Recommended readings 3
Psychedelics in the Treatment of Depression

 

This list was made by Jagoda Mackowiak in cooperation, and co-published, with Blossom.

Depression is a mental disorder characterized by symptoms like mood disturbances, persistent inability to feel pleasure, and suicidal tendencies. Roughly 264 million people worldwide were affected by depression in 2017.1 Studies suggest that up to 20% of the members of American society will experience depressive episodes during their lifetime.2 Anxiety disorders occur parallel to clinical depression in about 50% of the cases.3

Mainstream antidepressants have played an important role in alleviating the symptoms in patients suffering from depression. However, their effects are often delayed, unwanted side effects are common, and some patients do not respond to the treatment at all.4 The socioeconomic costs associated with depression are high,5 and many patients relapse after the treatment is terminated6 (to learn more about the efficacy of SSRIs and their interactions with other substances, read this MIND Blog post by Camile Bahi).

Psychedelics offer a new avenue in the treatment of depression. The studies that we have highlighted show a potential that is unmatched by any of the current alternatives. Yet, at the same time, we have to remain careful not to declare an early victory.

Although promising, the research presented in this list has mostly been done with a small sample size, with carefully designed settings, and with therapists with many years of experience. The therapeutic alliance – the relationship between the patient and therapist – and placebo effects are definitely at play. Moreover, psychedelics can’t directly impact the underlying (family, societal, economic) causes of depression.

Taking all of that into consideration, the following 10 publications will summarize the most important studies investigating the potential of psychedelics in the treatment of depression and anxiety.

1. Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017
https://ourworldindata.org/grapher/number-of-people-with-depression
2. Hasin DS, Sarvet AL, Meyers JL, et al. (2018) Epidemiology of Adult DSM-5 Major Depressive Disorder and Its Specifiers in the United States. JAMA Psychiatry 75(4):336–346. doi:10.1001/jamapsychiatry.2017.4602
3. Kircanski, K., LeMoult, J., Ordaz, S. and Gotlib, I. H. (2017) Investigating the nature of co-occurring depression and anxiety: Comparing diagnostic and dimensional research approaches. Journal of Affective Disorders 216:123-135
4. Penn, E., & Tracy, D. K. (2012). The drugs don’t work? antidepressants and the current and future pharmacological management of depression. Therapeutic Advances in Psychopharmacology, 2(5):179–188.
5. Whiteford, H. A., Degenhardt, L., Rehm, J., Baxter, A. J., … and Vos, T. (2013). Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. Lancet, 382(9904):1575–1586
6. Geddes, J., Carney, S., Davies, C., Furukawa, T., Kupfer, D., Frank, E.. (2003) Relapse prevention with antidepressant drug treatment in depressive disorders: a systematic review. Lancet, 361(9358):653–661.

A substantial amount of research on psychedelics in the treatment of psychiatric conditions has been done before their prohibition in the 1960s. A systematic review by Rucker and colleagues (2016) titled ‘Psychedelics in the treatment of unipolar mood disorders.’ investigates studies published between 1949 and 1973. The authors found that LSD had been used successfully in treating depression, showing an improvement in almost 80% of the 423 participants across 19 studies. Although the 20th century’s research standards were not nearly as strict as today, the potential of psychedelics in the treatment of mood disorders was recognized already more than 50 years ago.

Rucker, J. J., Jelen, L. A., Flynn, S., Frowde, K. D. and Young, A. H. (2016). Psychedelics in the treatment of unipolar mood disorders: a systematic review. Journal of Psychopharmacology, 30(12):1220-1229.

Unipolar mood disorders, including major depressive disorder and persistent depressive disorder (dysthymia), confer high rates of disability and mortality and a very high socioeconomic burden. Current treatment is suboptimal in most cases and there is little of note in the pharmaceutical development pipeline. The psychedelic drugs, including lysergic acid diethylamide and psilocybin, were used extensively in the treatment of mood disorders, and other psychiatric conditions, before their prohibition in the late 1960s. They are relatively safe when used in medically controlled environments, with no reported risk of dependence. Here, we present a systematic review of published clinical treatment studies using psychedelics in patients with broadly defined UMD, and consider their place in psychiatry. Whilst all of the included studies have methodological shortcomings, of 423 individuals in 19 studies, 335 (79.2%) showed clinician-judged improvement after treatment with psychedelics. A recently completed pilot study in the UK favours the use of psilocybin with psychological support in treatment resistant depressive disorder. The evidence overall strongly suggests that psychedelics should be re-examined in modern clinical trials for their use in unipolar mood disorders and other non-psychotic mental health conditions.

This review covers the major discoveries from the 2010s (and one article from 2007). The selected studies suggest a high potential of LSD, psilocybin, and ayahuasca in treating depression and anxiety, as well as alcohol and tobacco addictions. The authors discuss the limitations of the analyzed studies and discuss possible future improvements in study design. Together with the previous article, it gives the reader a solid overview of what has been found in the research on psychedelics in depression so far.

dos Santos, R.G, Bouso, J.C., Alcázar-Córcoles, M.A. and Hallak, J.E.C. (2018) Efficacy, tolerability, and safety of serotonergic psychedelics for the management of mood, anxiety, and substance-use disorders: a systematic review of systematic reviews, Expert Review of Clinical Pharmacology, 11(9):889-902

Introduction: Mood, anxiety, and substance-use disorders are among the most prevalent psychiatric disorders in the population. Although several pharmacological treatments are available, they are not effective for a significant proportion of patients and are associated with several adverse reactions. Therefore, new treatments should be explored. Recent studies suggest that serotonergic hallucinogens/psychedelics including ayahuasca, psilocybin, and lysergic acid diethylamide (LSD) have anxiolytic, antidepressive, and antiaddictive effects.

Areas Covered: A systematic review of systematic reviews assessing the efficacy, safety, and tolerability of serotonergic hallucinogens/psychedelic was performed using the PubMed data base until 11 April 2018. Systematic reviews with or without meta-analysis were analyzed, but only reviews that described at least one randomized controlled trial (RCT) were included.

Expert Commentary: Psilocybin and LSD reduced anxiety and depression in cancer patients and symptoms of alcohol and tobacco dependence, and ayahuasca reduced depression symptoms in treatment-resistant depression. Although the results are promising, several studies were open label, and only few were RCTs, and most had small sample sizes and a short duration. Single or few doses of these drugs seem to be well tolerated, but long-term studies are lacking. New RCTs with bigger samples and longer duration are needed to replicate these findings.

One of the possible mechanisms through which psychedelics achieve long-term positive effects on depression is a reduction in experiential avoidance. ‘Post-psychedelic reductions in experiential avoidance are associated with decreases in depression severity and suicidal ideation’ by Zeifman et al. (2020), also a survey study, found that after using psychedelics, participants had fewer instances of experiential avoidance, which is defined as an attempt at avoiding thoughts, feelings, memories, and other (negative) internal experiences. Additionally, the results support the hypothesis that the positive effects of psychedelics can be observed along the entire spectrum of depression severity, including the mild end of it.

Zeifman, R. J., Wagner, A. C., Watts, R., Kettner, H., Mertens, L. J. and Carhart-Harris, R. L. (2020). Post-psychedelic reductions in experiential avoidance are associated with decreases in depression severity and suicidal ideation. Frontiers in Psychiatry, 11:782

Psychedelic therapy shows promise as a novel intervention for a wide range of mental health concerns but its therapeutic action is incompletely understood. In line with acceptance and commitment therapy’s (ACT’s) transdiagnostic model, qualitative research has suggested that reductions in experiential avoidance are an important component of therapeutic outcomes associated with psychedelics. However, limited research has quantitatively explored the association between decreases in experiential avoidance and therapeutic outcomes associated with psychedelics. Therefore, in two prospective studies, using convenience samples of individuals with plans to use a psychedelic, we explored the impact of psychedelic use on experiential avoidance, depression severity, and suicidal ideation, as well as relationships between changes in these outcomes. Participants (Study 1, N=104; Study 2, N=254) completed self-report questionnaires of depression severity, suicidal ideation, and experiential avoidance: 1) before using a psychedelic (in ceremonial and non-ceremonial contexts), as well as 2) 2-weeks and 3) 4-weeks after psychedelic use. Across both studies, repeated measures ANOVAs indicated significant decreases in experiential avoidance, depression severity, and suicidal ideation after psychedelic use. Furthermore, decreases in experiential avoidance were significantly associated with decreases in depression severity and suicidal ideation. These results suggest that psychedelics may lead to significant decreases in experiential avoidance, depression severity, and suicidal ideation. Additionally, these findings imply that reduced experiential avoidance may be a transdiagnostic mechanism mediating treatment success within psychedelic therapy. We conclude that integrating psychedelics with psychotherapeutic interventions that target experiential avoidance (e.g. ACT) may enhance therapeutic outcomes.

Another theory was proposed by Alan Davis, Frederick Barrett, and Roland Griffiths. They suggest that increased mental flexibility may be one of the mechanisms playing a role in the improvement of symptoms associated with depression. After surveying almost 1000 users of psychedelics, the researchers found that ‘Psychological flexibility mediates the relations between acute psychedelic effects and subjective decreases in depression and anxiety’ (2020). In other words, the psychological insight and the occurrence of mystical experience during a psychedelic experience lead to an increase in psychological flexibility associated with decreases in depression and anxiety symptoms.

Davis, A. K., Barrett, F. S., and Griffiths, R. R. (2020). Psychological flexibility mediates the relations between acute psychedelic effects and subjective decreases in depression and anxiety. Journal of Contextual Behavioral Science, 15:39-45.

Prior research has shown that acute subjective psychedelic effects are associated with both spontaneous and intended changes in depression and anxiety. Psychedelics are also theorized to produce increases in psychological flexibility, which could explain decreases in depression and anxiety following a psychedelic experience. Therefore, the present cross-sectional survey study sought to examine whether psychological flexibility mediated the relationship between acute psychedelic experiences and spontaneous or intended changes in depression and anxiety among a large international sample of people who reported having used a psychedelic (n = 985; male = 71.6%; Caucasian/white = 84.1%; Mage = 32.2, SD = 12.6). A regression analysis showed that acute effects (i.e., mystical and insightful effects) were significantly associated with decreases in depression/anxiety following a psychedelic experience. A path analysis revealed that, while controlling for age and sex, increases in psychological flexibility fully mediated the effect of mystical and insightful experiences on decreases in depression and anxiety following a psychedelic experience. This suggests that psychological flexibility may be an important mediator of the therapeutic effects of psychedelic drugs. Future prospective experimental studies should examine the effect of psychedelic drug administration on psychological flexibility in order to gain a better understanding of the psychological processes that predict therapeutic effects of psychedelics.

The same research group at the Johns Hopkins Center for Psychedelic and Consciousness Research assessed the effects of psilocybin administration on 24 participants with major depressive disorder (MDD). This was the first-ever randomized controlled trial, where patients showed a clinically significant response to the intervention at week one and week four post-treatment. Although limitations were unavoidable, these results add to the mounting evidence of the large, rapid, and sustained effects of psilocybin in the treatment of MDD.

Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., Finan, P. H., & Griffiths, R. R. (2020). Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA psychiatry, e203285

Major depressive disorder (MDD) is a substantial public health burden, but current treatments have limited effectiveness and adherence. Recent evidence suggests that 1 or 2 administrations of psilocybin with psychological support produces antidepressant effects in patients with cancer and in those with treatment-resistant depression.

This randomized, waiting list–controlled clinical trial was conducted at the Center for Psychedelic and Consciousness Research at Johns Hopkins Bayview Medical Center in Baltimore, Maryland. Adults aged 21 to 75 years with an MDD diagnosis, not currently using antidepressant medications, and without histories of psychotic disorder, serious suicide attempt, or hospitalization were eligible to participate. Enrollment occurred between August 2017 and April 2019, and the 4-week primary outcome assessments were completed in July 2019. A total of 27 participants were randomized to an immediate treatment condition group (n = 15) or delayed treatment condition group (waiting list control condition; n = 12). Data analysis was conducted from July 1, 2019, to July 31, 2020, and included participants who completed the intervention (evaluable population).

The primary outcome, depression severity was assessed with the GRID-Hamilton Depression Rating Scale (GRID-HAMD) scores at baseline (score of ≥17 required for enrollment) and weeks 5 and 8 after enrollment for the delayed treatment group, which corresponded to weeks 1 and 4 after the intervention for the immediate treatment group. Secondary outcomes included the Quick Inventory of Depressive Symptomatology-Self Rated (QIDS-SR).

Leor Roseman, David Nutt, and Robin Carhart-Harris (2017) investigated the aspects of the psychedelic experience, which may potentially be the key mediators of long-term improvements in mental health. In their article titled ‘Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression,’ they suggest that the extent of oceanic boundlessness experience was the main predictor of the positive outcomes. The one aspect that turned out to be entirely unrelated to the clinical outcome was the visual imagery the participants saw during their psychedelic experience. These results mean that, in contrast to mainstream antidepressants, “the therapeutic effects of psilocybin are not a simple product of isolated pharmacological action but rather are experience-dependent.”

Roseman, L., Nutt, D. J. and Carhart-Harris, R. L. (2018). Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Frontiers in Pharmacology, 8:974.

Introduction: It is a basic principle of the “psychedelic” treatment model that the quality of the acute experience mediates long-term improvements in mental health. In the present paper we sought to test this using data from a clinical trial assessing psilocybin for treatment-resistant depression (TRD). In line with previous reports, we hypothesized that the occurrence and magnitude of Oceanic Boundlessness (OBN) (sharing features with mystical-type experience) and Dread of Ego Dissolution (DED) (similar to anxiety) would predict long-term positive outcomes, whereas sensory perceptual effects would have negligible predictive value.

Materials and Methods: Twenty patients with treatment resistant depression underwent treatment with psilocybin (two separate sessions: 10 and 25 mg psilocybin). The Altered States of Consciousness (ASC) questionnaire was used to assess the quality of experiences in the 25 mg psilocybin session. From the ASC, the dimensions OBN and DED were used to measure the mystical-type and challenging experiences, respectively. The Self-Reported Quick Inventory of Depressive Symptoms (QIDS-SR) at 5 weeks served as the endpoint clinical outcome measure, as in later time points some of the subjects had gone on to receive new treatments, thus confounding inferences. In a repeated measure ANOVA, Time was the within-subject factor (independent variable), with QIDS-SR as the within-subject dependent variable in baseline, 1-day, 1-week, 5-weeks. OBN and DED were independent variables. OBN-by-Time and DED-by-Time interactions were the primary outcomes of interest.

Results: For the interaction of OBN and DED with Time (QIDS-SR as dependent variable), the main effect and the effects at each time point compared to baseline were all significant (p = 0.002 and p = 0.003, respectively, for main effects), confirming our main hypothesis. Furthermore, Pearson's correlation of OBN with QIDS-SR (5 weeks) was specific compared to perceptual dimensions of the ASC (p < 0.05).

Discussion: This report further bolsters the view that the quality of the acute psychedelic experience is a key mediator of long-term changes in mental health. Future therapeutic work with psychedelics should recognize the essential importance of quality of experience in determining treatment efficacy and consider ways of enhancing mystical-type experiences and reducing anxiety.

Studying the promising paradigm of psilocybin-assisted therapy for treatment-resistant depressive patients has been done by Robin Carhart-Harris et al. in 2018. In ‘Psilocybin with psychological support for treatment-resistant depression: six-month follow-up,‘ they looked at how 20 participants fared after two sessions with a moderate (10mg) and high dose (25mg) of psilocybin. The treatment was generally well tolerated by the patients and there were no serious adverse events. The data suggested that the suicidality scores were significantly reduced and maximal effects were observed at 5 weeks post-treatment. The study also highlighted the importance of psychological support before, during, and post-psilocybin administration session.

Carhart-Harris, R. L., Bolstridge, M., Day, C. M. J., Rucker, J., Watts, R., Erritzoe, D. E., Kaelen, M., Giribaldi, B., Bloomfield, M., Pilling, S., Rickard, J. A., Forbes, B., Feilding, A., Taylor, D., Curran, H. V. and Nutt, D. J. (2018). Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology, 235(2):399-408.

Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy.

Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression.

Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure.

Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen’s d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen’s d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience.

Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.

A functional magnetic resonance imaging (fMRI) study by Robin Carhart-Harris et al. (2017) investigated the neurological basis of the response to psychedelics. The study looked at whole-brain cerebral blood flow (CBF) post-treatment with psilocybin. The data showed decreases in several areas of temporal and frontal lobes, and a relation between decreased CBF and the reduction in depressive symptoms was found. The results suggest that “the changes in brain activity observed just one-day after a high dose psychedelic experience are very different to those found during the acute psychedelic state.” Additionally, the authors observed an increased resting-state functional connectivity within the default-mode network (DMN) post-treatment, which is consistent with previous findings suggesting that DMN integrity changes are associated with mood improvements.

Carhart-Harris, R. L., Roseman, L., Bolstridge, M., Demetriou, L., Pannekoek, J. N., Wall, M. B., Tanner, M., Kaelen, M., McGonigle, J. Murphy, K., Leech, R., Curr, H. V. and Nutt, D. J. (2017). Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Scientific reports, 7(1):1-11.

Psilocybin with psychological support is showing promise as a treatment model in psychiatry but its therapeutic mechanisms are poorly understood. Here, cerebral blood flow (CBF) and blood oxygen-level dependent (BOLD) resting-state functional connectivity (RSFC) were measured with functional magnetic resonance imaging (fMRI) before and after treatment with psilocybin (serotonin agonist) for treatment-resistant depression (TRD). Quality pre and post treatment fMRI data were collected from 16 of 19 patients. Decreased depressive symptoms were observed in all 19 patients at 1-week post-treatment and 47% met criteria for response at 5 weeks. Whole-brain analyses revealed post-treatment decreases in CBF in the temporal cortex, including the amygdala. Decreased amygdala CBF correlated with reduced depressive symptoms. Focusing on a priori selected circuitry for RSFC analyses, increased RSFC was observed within the default-mode network (DMN) post-treatment. Increased ventromedial prefrontal cortex-bilateral inferior lateral parietal cortex RSFC was predictive of treatment response at 5-weeks, as was decreased parahippocampal-prefrontal cortex RSFC. These data fill an important knowledge gap regarding the post-treatment brain effects of psilocybin, and are the first in depressed patients. The post-treatment brain changes are different to previously observed acute effects of psilocybin and other ‘psychedelics’ yet were related to clinical outcomes. A ‘reset’ therapeutic mechanism is proposed.

Lea Mertens et al. (2020) investigated the functional connectivity between the amygdala, which is a brain structure involved in the expression of fear and which was also found to be active in the previous study, and the ventromedial prefrontal cortex, which is involved in social decision making, of 19 research participants during a face-processing task (versus a resting phase) before and after treatment with psilocybin. ‘Therapeutic mechanisms of psilocybin: Changes in the amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression’ suggests that the activity of neural pathways involved in emotional responsiveness is increased after a high dose of psilocybin. It was further hypothesized that the proposed functional connectivity changes in the amygdala and the ventromedial prefrontal cortex would relate to improvements in depression and anxiety.

Lea Mertens discussed the findings of this study in the interview with Lukas Basedow. She is also a part of our Psilocybin Depression Study.

Mertens, L. J., Wall, M. B., Roseman, L., Demetriou, L., Nutt, D. J., and Carhart-Harris, R. L. (2020). Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression. Journal of Psychopharmacology, 34(2):167-180.

Background: Psilocybin has shown promise as a treatment for depression but its therapeutic mechanisms are not properly understood. In contrast to the presumed actions of antidepressants, we recently found increased amygdala responsiveness to fearful faces one day after open-label treatment with psilocybin (25 mg) in 19 patients with treatment-resistant depression, which correlated with treatment efficacy.

Aims: Aiming to further unravel the therapeutic mechanisms of psilocybin, the present study extends this basic activation analysis. We hypothesised changed amygdala functional connectivity, more precisely decreased amygdala-ventromedial prefrontal cortex functional connectivity, during face processing after treatment with psilocybin.

Methods: Psychophysiological interaction analyses were conducted on functional magnetic resonance imaging data from a classic face/emotion perception task, with the bilateral amygdala and ventromedial prefrontal cortex time-series as physiological regressors. Average parameter estimates (beta weights) of significant clusters were correlated with clinical outcomes at one week.

Results: Results showed decreased ventromedial prefrontal cortex-right amygdala functional connectivity during face processing post- (versus pre-) treatment; this decrease was associated with levels of rumination at one week. This effect was driven by connectivity changes in response to fearful and neutral (but not happy) faces. Independent whole-brain analyses also revealed a post-treatment increase in functional connectivity between the amygdala and ventromedial prefrontal cortex to occipital-parietal cortices during face processing.

Conclusion: These results are consistent with the idea that psilocybin therapy revives emotional responsiveness on a neural and psychological level, which may be a key treatment mechanism for psychedelic therapy. Future larger placebo-controlled studies are needed to examine the replicability of the current findings.

Keywords: Amygdala; depression; emotional processing; functional connectivity; psilocybin; psychophysiological interaction; ventromedial prefrontal cortex.

Another alternative to classic antidepressants might be offered by ayahuasca – a botanical hallucinogen used in ritual and medicinal context by the native tribes of the Amazon. The ‘Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression’ (2019) double-blind placebo-controlled study shows that also ayahuasca has the potential to significantly improve the scores in the Depression Rating Scale. The authors showed that at one day and at seven days post-treatment with ayahuasca, MARDS-scores of depression (but not remission rates) were significantly lower. The Banisteriopsis caapi brew has been found to produce a rapid antidepressant effect in comparison to the placebo and offer high safety and tolerability profile.

Palhano-Fontes, F., Barreto, D., Onias, H., Andrade, K. C., Novaes, M. M., Pessoa, J. A., Mota-Rolim, S. A., Osório, F. L., Sanches, R., Dos Santos, R. G., … and Araújo, D. B. (2019). Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychological medicine, 49(4):655–663.

Recent open-label trials show that psychedelics, such as ayahuasca, hold promise as fast-onset antidepressants in treatment-resistant depression.

To test the antidepressant effects of ayahuasca, we conducted a parallel-arm, double-blind randomized placebo-controlled trial in 29 patients with treatment-resistant depression. Patients received a single dose of either ayahuasca or placebo. We assessed changes in depression severity with the Montgomery-Åsberg Depression Rating Scale (MADRS) and the Hamilton Depression Rating scale at baseline, and at 1 (D1), 2 (D2), and 7 (D7) days after dosing.

We observed significant antidepressant effects of ayahuasca when compared with placebo at all-time points. MADRS scores were significantly lower in the ayahuasca group compared with placebo at D1 and D2 (p = 0.04), and at D7 (p < 0.0001). Between-group effect sizes increased from D1 to D7 (D1: Cohen's d = 0.84; D2: Cohen's d = 0.84; D7: Cohen's d = 1.49). Response rates were high for both groups at D1 and D2, and significantly higher in the ayahuasca group at D7 (64% v. 27%; p = 0.04). Remission rate showed a trend toward significance at D7 (36% v. 7%, p = 0.054).

To our knowledge, this is the first controlled trial to test a psychedelic substance in treatment-resistant depression. Overall, this study brings new evidence supporting the safety and therapeutic value of ayahuasca, dosed within an appropriate setting, to help treat depression. This study is registered at http://clinicaltrials.gov (NCT02914769).

Key words: Ayahuasca, depression, HRS, MEQ, psychedelics, randomized controlled trial (RCT)

Although not exclusively focusing on depression, Joost Breeksema et al. (2020) reviewed the qualitative experiences of patients in the treatment of mental health disorders. In ‘Psychedelic Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences in Qualitative Studies,’ the group searched for patterns among patients’ experiences, considering both, the experiences across disorders and the therapeutic processes together with the insights they offered. Patients frequently reported the advantages of psychedelic-assisted therapy over mainstream approaches, emphasizing the positive role of trust, safety, attention, and even the presence of music. The study also found that psychedelics exhibit overlapping therapeutic effects across diseases, including introspective insights and the feeling of connectedness. The authors conclude that the understanding of factors coming into play during a therapy session “may contribute to optimizing treatment context, and lead to improved clinical responses and personal benefits.”

Breeksema, J. J., Niemeijer, A. R., Krediet, E., Vermetten, E., and Schoevers, R. A. (2020). Psychedelic Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences in Qualitative Studies. CNS drugs, 34:925–946.

Interest in the use of psychedelic substances for the treatment of mental disorders is increasing. Processes that may affect therapeutic change are not yet fully understood. Qualitative research methods are increasingly used to examine patient accounts; however, currently, no systematic review exists that synthesizes these findings in relation to the use of psychedelics for the treatment of mental disorders.

To provide an overview of salient themes in patient experiences of psychedelic treatments for mental disorders, presenting both common and diverging elements in patients’ accounts, and elucidating how these affect the treatment process.

We systematically searched the PubMed, MEDLINE, PsycINFO, and Embase databases for English-language qualitative literature without time limitations. Inclusion criteria were qualitative research design; peer-reviewed studies; based on verbalized patient utterances; and a level of abstraction or analysis of the results. Thematic synthesis was used to analyze and synthesize results across studies. A critical appraisal of study quality and methodological rigor was conducted using the Critical Appraisal Skills Programme (CASP).

Fifteen research articles, comprising 178 patient experiences, were included. Studies exhibited a broad heterogeneity in terms of substance, mental disorder, treatment context, and qualitative methodology. Substances included psilocybin, lysergic acid diethylamide (LSD), ibogaine, ayahuasca, ketamine and 3,4-methylenedioxymethamphetamine (MDMA). Disorders included anxiety, depression, eating disorders, post-traumatic stress disorder, and substance use disorders. While the included compounds were heterogeneous in pharmacology and treatment contexts, patients reported largely comparable experiences across disorders, which included phenomenological analogous effects, perspectives on the intervention, therapeutic processes and treatment outcomes. Comparable therapeutic processes included insights, altered self-perception, increased connectedness, transcendental experiences, and an expanded emotional spectrum, which patients reported contributed to clinically and personally relevant responses.

This review demonstrates how qualitative research of psychedelic treatments can contribute to distinguishing specific features of specific substances, and carry otherwise undiscovered implications for the treatment of specific psychiatric disorders.