OPEN Foundation

M. Johnson

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

Abstract

Importance: 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.

Objective: To investigate the effect of psilocybin therapy in patients with MDD.

Design, setting, and participants: 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).

Interventions: Two psilocybin sessions (session 1: 20 mg/70 kg; session 2: 30 mg/70 kg) were given (administered in opaque gelatin capsules with approximately 100 mL of water) in the context of supportive psychotherapy (approximately 11 hours). Participants were randomized to begin treatment immediately or after an 8-week delay.

Main outcomes and measures: 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).

Results: Of the randomized participants, 24 of 27 (89%) completed the intervention and the week 1 and week 4 postsession assessments. This population had a mean (SD) age of 39.8 (12.2) years, was composed of 16 women (67%), and had a mean (SD) baseline GRID-HAMD score of 22.8 (3.9). The mean (SD) GRID-HAMD scores at weeks 1 and 4 (8.0 [7.1] and 8.5 [5.7]) in the immediate treatment group were statistically significantly lower than the scores at the comparable time points of weeks 5 and 8 (23.8 [5.4] and 23.5 [6.0]) in the delayed treatment group. The effect sizes were large at week 5 (Cohen d = 2.5; 95% CI, 1.4-3.5; P < .001) and week 8 (Cohen d = 2.6; 95% CI, 1.5-3.7; P < .001). The QIDS-SR documented a rapid decrease in mean (SD) depression score from baseline to day 1 after session 1 (16.7 [3.5] vs 6.3 [4.4]; Cohen d = 2.6; 95% CI, 1.8-3.5; P < .001), which remained statistically significantly reduced through the week 4 follow-up (6.0 [5.7]; Cohen d = 2.3; 95% CI, 1.5-3.0; P < .001). In the overall sample, 17 participants (71%) at week 1 and 17 (71%) at week 4 had a clinically significant response to the intervention (≥50% reduction in GRID-HAMD score), and 14 participants (58%) at week 1 and 13 participants (54%) at week 4 were in remission (≤7 GRID-HAMD score).

Conclusions and relevance: Findings suggest that psilocybin with therapy is efficacious in treating MDD, thus extending the results of previous studies of this intervention in patients with cancer and depression and of a nonrandomized study in patients with treatment-resistant depression.

Trial registration: ClinicalTrials.gov Identifier: NCT03181529.

Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., Finan, P. H., & Griffiths, R. R. (2021). Effects of Psilocybin-Assisted Therapy on Major Depressive Disorder: A Randomized Clinical Trial. JAMA psychiatry, 78(5), 481–489. https://doi.org/10.1001/jamapsychiatry.2020.3285

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Set and Setting: A Randomized Study of Different Musical Genres in Supporting Psychedelic Therapy

Abstract

Mounting evidence supports the serotonin 2A receptor agonist psilocybin as a psychiatric pharmacotherapy. Little research has experimentally examined how session “set and setting” impacts subjective and therapeutic effects. We analyzed the effects of the musical genre played during sessions of a psilocybin study for tobacco smoking cessation. Participants (N = 10) received psilocybin (20-30 mg/70 kg) in two sessions, each with a different musical genre (Western classical versus overtone-based), with the order counterbalanced. Participants chose one genre for a third session (30 mg/70 kg). Mystical experiences scores tended to be higher in overtone-based sessions than in Western classical sessions. Six of ten participants chose the overtone-based music for a third session. Biologically confirmed smoking abstinence was similar based on musical choice, with a slight benefit for participants choosing the overtone-based playlist (66.7% versus 50%). These data call into question whether Western classical music typically used in psychedelic therapy holds a unique benefit. Broadly, we call for experimentally examining session components toward optimizing psychedelic therapeutic protocols.

Strickland, J. C., Garcia-Romeu, A., & Johnson, M. W. (2020). Set and Setting: A Randomized Study of Different Musical Genres in Supporting Psychedelic Therapy. ACS pharmacology & translational science, 4(2), 472–478. https://doi.org/10.1021/acsptsci.0c00187

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Consciousness, Religion, and Gurus: Pitfalls of Psychedelic Medicine

Abstract

This viewpoint identifies pitfalls in the study of psychedelic compounds, including those that pose challenges for the potential use of psychedelics as medicines. They are as follows: (1) Sloppiness regarding use of the term “consciousness”. (2) Inappropriate introduction of religious/spiritual beliefs of investigators or clinicians. (3) Clinical boundaries and other ethical challenges associated with psychedelic treatments.

Johnson M. W. (2020). Consciousness, Religion, and Gurus: Pitfalls of Psychedelic Medicine. ACS pharmacology & translational science, 4(2), 578–581. https://doi.org/10.1021/acsptsci.0c00198

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Psychedelics and Psychotherapy

Abstract

Psychedelics have shown great promise in modern clinical trials for treating various psychiatric conditions. As a transdiagnostic treatment that exerts its effects through subjective experiences that leave enduring effects, it is akin to psychotherapy. To date, there has been insufficient discussion of how psychedelic therapy is similar to and different from conventional psychotherapy. In this article, we review the shared features of effective conventional psychotherapies and situate therapeutic psychedelic effects within those. We then discuss how psychedelic drug effects might amplify conventional psychotherapeutic processes-particularly via effects on meaning and relationship-as well as features that make psychedelic treatment unique. Taking into account shared features of conventional psychotherapies and unique psychedelic drug effects, we create a framework for understanding why psychedelics are likely to be effective with very diverse types of psychotherapies. We also review the formal psychotherapies that have been adjunctively included in modern psychedelic trials and extend the understanding of psychedelics as psychotherapy towards implications for clinical ethics and trial design. We aim to provide some common conceptual vocabulary that can be used to frame therapeutic psychedelic effects beyond the confines of any one specific modality.

Nayak, S., & Johnson, M. W. (2021). Psychedelics and Psychotherapy. Pharmacopsychiatry, 54(4), 167–175. https://doi.org/10.1055/a-1312-7297

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The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain

Abstract

Salvinorin A (SA) is a κ-opioid receptor agonist and atypical dissociative hallucinogen found in Salvia divinorum. Despite the resurgence of hallucinogen studies, the effects of κ-opioid agonists on human brain function are not well-understood. This placebo-controlled, within-subject study used functional magnetic resonance imaging for the first time to explore the effects of inhaled SA on strength, variability, and entropy of functional connectivity (static, dynamic, and entropic functional connectivity, respectively, or sFC, dFC, and eFC). SA tended to decrease within-network sFC but increase between-network sFC, with the most prominent effect being attenuation of the default mode network (DMN) during the first half of a 20-min scan (i.e., during peak effects). SA reduced brainwide dFC but increased brainwide eFC, though only the former effect survived multiple comparison corrections. Finally, using connectome-based classification, most models trained on dFC network interactions could accurately classify the first half of SA scans. In contrast, few models trained on within- or between-network sFC and eFC performed above chance. Notably, models trained on within-DMN sFC and eFC performed better than models trained on other network interactions. This pattern of SA effects on human brain function is strikingly similar to that of other hallucinogens, necessitating studies of direct comparisons.

Doss, M. K., May, D. G., Johnson, M. W., Clifton, J. M., Hedrick, S. L., Prisinzano, T. E., Griffiths, R. R., & Barrett, F. S. (2020). The Acute Effects of the Atypical Dissociative Hallucinogen Salvinorin A on Functional Connectivity in the Human Brain. Scientific reports, 10(1), 16392. https://doi.org/10.1038/s41598-020-73216-8

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Subjective features of the psilocybin experience that may account for its self-administration by humans: a double-blind comparison of psilocybin and dextromethorphan

Abstract

Rationale

Although both psilocybin and dextromethorphan (DXM) produce psychedelic-like subjective effects, rates of non-medical use of psilocybin are consistently greater than DXM.

Objective

New data are presented from a study of psilocybin and DXM relevant to understanding the features of psilocybin subjective effects that may account for its higher rates of non-medical use.

Methods

Single, acute oral doses of psilocybin (10, 20, 30 mg/70 kg), DXM (400 mg/70 kg), and placebo were administered under double-blind conditions to 20 healthy participants with histories of hallucinogen use.

Results

High doses of both drugs produced similar time courses and increases in participant ratings of peak overall drug effect strength. Nine subjective effect domains are proposed to be related to the reinforcing effects of psilocybin: liking, visual effects, positive mood, insight, positive social effects, increased awareness of beauty (both visual and music), awe/amazement, meaningfulness, and mystical experience. For most ratings, (1) psilocybin and DXM both produced effects significantly greater than placebo; (2) psilocybin showed dose-related increases; 3, DXM was never significantly higher than psilocybin; (4) the two highest psilocybin doses were significantly greater than DXM. These differences were consistent with two measures of desire to take the drug condition again.

Conclusions

This analysis provides new information about domains of psilocybin subjective effects proposed to be related to its reinforcing effects (alternatively described as the “motivation” to use). Observed differences on these domains between psilocybin and DXM are consistent with the relative rates of non-medical use of psilocybin and DXM.

Carbonaro, T. M., Johnson, M. W., & Griffiths, R. R. (2020). Subjective features of the psilocybin experience that may account for its self-administration by humans: a double-blind comparison of psilocybin and dextromethorphan. Psychopharmacology, 1-12., https://doi.org/10.1007/s00213-020-05533-9
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Persisting Reductions in Cannabis, Opioid, and Stimulant Misuse After Naturalistic Psychedelic Use: An Online Survey.

Abstract

Background: Observational data and preliminary studies suggest serotonin 2A agonist psychedelics may hold potential in treating a variety of substance use disorders (SUDs), including opioid use disorder (OUD).

Aims: The study aim was to describe and analyze self-reported cases in which naturalistic psychedelic use was followed by cessation or reduction in other substance use.

Methods: An anonymous online survey of individuals reporting cessation or reduction in cannabis, opioid, or stimulant use following psychedelic use in non-clinical settings.

Results: Four hundred forty-four respondents, mostly in the USA (67%) completed the survey. Participants reported 4.5 years of problematic substance use on average before the psychedelic experience to which they attributed a reduction in drug consumption, with 79% meeting retrospective criteria for severe SUD. Most reported taking a moderate or high dose of LSD (43%) or psilocybin-containing mushrooms (29%), followed by significant reduction in drug consumption. Before the psychedelic experience 96% met SUD criteria, whereas only 27% met SUD criteria afterward. Participants rated their psychedelic experience as highly meaningful and insightful, with 28% endorsing psychedelic-associated changes in life priorities or values as facilitating reduced substance misuse. Greater psychedelic dose, insight, mystical-type effects, and personal meaning of experiences were associated with greater reduction in drug consumption.

Conclusions: While these cross-sectional and self-report methods cannot determine whether psychedelics caused changes in drug use, results suggest the potential that psychedelics cause reductions in problematic substance use, and support additional clinical research on psychedelic-assisted treatment for SUD.

Garcia-Romeu, A., Davis, A. K., Erowid, E., Griffiths, R. R., & Johnson, M. W. (2020). Persisting reductions in cannabis, opioid, and stimulant misuse after naturalistic psychedelic use: An online survey. Frontiers in psychiatry10, 955; 10.3389/fpsyt.2019.00955
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Cessation and reduction in alcohol consumption and misuse after psychedelic use

Meta-analysis of randomized studies using lysergic acid diethylamide (LSD) for alcohol use disorder (AUD) showed large, significant effects for LSD efficacy compared to control conditions. Clinical studies suggest potential anti-addiction effects of LSD and mechanistically-related classic psychedelics for alcohol and other substance use disorders.

To supplement clinical studies, reports of psychedelic use in naturalistic settings can provide further data regarding potential effects of psychedelics on alcohol use.

An anonymous online survey of individuals with prior AUD reporting cessation or reduction in alcohol use following psychedelic use in non-clinical settings.

343 respondents, mostly White (89%), males (78%), in the USA (60%) completed the survey. Participants reported seven years of problematic alcohol use on average before the psychedelic experience to which they attributed reduced alcohol consumption, with 72% meeting retrospective criteria for severe AUD. Most reported taking a moderate or high dose of LSD (38%) or psilocybin (36%), followed by significant reduction in alcohol consumption. After the psychedelic experience 83% no longer met AUD criteria. Participants rated their psychedelic experience as highly meaningful and insightful, with 28% endorsing psychedelic-associated changes in life priorities or values as facilitating reduced alcohol misuse. Greater psychedelic dose, insight, mystical-type effects, and personal meaning of experiences were associated with a greater reduction in alcohol consumption, controlling for prior alcohol consumption and related distress.

Although results cannot demonstrate causality, they suggest that naturalistic psychedelic use may lead to cessation or reduction in problematic alcohol use, supporting further investigation of psychedelic-assisted treatment for AUD.
Garcia-Romeu, A., Davis, A. K., Erowid, F., Erowid, E., Griffiths, R. R., & Johnson, M. W. (2019). Cessation and reduction in alcohol consumption and misuse after psychedelic use. Journal of Psychopharmacology, 0269881119845793., https://doi.org/10.1177%2F0269881119845793
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Survey of subjective "God encounter experiences": Comparisons among naturally occurring experiences and those occasioned by the classic psychedelics psilocybin, LSD, ayahuasca, or DMT.

Abstract

Naturally occurring and psychedelic drug-occasioned experiences interpreted as personal encounters with God are well described but have not been systematically compared. In this study, five groups of individuals participated in an online survey with detailed questions characterizing the subjective phenomena, interpretation, and persisting changes attributed to their single most memorable God encounter experience (n = 809 Non-Drug, 1184 psilocybin, 1251 lysergic acid diethylamide (LSD), 435 ayahuasca, and 606 N,N-dimethyltryptamine (DMT)). Analyses of differences in experiences were adjusted statistically for demographic differences between groups. The Non-Drug Group was most likely to choose “God” as the best descriptor of that which was encountered while the psychedelic groups were most likely to choose “Ultimate Reality.” Although there were some other differences between non-drug and the combined psychedelic group, as well as between the four psychedelic groups, the similarities among these groups were most striking. Most participants reported vivid memories of the encounter experience, which frequently involved communication with something having the attributes of being conscious, benevolent, intelligent, sacred, eternal, and all-knowing. The encounter experience fulfilled a priori criteria for being a complete mystical experience in approximately half of the participants. More than two-thirds of those who identified as atheist before the experience no longer identified as atheist afterwards. These experiences were rated as among the most personally meaningful and spiritually significant lifetime experiences, with moderate to strong persisting positive changes in life satisfaction, purpose, and meaning attributed to these experiences. Among the four groups of psychedelic users, the psilocybin and LSD groups were most similar and the ayahuasca group tended to have the highest rates of endorsing positive features and enduring consequences of the experience. Future exploration of predisposing factors and phenomenological and neural correlates of such experiences may provide new insights into religious and spiritual beliefs that have been integral to shaping human culture since time immemorial.
Griffiths, R. R., Hurwitz, E. S., Davis, A. K., Johnson, M. W., & Jesse, R. (2019). Survey of subjective” God encounter experiences”: Comparisons among naturally occurring experiences and those occasioned by the classic psychedelics psilocybin, LSD, ayahuasca, or DMT. PloS one14(4), e0214377., https://doi.org/10.1371/journal.pone.0214377
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Survey of subjective “God encounter experiences”: Comparisons among naturally occurring experiences and those occasioned by the classic psychedelics psilocybin, LSD, ayahuasca, or DMT.

Abstract

Naturally occurring and psychedelic drug-occasioned experiences interpreted as personal encounters with God are well described but have not been systematically compared. In this study, five groups of individuals participated in an online survey with detailed questions characterizing the subjective phenomena, interpretation, and persisting changes attributed to their single most memorable God encounter experience (n = 809 Non-Drug, 1184 psilocybin, 1251 lysergic acid diethylamide (LSD), 435 ayahuasca, and 606 N,N-dimethyltryptamine (DMT)). Analyses of differences in experiences were adjusted statistically for demographic differences between groups. The Non-Drug Group was most likely to choose “God” as the best descriptor of that which was encountered while the psychedelic groups were most likely to choose “Ultimate Reality.” Although there were some other differences between non-drug and the combined psychedelic group, as well as between the four psychedelic groups, the similarities among these groups were most striking. Most participants reported vivid memories of the encounter experience, which frequently involved communication with something having the attributes of being conscious, benevolent, intelligent, sacred, eternal, and all-knowing. The encounter experience fulfilled a priori criteria for being a complete mystical experience in approximately half of the participants. More than two-thirds of those who identified as atheist before the experience no longer identified as atheist afterwards. These experiences were rated as among the most personally meaningful and spiritually significant lifetime experiences, with moderate to strong persisting positive changes in life satisfaction, purpose, and meaning attributed to these experiences. Among the four groups of psychedelic users, the psilocybin and LSD groups were most similar and the ayahuasca group tended to have the highest rates of endorsing positive features and enduring consequences of the experience. Future exploration of predisposing factors and phenomenological and neural correlates of such experiences may provide new insights into religious and spiritual beliefs that have been integral to shaping human culture since time immemorial.
Griffiths, R. R., Hurwitz, E. S., Davis, A. K., Johnson, M. W., & Jesse, R. (2019). Survey of subjective” God encounter experiences”: Comparisons among naturally occurring experiences and those occasioned by the classic psychedelics psilocybin, LSD, ayahuasca, or DMT. PloS one14(4), e0214377., https://doi.org/10.1371/journal.pone.0214377
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