Recommended readings
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.

Psychedelics in the treatment of unipolar mood disorders: a systematic review (2016)

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.

Efficacy, tolerability, and safety of serotonergic psychedelics for the management of mood, anxiety, and substance-use disorders: a systematic review of systematic reviews (2018)

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

Post-Psychedelic Reductions in Experiential Avoidance Are Associated With Decreases in Depression Severity and Suicidal Ideation (2020)

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

Psychological flexibility mediates the relations between acute psychedelic effects and subjective decreases in depression and anxiety (2020)

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.

Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial (2020)

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

Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression (2018)

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.

Psilocybin with psychological support for treatment-resistant depression: six-month follow-up (2018)

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.

Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms (2017)

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.

Therapeutic mechanisms of psilocybin: Changes in amygdala and prefrontal functional connectivity during emotional processing after psilocybin for treatment-resistant depression (2020)

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.

Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial (2019)

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.

Psychedelic Treatments for Psychiatric Disorders: A Systematic Review and Thematic Synthesis of Patient Experiences in Qualitative Studies (2020)

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.