane registers, Allied and Complementary Medicine, PsycINFO, Ovid MEDLINE, Web of Science and related databases up to May 2020. Four independent raters screened titles and abstracts; full texts were then reviewed for eligibility. Eligibility required adult participants who were either healthy volunteers or diagnosed with a mood disorder (DSM‑IV), and interventions in the ‘‘psychedelic model’’—single or multiple moderate‑to‑high dose administrations of mescaline, LSD, DMT/ayahuasca or psilocybin. Microdosing and very low doses (for example psilocybin < 100 μg/kg) were excluded. All included trials were double‑blind RCTs with inactive comparators (placebo, low‑dose psychedelic or non‑psychoactive agent such as niacin). Outcomes had to use validated depression or mood scales (HAM‑D, MADRS, BDI, HADS; AMRS, PANAS negative, POMS, PEQ negative) and were analysed by time windows: acute (3 h to 1 day), medium (2–15 days) and long (16–60 days). The authors excluded assessments within 3 h to avoid acute cognitive/perceptual confounds and outcomes at ≥ 60 days for reliability concerns. Trial quality was appraised using the Jadad scale. Effect sizes were extracted and converted to standardised mean differences (SMD, Hedges' g) with 95% confidence intervals; analyses used random‑effects models to accommodate between‑study variability. Heterogeneity was quantified with I2 and categorised as low (< 25%), moderate (25–50%) or high (> 50%). Where multiple outcomes or doses were reported, the authors averaged effect sizes for the meta‑analysis. Safety data were narratively summarised due to heterogeneity in reporting. Publication bias was assessed with fail‑safe N and Egger’s regression test. A p value < 0.05 was considered statistically significant.
The systematic search yielded 570 records (565 after deduplication); after screening and exclusions the authors included 12 double‑blind RCTs (n = 257 participants: 124 healthy volunteers, 133 patients with mood disorders). Intervention distribution was psilocybin (8 studies), LSD (3 studies) and DMT/ayahuasca (1 study). Most trials were crossover designs with a single psychedelic administration; one trial (Palhano‑Fontes et al.) used a parallel design. The extracted text indicates that some trials incorporated psychotherapy support, but details are not consistently reported in the extraction. Quality assessment found methodological limitations: only 2 trials scored 5/5 on the Jadad scale, just 2 trials described randomisation methods, and 7 reported participant withdrawals. Blinding was a recurrent concern; three studies omitted placebo details, and only a minority used strategies to reduce expectancy or formally assess blinding integrity. Active placebos (low‑dose psychedelics, methylphenidate, niacin) were used in some trials. Mood state outcomes: For acute negative mood (3 h–1 day), meta‑analysis showed moderate effects favouring psychedelics versus placebo in healthy volunteers (N = 103, K = 6, SMD = −0.705, 95% CI −0.987 to −0.424, p < 0.01; I2 = 2.1%) and in patients with mood disorders (N = 41, K = 2, SMD = −0.632, 95% CI −1.171 to −0.092, p = 0.022; I2 = 7.6%). Drug‑specific subanalyses in healthy volunteers indicated moderate effects for LSD (N = 32, K = 2, SMD = −0.757, 95% CI −1.203 to −0.311, p = 0.001; I2 = 5.2%) and for psilocybin (N = 62, K = 4, SMD = −0.671, 95% CI −1.034 to −0.309, p < 0.001; I2 = 3.4%). Long‑term mood state (16–60 days) in patients showed a moderate effect for psilocybin (N = 110, K = 3, SMD = −0.495, 95% CI −0.829 to −0.161, p = 0.004; I2 = 2.9%). No long‑term mood data were available for healthy participants or for LSD/ayahuasca in this domain. Depressive symptom outcomes (patients only): Acute effects (3 h–1 day) across three trials (psilocybin and ayahuasca) produced a moderate effect on depressive symptoms (N = 70, K = 3, SMD = −0.720, 95% CI −1.189 to −0.251, p = 0.003; I2 = 5.7%). Psilocybin subanalysis for acute depressive symptoms (N = 41, K = 2) yielded SMD = −0.665 (95% CI −1.262 to −0.048, p = 0.034; I2 = 9.6%). Medium‑term assessment (2–15 days) showed a large pooled effect (N = 70, K = 3, SMD = −0.841, 95% CI −1.359 to −0.323, p = 0.001; I2 = 7.0%), though the authors note this medium‑term effect was driven primarily by the single ayahuasca trial. A psilocybin‑only medium‑term subanalysis was marginally non‑significant (N = 41, K = 2, SMD = −0.666, 95% CI −1.374 to −0.042, p = 0.065; I2 = 13%). Longer‑term depressive symptom effects (16–60 days) were statistically significant with moderate‑to‑large magnitude (N = 92, K = 3, SMD = −0.792, 95% CI −1.222 to −0.362, p < 0.001; I2 = 4.8%); psilocybin subanalysis showed SMD = −0.826 (N = 80, K = 2, 95% CI −1.285 to −0.367, p < 0.001; I2 = 5.5%). Safety and tolerability: Safety reporting was inconsistent (3/12 studies provided no safety detail). Where reported, classic psychedelics were generally well tolerated. Acute adverse effects were mainly transient and psychological or sympathomimetic: mild anxiety, crying, nausea/vomiting, headache, increased blood pressure and heart rate, mydriasis, and rare paranoia. No participants required pharmacological rescue for these effects, and longer‑term follow‑up did not report persistent anxiety, suicidal crises or psychosis in the included trials. Publication bias: The fail‑safe N was 114, interpreted by the authors as requiring about 9.5 unpublished null studies per observed study to nullify the effect. Egger’s regression did not indicate small‑study bias (intercept B0 = −0.191, 95% CI −2.541 to 2.158, t = 0.181, df = 10, one‑tailed p = 0.429).
Galvão‑Coelho and colleagues interpret the pooled evidence as broadly encouraging: classic serotonergic psychedelics produced moderate reductions in acute negative mood in healthy volunteers and in patients, and for depressive symptoms in patients they observed a large medium‑term effect and moderate acute and longer‑term effects versus placebo. The authors emphasise the rapid onset of effect (hours to days) and note parallels with other rapid‑acting agents such as ketamine. Biological mechanisms discussed by the authors include induction of neuroplasticity (for example via BDNF‑related pathways) and psychological processes such as reframing of negative memories; however, these mechanistic remarks are framed as hypotheses rather than demonstrated causal pathways in the included trials. The investigators also highlight important methodological caveats that limit confidence in the findings. Chief among these is the difficulty of maintaining effective blinding in psychedelic trials, with some studies lacking placebo details, inconsistent use of active placebos, and little formal measurement of expectancy effects. The predominance of crossover designs raises concerns about carry‑over and expectation bias, and many trials were small, heterogeneous in design, varied in dose and outcome measures, and often lacked detailed reporting on randomisation and handling of withdrawals. Safety reporting and long‑term follow‑up were also inconsistent. The authors therefore call for further robust double‑blind, placebo‑controlled trials with better blinding strategies, transparent reporting, pre‑specified handling of crossover data, routine measurement of expectancy, and improved adverse‑event surveillance. Finally, the authors note potential clinical and research implications: the observed fast and sometimes enduring antidepressant effects warrant further investigation, including trials that compare psychedelic intervention alone versus psychedelic plus psychotherapy to test for additive or synergistic effects, and focussed study in clinically relevant populations such as patients with life‑threatening illness. Despite limitations, the reviewers conclude that the evidence justifies ongoing, more rigorous research into classic psychedelics for mood and depressive disorders.
There is currently a resurgence of research investigating the use of psychedelic substances in the treatment of mood disorders, mainly the "classic serotonergic psychedelics". This class of psychedelics includes psilocybin, dimethyltryptamine, often consumed via the traditional plant preparation ayahuasca), lysergic acid diethylamide (LSD), and mescaline. These substances may induce psychedelics effects as potential agonists of the serotonin 2A receptors. Although it is recognized, they may also interact to a lesser extent with other neurotransmitter pathways, such as partial agonism of the serotonin 2C receptors, through which they may also induce antidepressant activity. One factor contributing to this resurgence is the limited success of existing pharmacotherapies for patients with depressive disorders. Many antidepressants may have a long latency to therapeutic response, requiring two to 6 weeks to produce effects, and can potentially induce undesirable side-effects, resulting in increased patient distress or discontinuation of treatment. A substantial portion of depressed patients do not benefit substantially from antidepressant treatment,). As a result, up to half of patients with depression may develop treatment-resistant disorders, defined as a failure to achieve remission with two or more adequate antidepressant trials. Given the scale and impact of this problem, innovative treatment approaches for major depression are urgently needed, and it is in this context that there has been renewed clinical and research interest in the classic serotonergic psychedelics (Dos. In general, serotonergic psychedelics do not lead to withdrawal or compulsive drug-seeking behaviors, as are observed with substances such as opioids and cocaine. They are generally considered safe and do not induce physiological toxicity or lasting adverse effects, although transitory signs of cognitive and emotional alterations, and mild sympathetic activity, are common. Studies examining data from the National Survey on Drug Use and Healthin the USA have reported no significant associations between lifetime psychedelic use and adverse mental health outcomes, including psychosis, with some evidence of reduced risk of these outcomes). However, restrictions on the use of psychedelics are indicated for individuals with severe cardiac disease and either a personal or family history of psychosis. Therefore, the classic psychedelics are again being utilized in pre-clinical, observational, open-label, and randomized controlled trials examining effects on mood in psychiatry patients and healthy volunteers, with highly encouraging initial results being reported). Mescaline, usually derived from the peyote cactus, and LSD were investigated in older psychiatric studies, conducted to explore effects on psychosis and alcoholism). More recently, LSD studies have turned to the investigation of its effect on mood. The current second wave of psychedelic research has primarily involved psilocybin, the main psychedelic compound of Psilocybe spp. fungi. Open-label trials have been conducted in obsessive-compulsive disorder, addiction, and treatment-resistant depression, whereas double-blind trials have been conducted in patients with life-threatening cancer diagnoses (commonly exploring effects on mood and existential anxiety)). On the strength of this evidence, the United States Food and Drug Administration granted "breakthrough therapy" status to psilocybin in 2019, concluding that initial data indicate that it may provide a substantial improvement over existing treatments for treatment-resistant depression. Ayahuasca is an Amazonian brew made with Psychotria viridis, a rubacea containing N, N-DMT, and Banisteriopsis caapi, a vine which contains β-carbolines that are reversible inhibitors of monoamine oxidase and an inhibitor of serotonin reuptake. This psychedelic also has been subject to increasing research, which has included effects on mood and addiction in healthy volunteers, as well as clinical trials investigating its psychological and neurobiological antidepressant effects in open-label and double-blind designs.
As a consequence of the expanding number of clinical studies investigating psychedelic treatments for psychiatric disorders, the number of reviews on this topic has also increased in recent years. A recent metaanalysis review showed that psychedelic-assisted therapy, which included both the classic serotonergic psychedelics and MDMA (3,4-methylenedioxymethamphetamine), significantly outperformed placebo, with large effect sizes across a range of mental disorders such as unipolar depression, anxiety, and post-traumatic stress disorder. However, to date, no meta-analysis of double-blind randomized controlled trials (RCTs) comparing the clinical efficacy of classic serotonergic psychedelics with placebo, for mood and depressive symptoms, has been published. Our aim is to present the first meta-analysis in this area, by evaluating the clinical effect of classic serotonergic psychedelics on negative mood state and depressive symptoms, in double-blind RCTs, separately for both healthy volunteers and patients diagnosed with a mood disorder.
The search strategy and data synthesis were conducted in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement) and followed a registered protocol (PROSPERO registration number: CRD42020158356).
The systematic search was conducted using the Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Health Technology Assessment Database, Allied and Complementary Medicine, PsycINFO, and Ovid MEDLINE(R), from journal inception to May, 2020. A search via Web of Science was conducted using the same keywords to identify any additional relevant articles. Reference lists of included articles were also searched. During the initial screening, 4 raters (NLGC, MG, JS, and MM) independently assessed articles retrieved for eligibility based on the title, abstract, and in method, after which full text articles were retrieved and screened.
Eligibility criteria were organized in accordance with thereporting structure, as described below. The search terms used in systematic review search are summarized in Table.
After a systematic search of the relevant data, we included studies with both healthy individuals and patients with mood disorders who were diagnosed using the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV) (Table). The data for patients with a mood disorder and healthy participants were analyzed separately to avoid conflating heterogeneous populations.
All classic serotonergic psychedelic interventions were included: mescaline, LSD, DMT/Ayahuasca, and psilocybin. However, after a systematic search, we included studies that investigated psychedelic interventions using the "psychedelic model," where interventions were provided to participants in moderate to high doses in single or multiple sessions. Studies using micro-doses and low doses of psychedelics (e.g., for psilocybin below 100 μg/kg)) were excluded.
All studies included were randomized, placebo-controlled, and double-blind trials, which had either a cross-over or parallel design, with outcomes between 3 h and 60 days after dosing session (see below the "Outcomes" section for more details). Control groups must have been an inactive comparator such as a placebo, low-dose psychedelic, or a nonpsychoactive pharmacological agent (e.g., niacin).
We included trials that used clinically validated scales for depression or mood state outcomes. For depression symptoms, those scales were as follows: Hamilton Depression Rating Scale (HAM-D), Montgomery-Åsberg Depression Rating Scale (MADRS), Beck Depression Inventory (BDI), and Hospital Anxiety and Depression Scale (HADS; specifically, the depressive sub-score). To measure mood state, the following scales were included: Adjective Mood Rating Scale (AMRS; specifically anxiety-depressiveness subscore), Positive and Negative Affect Schedule (PANAS; specifically negative score), Profile of Mood States (POMS), and Persisting Effects Questionnaire (PEQ; specifically negative mood). To provide temporal clarity of the psychedelic's effects, the outcomes of mood state and depressive symptoms were categorized and analyzed with respect to time-point collected after the respective dosing session: & Acute effects: outcomes from 3 h to 1 day after dosing session. & Medium-term effects: outcomes from 2 to 15 days after dosing session. & Long-term effects: outcomes from 16 to 60 days after dosing session. These time-points were selected because antidepressant drugs commonly require approximately 2 weeks to initiate a therapeutic response, while the psychotropic effects of substances with psychedelic actions, for instance ketamine and classical serotonergic psychedelics, commence within hours and have been reported to last approximately 2 weeks. We excluded data from studies with outcomes measured within less than 3 h of receiving the psychedelic to avoid assessment confounding from changes in cognition and perception induced acutely by the substance. Furthermore, data was also excluded from trials with data collected 60 days or longer after the intervention due to the poor reliability of retrospective data. Outcomes from the open-label phase of double-blind studies were also not included. There was no restriction based on sample size, the duration or severity of symptoms, comorbid disorders, or participant demographics.
The quality of eligible clinical trials was assessed using the Jadad scalecompleted by author NLGC and cross-checked by WM and JS.
Effect size data of each experimental group was extracted and converted to standardized mean differences (SMD) with 95% confidence intervals (CIs). Data were initially extracted by one author (NLGC), and then cross-checked independently by an additional author (WM). In line with conventional interpretations, SMD were classified as negligible (< 0.2), small (0.2-0.4), moderate (0.4-0.8), or large (> 0.8). In cases where continuous outcomes were reported as weighted mean differences or raw mean differences, these were recalculated into an SMD (Hedges' g) using Comprehensive Meta-Analysis 3.0. Studies that reported the outcomes by the following: (a) psychedelics dose) and (b) separately for sessions before and after cross-over, each outcome having their data combined and the mean of the SMD being used in analysis. When there was more than one outcome, the effect sizes were calculated for each one and then the averaged was used in the meta-analysis. We also extracted the number of participants (N), along with the number of trials/comparisons (K) from which the pooled effect size was derived. Additionally, all analyses were performed with a random-effect model, which considers both between-study and within-study variability. The heterogeneity was quantified using the I 2 statistic, and categorized as low (I 2 < 25%), moderate (I 2 = 25-50%), or high (I 2 > 50%). Other relevant study characteristics were also extracted, specifically with regard to dose and if psychotherapy support was offered. Sub-group or secondary analyses of clinical response with respect to the type of psychedelic substance or population (patients with a mood disorder or healthy volunteers) were also undertaken. Safety and tolerability outcomes were not included in the meta-analysis due to marked heterogeneity in reporting. Instead, this information was extracted and narratively reviewed. Although there is a recognized difficulty in having appropriate blinding in studies with psychedelics, we assumed for the calculation of the JADAD score that an appropriate placebo could include substances that may induce some similar physiological and/or cognitive effect of psychedelics, such as methylphenidate, niacin, or low doses of the psychedelics. The potential impact of publication bias was assessed using fail-safe N and Egger's regression test of the intercept. A statistically significant effect was regarded as a p value of < 0.05. The data was analyzed and figures prepared via Comprehensive Meta-Analysis 3.0.
The search returned 570 results, which was reduced to 565 after duplicates were removed. Title and abstract screening removed 533 articles, while 32 manuscripts were retrieved and reviewed in full. Of these, 14 were open-label clinical trials and consequently were not included in this metaanalysis. From the 18 double-blind trials selected, 6 were excluded because they did not meet the inclusion criteria. Specifically, 3 did not have a placebo-control design; 1 clinical trial used microdoses of LSD); 1 trial measured outcomes only 2 h after treatment, and one clinical trial showed unpublished outcomes collected after 60 days of psychedelic dosing session. Thus, we were left 12 studies which met the criteria for inclusion. For the PRISMA flow diagram, see Fig..
For study attributes involving type of participants, mood diagnosis, number of treatment session, psychedelic doses, and placebo type, see Table. Of the 12 studies included, 8 used psilocybin), 3 used LSD, and 1 used DMT in the form of ayahuasca. In summary, these involved 257 participants, made up of 124 healthy volunteers and 133 patients with mood disorders. All trials provided a single psychedelic administration by dose, with exception of, where LSD was administered twice. All studies utilized a cross-over design, other than Palhano-Fontes et al. (), which used a parallel design.,,, andalso included psychotherapy to support the psychedelic intervention. No clinical trials involving mescaline met the criteria for inclusion.
For methodological quality scores of all the clinical trials included, see supplementary material Table. Two studies had a maximum score of 5/5: Ross et al. () (psilocybin) and. Of note, from 12 studies, only 2 trials described the randomization technique used while only 7 detailed participant withdrawal. The main issue related to studies quality was the blinding process. From 12 studies included, 3 did not present details regarding the placebo condition used. However, for two of them, we were able to obtain further information directly from the study authors (Table). Few studies analyzed the integrity of the blinding process by questionnaires assessed in volunteers and/or via the research team; Although the participant expectancy about the study is not part of the JADAD scale, it is relevant to analyze as it can play a significant role both in blinding and in participants and evaluators responses. From 12 studies, 3 detailed some strategies aiming to reduce these expectancies, such as the use of instructional sets, multiples evaluators, naïve volunteers, individual, and not groups experiments, parallel study designer. However, no studies used expectancy measures as a cofactor in statistical analysis of clinical response.
Meta-analyses were conducted on the measures of negative mood state of healthy volunteers and also in patients with a mood disorder, separately. Only one study was included in the systematic review, analyzing medium-term mood changes; therefore, it was not possible to undertake a meta-analysis for this time-point. Meta-analysis of acute measures of mood state, collected between 3 h and 1 day after treatment, showed a moderate clinical effect size of psychedelics in the reduction of negative mood when compared to placebo in both healthy participants (N = 103, K = 6, SMD = -0.705, CIs -0.987 to -0.424, p < 0.01; I 2 = 2.1%) and patients with a mood disorder (N = 41, K = 2, SMD = -0.632, CIs -1.171 to -0.092, p = 0.022; I 2 = 7.6%), with low variance across studies (Healthy volunteers:) (Fig.and supplementary material table). No study was located providing data on acute mood state changes after ayahuasca treatment. Sub-analysis by psychedelic drug in healthy volunteers revealed a highly significant effect with a moderate effect size for both LSD (N = 32, K = 2, SMD = -0.757, CIs -1.203 to -0.311, p = 0.001; I 2 = 5.2%)and psilocybin in negative mood reduction with low variability across studies (N = 62, K = 4, SMD = -0.671, CIs -1.034 to -0.309, p < 0.001; I 2 = 3.4%)) (Fig.and table). Moreover, the meta-analysis of long-term measures of mood state, between 16 and 60 days after treatment, showed that psilocybin also had a moderate long-term effects in reduction of negative mood in patients with a mood disorder, with low heterogeneity across trials (N = 110, K = 3, SMD = -0.495, CIs -0.829 to -0.161, p = 0.004; I 2 = 2.9%)) (Table). No studies examined long-term changes on mood state in healthy participants, and after LSD or ayahuasca treatment.
Three meta-analyses were conducted with measures of depressive symptoms assessed by depression symptom rating scales from patients with a mood disorder: acute effects, medium-term, and longer-term clinical effects. The meta-analysis of acute effects (between 3 h and 1 day) on depressive symptoms showed a significant and moderate clinical effect size of psychedelics (psilocybin and ayahuasca) for reduction of depressive symptoms. Again, low heterogeneity was observed across studies (N = 70, K = 3, SMD = -0.720, CIs -1.189 to -0.251, p = 0.003; I 2 = 5.7%)) (Fig.and table). A sub-analysis of the individual psychedelics revealed that psilocybin had a significant and moderate clinical effect size on the reduction of depressive symptoms in patients with a mood disorder, with low variance across studies (N = 41, K = 2, SMD = -0.665, CIs -1.262 to -0.048, p = 0.034; I 2 = 9.6%)) (Fig.and table). There were no clinical trials located involving the acute assessment of LSD's effects on depressive symptoms. We found a significant and large effect of classic psychedelics (psilocybin and ayahuasca) in the medium-term assessment of depressive symptoms, with low heterogeneity across studies (N = 70, K = 3, SMD = -0.841, CIs -1.359 to -0.323, p = 0.001; I 2 = 7.0%)) (Fig.and table). However, a secondary analysis of psilocybin studies showed a marginally non-significant effect for reduction of depression between 7 and 15 days after treatment (N = 41, K = 2, SMD = -0.666, CIs -1.374 to -0.042, p = 0.065; I 2 = 13%)) (Fig.and table). We can note that the medium-term clinical effects of classic psychedelics on depressive symptoms were mainly driven by data from the ayahuasca study. The assessment of the longer-term (16 to 60 days) effect of psychedelics on the reduction of depressive symptoms revealed a highly significant effect with a moderate to large effect size (N = 92, K = 3, SMD = -0.792, CIs -1.222 to -0.362, p < 0.001; I 2 = 4.8%)) (Fig.and table). The sub-analysis of psilocybin trials only also showed a large clinical effect in the reduction of depressive symptoms in patients with mood disorders, with low heterogeneity between studies (N = 80, K = 2, SMD = -0.826, CIs -1.285 to -0.367, p < 0.001; I 2 = 5.5%)) (Fig.and table).
From the 12 studies included, 3 did not detail data pertaining to safety or tolerability of the psychedelic used). In general, the other clinical trials reported that classic serotonergic psychedelics were well-tolerated. Acute psychological side-effects induced by psychedelics in the included studies were mainly mild anxiety episodes, tearing/crying, nausea, vomit, headache, and slight sympathomimetic effect, such as increase in blood pressure, heart rate, and pupil size, and rare episodes of paranoia was related. No study participants were noted as requiring pharmacological intervention to address these side-effects. Long-term studies did not indicate any persistent anxiety, suicidal crisis, or psychotic state.
With concern of publication bias, the fail-safe N of this metaanalysis is 114 (N = 12, Z = -6.339, p < 0.001). There would need to be 9.5 missing studies for every observed study for the effect to be nullified. Egger's regression test of the intercept also did not report publication bias (B0 = -0.191, IC = -2.541 to 2.158, t = 0. 181, df = 10, 1-tailed p = 0.429). For the funnel plot of publication bias, see supplementary material figure.
This meta-analysis combined and evaluated data from 12 double-blind RCTs investigating the efficacy of classic serotonergic psychedelics on mood state and depressive symptoms, between 3 h 60 days after administration, in patients with mood disorders, and healthy volunteers, separately. We observed a significant moderate effect size for reduction of acute negative mood outcomes in healthy volunteers, compared to placebo, as well as significant moderate effects sizes for acute and long-term reductions of negative mood state in patients with mood disorders. For depressive symptoms, a significant large effect size was detected from a mediumterm assessment, and a moderate effect size for both acute and long-term outcomes was observed for patients, compared to placebo. Trials that assessed mood state response to psychedelics were in general conducted in healthy volunteers and mainly assessed acute outcomes. In this context, secondary analysis by psychedelic drug revealed moderate effect sizes for both psilocybin and LSD, with a slightly larger effect size for LSD. A significant moderate effect size in studies assessing the acute reduction of negative mood also was observed to patients in psilocybin trials. An analysis of longer-term data (16-60 days after treatment) indicated that psilocybin maintains its response on negative mood reduction of patients, with a moderate effect size compared to placebo. In this meta-analysis, it was not possible to undertake a meta-analysis for medium-term mood changes due to insufficient clinical trials. It is important study the effects of classic psychedelics in both healthy volunteers and those with diagnosed mood disorders because as their neurobiology is distinct, and the psychobiological responses to drugs can be different between these populations. It is essential to understand if any mood-elevating effects are evident in healthy participants, and to be able to compare this with the response of those with clinical depression. For note, it is usual that clinical trials select only one of these groups, with few studies assessing parallels groups of patients and healthy controls. This meta-analysis provides a data analysis of negative mood in both healthy participants and patients with mood disorders, to differentially assess both populations. The larger effect size of LSD in acute reductions of negative mood, in comparison to psilocybin, may be due to differing pharmacokinetic profiles. While the onset of psychedelic effects is typically faster with psilocybin, around 30 min vs 1 h for LSD, the total duration of psilocybin acute effects are substantially shorter, at around 3.5 h, compared with 8 to 12 h for LSD, depending on dose). However, pharmacokinetic data in this area remains limited. Besides classic serotonergic psychedelics, few double-blinded, placebo-controlled clinical trials have aimed to analyze acute mood changes in response to substances with psychedelic action. Furthermore, positive results for ketamine treatment in reduction of negative mood are for example observed 1 day after its administration, when compared with midazolam treatment. Psychedelics, specifically psilocybin and ayahuasca, demonstrated a moderate effect size in the acute reduction of depressive symptoms compared to placebo. The fast onset of therapeutic response is a key characteristic of new potential "fast-acting antidepressants," which aside from classic psychedelics also may include ketamine. Animal models reveal that the biological therapeutic actions of antidepressants may in part be mediated via increased neuroplasticity through the expression of brain-derived neurotropic factor (BDNF) and its tyrosine kinase receptors type B in the prefrontal cortex and hippocampus. Therefore, the delay in the therapeutic onset may potentially correlate with the time required for the elevation of the BDNF. While fast-acting antidepressants also induce neuroplasticity by BDNF increases, both in vitro and in vivo, this occurs through a pathway different and faster than that of antidepressants, involving the mammalian target of rapamycin). Moreover, it has been suggested that substances with psychedelic effect are able to reframe negative memories, which is in contrast to standard antidepressant pharmacotherapy in which new information is processed with a positive bias. The present meta-analysis also revealed a large effect size of psychedelics (psilocybin, LSD, and ayahuasca) compared to placebo, in the reduction of depressive symptoms in mediumterm investigations, that is, between 2 and 15 days after treatment, which was evident from the ayahuasca study. A moderate effect size was seen for other psychedelics (LSD and psilocybin) in the longer-term analysis (between 16 and 60 days after interventions). Though it should be noted that this was due to the assessment time-points employed, and not necessarily to do with the length of ongoing antidepressant effect, another agent with a shorter alacrity of response than standard antidepressants, ketamine, suggests a similar temporal effects profile, with the strongest responses occurring between 1 and 2 weeks posttreatment. Furthermore, a recent meta-analysis showed stronger effect sizes of classic psychedelics in reduction of depressive symptoms on days 7 and 21 after treatment comparing with baseline scores. Sub-analysis of trials using psilocybin with patients with a mood disorder and life-threatening disease identified moderate acute and large long-term effects of this substance in the reduction of depressive symptoms, when compared to placebo. These results are highly encouraging of further research with this group, as a recent meta-analysis of the use of antidepressants for cancer patients reported no indication of effects superior to placebo. The use of psychedelics in this population may extend beyond addressing affective symptoms, having a potentially specialized role in assisting with existential psychological distress involving mortality. However, it is important to highlight that mood disorders in these patients are often a comorbidity of the lifethreatening disease, and the depressive symptoms can be expressed in different ways for instance from the depressive patients where the depression is the main pathology. Although anxiety symptoms are often present in mood disorders, from 12 selected studies in systematic review, only 6 measured anxiety, and due the heterogeneity of these studies, it was not possible to conduct a meta-analysis with them (LSD,). However, it is important to highlight the importance of conducting this analysis when the data becomes available. An additionally important point in this context is the use of "psychotherapy-assisted" applications of psychedelics. This approach may not only be safer (and more ethical); it may also provide a potentially stronger therapeutic effect. The psychedelic-assisted therapy, analyzed by studies that used MDMA and classic psychedelics, showed stronger clinical improvement of different mood and anxiety disorder than placebo. This would however in the future be advised to be assessed via controlled research comparing psychedelic interventions alone and in combination with psychological assistance to determine if any additive or synergistic effect was evident. Moreover, such comparison would determine whether either intervention provides better management of any psychological distress which may emerge during consumption of the psychedelic. It is also important to note that despite the low number of studies included in meta-analysis, low statistical heterogeneity was observed across clinical trials and no publication bias was detected. Moreover, in general, the included clinical trials indicated that classic serotonergic psychedelics are well-tolerated, although more reporting precision on adverse effects and longer safety follow-ups are recommended in future studies. Acute psychological and psychological side-effects were mainly mild anxiety episodes and sympathomimetic effects, such as increases in blood pressure, heart rate, and pupil size, which were short-lived and did not require pharmacological intervention. There are several critical challenges recognized in conducting robust double-blind studies involving psychedelics. As revealed in our assessment of the methodological quality of the studies reviewed, a significant issue was evident regarding the presence of adequate blinding. In particular, some studies did not report any details regarding the placebo used, while others used a placebo which may or may not have active effects. To address the issue of sufficient blinding, some trials have used "active" placebos, such as low doses of psychedelics or methylphenidate and niacin, which can induce mild physiologic and cognitive changes. This is a wellneeded methodological advancement; however, some studies still find issues in blinding process even after this approach. Therefore, we must consider that unblinding is, at least in part, responsible for the magnitude of the effect size provided in this meta-analysis. Moreover, the expectancy of participants and evaluators about the treatment can also modulate the results. Despite 3 studies detailing strategies to deal with this potential expectation, none included expectancy measures as a covariate in statistical analysis of clinical response, and this should be considered in future studies. Another issue of concern is the conducting of trials with multiple sessions of psychedelics or cross-over designs. Most included studies in this review used a cross-over study design, introducing possible limitations related to potential carry-over effects, as this raises the chance of the first session experience increasing the expectation bias of next session (or resulting in a carry-over effect if the active intervention is firstly used). Moreover, how the data analysis is communicated in crossover studies should be better considered by the researchers. For instance, separate analyses of the first and second crossover treatment administered, rather than having these both results analyzed together, are potentially a clearer method. Additionally, some included clinical trials did not provide adequate detail about the randomization strategy used and how participant withdrawals were handled in the analysis, making risk of bias assessment for these domains difficult. Further studies in this area are recommended to ensure adequate reporting of randomization procedures in line with international reporting guidelines. Other limitations should also be taken in account in this meta-analysis: the small sample sizes of the included studies, the high heterogeneity in study design and population, multiple psychedelic doses, variety of outcome scales used, and different time-points assessed. For the last point, we acknowledge that analyzing the long-term effects may not entirely be methodologically sound due to the long duration between substance use and data collection. Therefore, future studies should consider these aspects with the aim of improving the quality of trials. In summation, methodological weaknesses aside, our meta-analysis provides encouraging evidence for the potential use of classic serotonergic psychedelics in the reduction of both negative mood state and depressive symptoms. While there are currently limited studies that have investigated some of these agents (in particular ayahuasca), the promising results of this review support the need for ongoing and more robust research in this emerging field to further explore the effect of psychedelics in adults with depression.
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Bogenschutz, M. P., Johnson, M. W. · Progress in Neuro-Psychopharmacology and Biological Psychiatry (2016)
Bogenschutz, M. P., Forcehimes, A. A., Pommy, J. A. et al. · Journal of Psychopharmacology (2015)
Carhart-Harris, R. L., Williams, T. M., Sessa, B. et al. · Journal of Psychopharmacology (2010)
Carhart-Harris, R. L., Bolstridge, M., Rucker, J. et al. · Lancet Psychiatry (2016)
Carhart-Harris, R. L., Kaelen, M., Bolstridge, M. et al. · Psychological Medicine (2016)
Carhart-Harris, R. L., Roseman, L., Bolstridge, M. et al. · Scientific Reports (2017)
Carhart-Harris, R. L., Bolstridge, &. M., Day, C. M. J. et al. · Psychopharmacology (2017)
Chi, T., Gold, J. A. · Journal of the Neurological Sciences (2020)
Galvão-Coelho, N. L., de Almeida, R. N., de Menezes Galvão, A. C. et al. · Frontiers in Psychology (2019)
Dolder, P. C., Schmid, Y., Müller, F. et al. · Neuropsychopharmacology (2016)
Dolder, P. C., Schmid, Y., Steuer, A. E. et al. · Clinical Pharmacokinetics (2017)
Dos Santos, R. G., Bouso, J. C., Hallak, J. E. · Expert Review of Clinical Pharmacology (2018)
Fuentes, J. J., Fonseca, F., Elices, M. et al. · Frontiers in Psychiatry (2020)
Galvão-Coelho, N. L., de Menezes Galvão, A. C., de Almeida, R. N. et al. · Journal of Psychopharmacology (2020)
Gasser, P., Holstein, D., Michel, Y. et al. · Journal of Nervous and Mental Disease (2014)
Kirchner, K. · Journal of Psychopharmacology (2014)
Gouzoulis-Mayfrank, E., Heekeren, K., Neukirch, A. et al. · Pharmacopsychiatry (2005)
Griffiths, R. R., Richards, W. A., Mccann, U. et al. · Journal of Psychopharmacology (2006)
Griffiths, R. R. · Journal of Psychopharmacology (2008)
Griffiths, R. R., Johnson, M. W. · Journal of Psychopharmacology (2016)
Grob, C. S., Danforth, A. L., Chopra, G. S. et al. · JAMA Psychiatry (2011)
Grunebaum, M. F., Galfalvy, H. C., Choo, T. H. et al. · American Journal of Psychiatry (2018)
Halberstadt, A. L., Geyer, M. A. · Neuropharmacology (2011)
Hasler, F., Grimberg, U., Benz, M. A. et al. · Psychopharmacology (2004)
Johansen, P. Ø., Krebs, T. S. · Journal of Psychopharmacology (2015)
Johnson, M. W., Richards, W. A., Griffiths, R. R. · Journal of Psychopharmacology (2008)
Johnson, M. W., Garcia-Romeu, A., Cosimano, M. P. et al. · Journal of Psychopharmacology (2014)
Johnson, M. W., Hendricks, P. S., Barrett, F. S. et al. · Pharmacology and Therapeutics (2019)
Kaelen, M., Giribaldi, B., Raine, J. et al. · Psychopharmacology (2018)
Kometer, M., Schmidt, A., Bachmann, R. et al. · Biological Psychiatry (2012)
Kraehenmann, R., Preller, K. H., Scheidegger, M. et al. · Biological Psychiatry (2015)
Krebs, T. S., Johansen, P. Ø. · Journal of Psychopharmacology (2012)
Krebs, T. S., Johansen, P. ˚. Ø. · PLOS ONE (2013)
Libânio Osório Marta, R. F. · Drug Metabolism Reviews (2019)
Luoma, J. B., Chwyl, C., Bathje, G. J. et al. · Journal of Psychoactive Drugs (2020)
Ly, C., Greb, A. C., Cameron, L. P. et al. · Cell Reports (2018)
Lyons, T., Carhart-Harris, R. L. · Journal of Psychopharmacology (2018)
Lyons, T., Carhart-Harris, R. L. · Frontiers in Psychology (2018)
McKenna, D. · ACS Chemical Neuroscience (2004)
Osório, F. L., Sanches, R. F., Macedo, L. et al. · brazilian Journal of Psychiatry (2015)
Palhano-Fontes, F., Barreto, D., Onias, H. et al. · Psychological Medicine (2018)
Reiff, C. M., Richman, E. E., Nemeroff, C. B. et al. · American Journal of Psychiatry (2020)
Riba, J., Urbano, G., Morte, A. et al. · Psychopharmacology (2001)
Roseman, L., Nutt, D. J., Carhart-Harris, R. L. · Frontiers in Pharmacology (2018)
Ross, S. · International Review of Psychiatry (2018)
Ross, S., Bossis, A. P., Guss, J. et al. · Journal of Psychopharmacology (2016)
Rucker, J., Iliff, J., Nutt, D. J. · Neuropharmacology (2017)
Sanacora, G., Frye, M. A., McDonald, W. et al. · JAMA Psychiatry (2017)
Sanches, R. F., Osório, F. L., Dos Santos, R. G. et al. · Journal of Clinical Psychopharmacology (2016)
Santos, R. G., Landeira-Fernandez, J., Strassman, R. J. et al. · Journal of Ethnopharmacology (2007)
Schenberg, E. E. · Frontiers in Pharmacology (2018)
Schmid, Y., Liechti, M. E. · Psychopharmacology (2017)
Schmid, Y., Enzler, F., Gasser, P. et al. · Biological Psychiatry (2015)
Stroud, J., Freeman, T. P., Leech, R. et al. · Psychopharmacology (2017)
Uthaug, M. V., Van Oorsouw, &. K., Kuypers, &. K. P. C. et al. · Psychopharmacology (2018)
Wittmann, M., Carter, O., Hasler, F. et al. · Journal of Psychopharmacology (2007)
Araújo, D. B., Zeifman, R. J., Palhano-Fontes, F. et al. · Frontiers in Pharmacology (2019)
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Borkel, L. F., Rojas-Hernández, J., Henríquez-Hernández, L. A. et al. · Expert Review of Clinical Pharmacology (2023)
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