Background and aims: Ibogaine is an indole alkaloid used in rituals of the African Bwiti tribe. It is also used in non-medical settings to treat addiction. However, ibogaine has been linked to several deaths, mainly due to cardiac events called torsades des pointes preceded by QTc prolongation as well as other safety concerns. This study aimed to evaluate the cardiac, cerebellar and psychomimetic safety of ibogaine in patients with opioid use disorder.
Design: A descriptive open-label observational study.
Setting: Department of psychiatry in a university medical center, the Netherlands.
Participants: Patients with opioid use disorder (n = 14) on opioid maintenance treatment with a lasting wish for abstinence, who failed to reach abstinence with standard care.
Intervention and measurements: After conversion to morphine-sulphate, a single dose of ibogaine-HCl 10 mg/kg was administered and patients were monitored at regular intervals for at least 24 hours assessing QTc, blood pressure and heart rate, scale for the assessment and rating of ataxia (SARA) to assess cerebellar side effects and the delirium observation scale (DOS) to assess psychomimetic effects.
Findings: The maximum QTc (Fridericia) prolongation was on average 95ms (range 29-146ms). Fifty percent of subjects reached a QTc of over 500ms during the observation period. In six out 14 subjects prolongation above 450ms lasted beyond 24 hours after ingestion of ibogaine. No torsades des pointes were observed. Severe transient ataxia with inability to walk without support was seen in all patients. Withdrawal and psychomimetic effects were mostly well-tolerated and manageable (11/14 did not return to morphine within 24 hours, DOS scores remained below threshold).
Conclusions: This open-label observational study found that ibogaine treatment of patients with opioid use disorder can induce a clinically relevant but reversible QTc prolongation, bradycardia, and severe ataxia.
Knuijver, T., Schellekens, A., Belgers, M., Donders, R., van Oosteren, T., Kramers, K., & Verkes, R. (2022). Safety of ibogaine administration in detoxification of opioid-dependent individuals: a descriptive open-label observational study. Addiction (Abingdon, England), 117(1), 118–128. https://doi.org/10.1111/add.15448
Objective: Whether for spiritual, recreational, or potential therapeutic use, interest in ayahuasca has grown remarkably. Ayahuasca’s main active substances are N,N-dimethyltryptamine and certain monoamine oxidase inhibitor β-carbolines. Possible drug interactions are a major concern, and research is lacking in this area. The objective of this study was to evaluate the safety of ritual ayahuasca use regarding adverse effects and risk factors.
Methods: In this cross-sectional study, ayahuasca users from a religious institution answered an online questionnaire about its safety. Adverse effects, safety measures, and possible risk factors (psychiatric diagnosis and medications) were investigated.
Results: The most frequent adverse effects among the 614 participants were transient gastrointestinal effects (nausea and vomiting). Fifty participants self-reported a psychiatric diagnosis (depression and anxiety were the most prevalent), and these participants experienced adverse effects more frequently. Psychiatric medication use was reported by 31 participants. No indication of increased adverse effects due to drug-drug interactions was found.
Conclusion: A minority of participants reported being very negatively affected by persistent adverse effects. Psychiatric medication use while participating in ayahuasca rituals was not associated with increased adverse effects. For the most part, the institution’s practices seem sufficient to prevent exacerbated reactions. Future studies may focus on negatively affected users.
Durante, Í., Dos Santos, R. G., Bouso, J. C., & Hallak, J. E. (2021). Risk assessment of ayahuasca use in a religious context: self-reported risk factors and adverse effects. Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999), 43(4), 362–369. https://doi.org/10.1590/1516-4446-2020-0913
Background: Ketamine’s potent and rapid antidepressant properties have shown great promise to treat severe forms of major depressive disorder (MDD). A recently hypothesized antidepressant mechanism of action of ketamine is the inhibition of N-methyl-D-aspartate receptor-dependent bursting activity of the habenula (Hb), a small brain structure that modulates reward and affective states.
Methods: Resting-state functional magnetic resonance imaging was conducted in 35 patients with MDD at baseline and 24 hours following treatment with i.v. ketamine. A seed-to-voxel functional connectivity (FC) analysis was performed with the Hb as a seed-of-interest. Pre-post changes in FC and the associations between changes in FC of the Hb and depressive symptom severity were examined.
Results: A reduction in Montgomery-Åsberg Depression Rating Scale scores from baseline to 24 hours after ketamine infusion was associated with increased FC between the right Hb and a cluster in the right frontal pole (t = 4.65, P = .03, false discovery rate [FDR]-corrected). A reduction in Quick Inventory of Depressive Symptomatology-Self Report score following ketamine was associated with increased FC between the right Hb and clusters in the right occipital pole (t = 5.18, P < .0001, FDR-corrected), right temporal pole (t = 4.97, P < .0001, FDR-corrected), right parahippocampal gyrus (t = 5.80, P = .001, FDR-corrected), and left lateral occipital cortex (t = 4.73, P = .03, FDR-corrected). Given the small size of the Hb, it is possible that peri-habenular regions contributed to the results.
Conclusions: These preliminary results suggest that the Hb might be involved in ketamine’s antidepressant action in patients with MDD, although these findings are limited by the lack of a control group.
Rivas-Grajales, A. M., Salas, R., Robinson, M. E., Qi, K., Murrough, J. W., & Mathew, S. J. (2021). Habenula Connectivity and Intravenous Ketamine in Treatment-Resistant Depression. The international journal of neuropsychopharmacology, 24(5), 383–391. https://doi.org/10.1093/ijnp/pyaa089
The promising results of psychedelic treatments in small scale clinical trials are feeding an emergent health and wellness industry around these substances. The Netherlands, where psilocybin truffles remain unregulated, has become fertile ground for entrepreneurs aiming to position themselves at the cutting-edge of the psychedelic medicine market. Even though most of these psychedelic retreats cater to healthy participants, an increasing number of companies are planning to offer truffle sessions as psychedelic therapy to psychiatric patients. At the current stage, when scientific evidence proves promising but not yet conclusive, researchers are worried about the risks of commercial providers running ahead of the ongoing research. Should companies tread more carefully and let clinical researchers take the lead in the development of psychedelic therapy?
In the upcoming ICPR 2024, leading experts and cutting-edge research around the use of psilocybin for therapy will be presented.
Psilocybin in the Netherlands
Psilocybin is a controlled substance in the Netherlands and the possession and sale of any species of psilocybin containing mushrooms is forbidden. However, this regulation does not apply to truffles, given that these are not strictly mushrooms but a different part of the fungus. This legal loophole has allowed the spread of psychedelic retreat centers offering truffle ceremonies for self-development or spiritual purposes.
Even though truffles qualify as a legal food in the Netherlands, they cannot be advertised as a medical treatment. The Dutch Health and Youth Care Inspectorate (IGJ) states that truffles may fall under the regulatory scope of the Medicines Act if medical claims are made. “In that case, we qualify the truffles as a medicine, for which no trade permit has been granted in the Netherlands”, an IGJ spokesperson declared.
Most entrepreneurs, aware of the existing regulation, avoid making explicit medical claims when advertising their services and try to use terms like “inner healing” and “personal development” instead. Many also warn that their ceremonies are not meant to substitute medical or psychotherapeutic care and make an effort to exclude clients with mental diagnoses and possible physical risks from participating through careful health screening.
This is, however, not always the case. The clinical director of a new truffle clinic recently declared to Dutch media: “We administer truffles to people in order to make them feel better and to overcome psychological disorders such as depression, anxiety and stress”. Others openly claim to provide “psychedelic-assisted therapy” on their websites and display the available scientific evidence to illustrate its efficacy in the treatment of depression, addiction or PTSD. We asked Nick (whose real name is not disclosed) about the apparent targeting of mental health patients on his retreat center’s website. “We are not pretending to treat or cure PTSD”, he assured, “we are acknowledging that there are people who have PTSD and that those clients that we have received (and not targeted) had very beneficial experiences”.
The hype around psychedelics is sparking a race among startups to become pioneers of a new therapeutic or wellness market, the boundaries are not always clear. But the emergence of truffle therapy is not just about opportunistic entrepreneurship. The mainstreaming of psychedelics is also bringing some of the underground therapists to the surface and from their perspective, there might not be meaningful reasons to wait for approval and regulation. Peter (whose real name is not disclosed) has conducted truffle therapy for the last eight years and more recently decided to start advertising their services online. “Back then we also thought we were moving too fast but people were really searching for this. We just couldn’t wait. Regulation can be helpful, but for a lot of us who already walked that path it’s not that great, especially for the ones who believe more in alternative therapies”.
The lack of formal regulation governing the profession has led some psychedelic guides in the Netherlands to found the Guild of Guides. This professional association is developing its own ethical codes in order to ensure best practices during psychedelic sessions. Peter also acknowledges the importance of the guild in the self-regulation of psychedelic facilitators. When it comes to offering therapy, however, their guidelines are unequivocal: “Guides do not claim to be psychedelic therapists nor offer ‘therapeutic’ services when they lack the appropriate accreditation.”
Scientists’ call for caution
A number of Dutch researchers and therapists are currently working on trials investigating the safety and efficacy of psilocybin for patients with treatment-resistant depression. They are concerned about commercial providers rushing to open up the market even before the scientific evidence is established. Clinical psychologist Jan Mars, therapist at the University Medical Centre Groningen (UMCG), says: “I am not a supporter of this practice because we are still doing research right now and you don’t want to run ahead of the science”. Joost Breeksema, researcher at the UMCG and director of the OPEN Foundation, echoed similar concerns: “The main problem is that we don’t know yet if this can be done safely and if so, which patients might benefit and which may be more at risk. And we’re only talking about the treatment of depression, where clinical research with psilocybin is relatively advanced. Offering psilocybin truffles to treat PTSD is even more problematic, not just because of the nature of this disorder, but also because we lack solid research. I understand the need for better treatments, and the impatience of patients who’ve sometimes suffered for decades, but it’s unethical, unwise and irresponsible to experiment blindly with these powerful treatments.”
It is important to remark that most scientists and therapists see no harm in conducting truffle ceremonies with experienced guides outside the medical realm. Renske Blom, psychiatrist at GGZ Centraal and therapist at UMC Utrecht, noted: “Truffles are legally available in the Netherlands so they can be and are being offered for spiritual care, wellbeing and self-improvement”.
While there are signs to be hopeful about the potential of psychedelics for the future of mental health treatments, research has not yet offered conclusive evidence that would warrant safe and efficacious provision of psilocybin therapy. Two psilocybin trials so far have shown significant and long-term improvements for depression. However, these trials lacked placebo controls and the samples were pretty small. Several ongoing multisite trials with hundreds of participants will be able to give more reliable evidence about the therapeutic value of psilocybin. Nonetheless, these studies have not yet been completed and experts warn that it is precisely at this stage of drug development where most new pharmaceuticals fail. In the case of PTSD, larger studies are proving that MDMA-assisted psychotherapy may be useful, but not a single clinical trial has investigated psilocybin for this indication yet. In general, there are still a number of incognitas around safety, short- and long-term efficacy, relapse rates and the optimal amount of integration sessions.
The mainstreaming of psychedelics causes challenges for the psychedelic field.
One of the main concerns of researchers relates to the qualifications and therapeutic experience of these truffle providers. This is a complicated issue given that clinicians and researchers are still debating the adequate standards and training requirements for the certification of future psychedelic therapists. Some companies currently offering truffle therapy have a team of professionals with a background in mental health. In other cases, the psychotherapeutic and medical credentials of guides and their experience with disorders such as PTSD or depression are dubious.
The exposure of these sensitive populations to the intensity of the psychedelic experience can be risky if guides are not able to respond to the particular needs of psychiatric patients. In working with depression and psychedelics, Jan Mars emphasizes that “supporting a psychedelic journey is a humbling experience. You don’t know what is going to happen during the session. You can expect anything to happen,” and therefore, he adds, “It’s important that therapists know how to provide a safe environment. We still need much more experience and knowledge about how to work with patients who suffer from chronic psychological conditions. Trauma often lies beneath the surface and pops up during a session with psychedelics”. In regard to trauma therapy with these substances, Joost Breeksema adds: “Patients may relive traumatic moments, completely dissociate or become overwhelmed with fear and anxiety. This can be hard to handle even for an experienced therapist. Now imagine what happens with well-intended, but under-qualified and unprepared guides”.
Although these treatments are known to be generally safe in terms of toxicology and no serious adverse events are commonly reported in trials, their safety profile resides precisely in the close psychotherapeutic support and monitoring performed before, during and after psilocybin administration. Jan Mars hopes that in future clinical practice, “psychedelic journeys will be embedded in a safe and trusting therapeutic environment. These journeys are no magic bullets.”
In general, truffle providers understand the concerns of scientists, but they feel that the benefits of psilocybin treatment outweigh its risks. According to the clinical director of a truffle clinic, clients with depression may be thinking: “Damned! Science says that this can help me. It is not yet approved but there are places where it can be done safely so I am going to try”. From his own experience guiding sessions, Peter concluded that: “It all comes down to a balance between safety and effectiveness. We are all trying to find out, but at the moment psychedelic sessions do more to help people than to harm them”.
For psychiatric patients for whom other treatments have failed, this call for patience and caution may be difficult to accept. At the same time, they should be able to make informed decisions. Given the current exclusion criteria in psychedelic trials, researchers discourage patients with a history of personality or psychotic disorders from seeking these treatments at all. Jan Mars sends a piece of advice to those other patients without complex comorbidities who, despite potential risks, decide to seek truffle therapy: “Involve a loved one in the journey that you are about to embark on, for support before and after. Do some research on who is guiding it, what the setting will be like and whether there is enough time dedicated to the preparation of the session. Make sure that you feel you can trust the guide. If you have doubts, then there is probably a good reason for it, and it might not be a good idea.”
The relation between retreat and research
Truffle therapists in the Netherlands definitely have clinical research on psilocybin as their reference of best practice. Nick explained: “We frame it in a therapeutic setting to optimize positive outcomes and keep clients safe”. Nonetheless, researchers remain sceptical about the degree to which truffle providers actually manage to screen out participants with mental diagnoses or maintain high standards of care. To be fair, even some research protocols could be criticized for including the minimal amount of preparation and integration sessions.
Besides the potential harm to patients, researchers also seem to be worried about the future of research itself. The controversial history of the field has made psychedelic scientists generally cautious about avoiding any kind of social backlash. An unfortunate incident with a patient could set back the progress made in the last years. Renske Blom added: “If a major incident happens in the context of these therapy sessions, inside or outside clinical trials, it could influence upcoming research as well”.
Check out the speaker list to discover which experts might be speaking about the latest advancements in the use of psilocybin in therapy!
While acknowledging the importance of further research, Nick also stressed that “truffles were never researched. They cannot say that psilocybin session guides are too early. Actually, the research is late because more people trip on naturals than on lab-grade psilocybin”. Bearing in mind the likely pharmacological difference between the synthetic compound and whole truffles, the current research agenda may not represent the interests of truffle therapists. In other words, it is unclear whether research with pure psilocybin would ever be considered valid evidence to justify their practice. Joost Breeksema said: “We don’t really know what truffles contain because they haven’t been standardized or analyzed in the laboratory, but I do think that if psilocybin goes through the approval process, it is likely that people and investors will get interested in the whole product as well.”
Despite the rather marginal position of truffles in current research, some investigators have realized the potential role that the retreat ecosystem can play in psychedelic science. In collaboration with retreat centers, several research projects have administered questionnaires to participants to learn more about the effects of these substances and their ritual use on healthy people. These centers could also become a place where all kinds of alternative models of psychedelic care can develop. The rigid regulatory and scientific frameworks within which researchers operate may limit the possible treatment conditions. In contrast, retreats offer the chance to explore new experimental protocols such as group sessions or natural settings. Joost Breeksema said: “The retreats may offer an infrastructure that is better suited to the psychedelic experience than clinical hospital settings”.
Nick is enthusiastic about future collaborations: “We want to set up research at our centers and we would love to count on scientific organizations, so we can actually build up the science needed and move beyond this internal dialogue about truffle therapy.” Joost Breeksema adds: “If they do proper data collection and analysis, they can contribute to the body of knowledge about the potential effects and risks of psychedelics. There are definitely options for collaboration but it has to be done judiciously and cautiously.”
The medicalization of psilocybin appears to raise tensions among different stakeholders in the psychedelic field. In the eyes of researchers, the underground therapy scene and the booming industry around psychedelic medicine may entail risks for patients and for the public image of ongoing research. Hopefully, future collaborations between retreat centers and research teams may offer a way forward to generate the evidence needed for an eventual regulation of the medical, as well as the non-medical uses of psilocybin truffles. However, at this stage, the open commercialization of psychedelic therapy to potentially vulnerable patients may be an unwise step ahead.
Written by Alberto Cantizani López Art by Anna Temczuk *The names of all informants involved in the commercial provision of truffles as therapy have been omitted or replaced by pseudonyms
Background: The recognition of emotions in facial expressions (REFE) is a core aspect of social cognition. Previous studies with the serotonergic hallucinogens lysergic acid diethylamide and psilocybin showed that these drugs reduced the recognition of negative (fear) faces in healthy volunteers. This trial assessed the acute and prolonged effects of a single dose of ayahuasca on the REFE.
Methods: Twenty-two healthy volunteers participated in a pilot, proof-of-concept, randomized trial. Study variables included a REFE task performed before and 4 hours after drug intake, subjective effects (self-reports/observer impressions), tolerability measures (cardiovascular measures, self-reports), and brain-derived neurotrophic factor plasma levels. The REFE task was applied again 1, 7, 14, and 21 days and 3 months after drug intake. Stability of ayahuasca alkaloids during the study was also assessed (room temperature, 18 months).
Findings: Compared with placebo, ayahuasca did not modify the REFE. No significant effects were observed on cardiovascular measures and brain-derived neurotrophic factor levels. Volunteers reported visual effects, tranquility/relaxation, and well-being, with few reports of transient anxiety/confusion. Ayahuasca was well tolerated, producing mainly nausea, gastrointestinal discomfort, and vomiting. A significant time-dependent deterioration of alkaloids was observed, especially for dimethyltryptamine.
Conclusions: Absence of significant effects on the REFE task could be due to lack of effects of ayahuasca (at the doses used), alkaloid degradation, learning effects, and the high educational level of the sample. Further trials with different samples are needed to better understand the effects of ayahuasca and other serotonergic hallucinogens on the REFE. Future trials should improve methods to guarantee the stability of ayahuasca alkaloids.
Rocha, J. M., Rossi, G. N., de Lima Osório, F., Bouso, J. C., de Oliveira Silveira, G., Yonamine, M., Campos, A. C., Bertozi, G., Cecílio Hallak, J. E., & Dos Santos, R. G. (2021). Effects of Ayahuasca on the Recognition of Facial Expressions of Emotions in Naive Healthy Volunteers: A Pilot, Proof-of-Concept, Randomized Controlled Trial. Journal of clinical psychopharmacology, 41(3), 267–274. https://doi.org/10.1097/JCP.0000000000001396
Yaden, D. B., Yaden, M. E., & Griffiths, R. R. (2021). Psychedelics in Psychiatry-Keeping the Renaissance From Going Off the Rails. JAMA psychiatry, 78(5), 469–470. https://doi.org/10.1001/jamapsychiatry.2020.3672
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.
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
In the last 2 decades, there is a renaissance in the scientific investigation of the therapeutic potential of psychedelic compounds. It is studied for the treatment of many psychiatric disorders, including posttraumatic stress disorder. The treatment is always done in the setting of psychedelic-assisted psychotherapy. A little is known about the potential effects, outside of the setting of psychedelic-assisted psychotherapy, on people diagnosed with a mental disorder or have a significant trauma history. In this case report, we present a young man who developed posttraumatic stress disorder after a psychedelic experience, induced by both Lysergic Acid Diethylamide (LSD) and N, N Dimethyltryptamine (DMT). In the psychedelic experience, a repressed memory of childhood sexual abuse was recovered. To our knowledge, this is the first report on posttraumatic stress disorder onset after a psychedelic experience. We believe that this case report is important since the history of trauma is prevalent among individuals with substance use disorder. Medical staff that treat people with either substance use disorder or trauma should be familiar with irregular presentations, such as the one described in this case.
Rubin-Kahana, D. S., Hassan, A. N., & Le Foll, B. (2021). Posttraumatic Stress Disorder After a Psychedelic Experience, a Case Report. Journal of addiction medicine, 15(3), 248–251. https://doi.org/10.1097/ADM.0000000000000734
Depression is a widespread and devastating mental illness and the search for rapid-acting antidepressants remains critical. There is now exciting evidence that the psychedelic compound psilocybin produces not only powerful alterations of consciousness, but also rapid and persistent antidepressant effects. How psilocybin exerts its therapeutic actions is not known, but it is widely presumed that these actions require altered consciousness, which is known to be dependent on serotonin 2A receptor (5-HT2AR) activation. This hypothesis has never been tested, however. We therefore asked whether psilocybin would exert antidepressant-like responses in mice and, if so, whether these responses required 5-HT2AR activation. Using chronically stressed male mice, we observed that a single injection of psilocybin reversed anhedonic responses assessed with the sucrose preference and female urine preference tests. The antianhedonic response to psilocybin was accompanied by a strengthening of excitatory synapses in the hippocampus-a characteristic of traditional and fast-acting antidepressants. Neither behavioral nor electrophysiological responses to psilocybin were prevented by pretreatment with the 5-HT2A/2C antagonist ketanserin, despite positive evidence of ketanserin’s efficacy. We conclude that psilocybin’s mechanism of antidepressant action can be studied in animal models and suggest that altered perception may not be required for its antidepressant effects. We further suggest that a 5-HT2AR-independent restoration of synaptic strength in cortico-mesolimbic reward circuits may contribute to its antidepressant action. The possibility of combining psychedelic compounds and a 5-HT2AR antagonist offers a potential means to increase their acceptance and clinical utility and should be studied in human depression.
Hesselgrave, N., Troppoli, T. A., Wulff, A. B., Cole, A. B., & Thompson, S. M. (2021). Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice. Proceedings of the National Academy of Sciences of the United States of America, 118(17), e2022489118. https://doi.org/10.1073/pnas.2022489118
Background: Psilocybin may have antidepressant properties, but direct comparisons between psilocybin and established treatments for depression are lacking.
Methods: In a phase 2, double-blind, randomized, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder, we compared psilocybin with escitalopram, a selective serotonin-reuptake inhibitor, over a 6-week period. Patients were assigned in a 1:1 ratio to receive two separate doses of 25 mg of psilocybin 3 weeks apart plus 6 weeks of daily placebo (psilocybin group) or two separate doses of 1 mg of psilocybin 3 weeks apart plus 6 weeks of daily oral escitalopram (escitalopram group); all the patients received psychological support. The primary outcome was the change from baseline in the score on the 16-item Quick Inventory of Depressive Symptomatology-Self-Report (QIDS-SR-16; scores range from 0 to 27, with higher scores indicating greater depression) at week 6. There were 16 secondary outcomes, including QIDS-SR-16 response (defined as a reduction in score of >50%) and QIDS-SR-16 remission (defined as a score of ≤5) at week 6.
Results: A total of 59 patients were enrolled; 30 were assigned to the psilocybin group and 29 to the escitalopram group. The mean scores on the QIDS-SR-16 at baseline were 14.5 in the psilocybin group and 16.4 in the escitalopram group. The mean (±SE) changes in the scores from baseline to week 6 were -8.0±1.0 points in the psilocybin group and -6.0±1.0 in the escitalopram group, for a between-group difference of 2.0 points (95% confidence interval [CI], -5.0 to 0.9) (P = 0.17). A QIDS-SR-16 response occurred in 70% of the patients in the psilocybin group and in 48% of those in the escitalopram group, for a between-group difference of 22 percentage points (95% CI, -3 to 48); QIDS-SR-16 remission occurred in 57% and 28%, respectively, for a between-group difference of 28 percentage points (95% CI, 2 to 54). Other secondary outcomes generally favored psilocybin over escitalopram, but the analyses were not corrected for multiple comparisons. The incidence of adverse events was similar in the trial groups.
Conclusions: On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Secondary outcomes generally favored psilocybin over escitalopram, but the analyses of these outcomes lacked correction for multiple comparisons. Larger and longer trials are required to compare psilocybin with established antidepressants.
Carhart-Harris, R., Giribaldi, B., Watts, R., Baker-Jones, M., Murphy-Beiner, A., Murphy, R., Martell, J., Blemings, A., Erritzoe, D., & Nutt, D. J. (2021). Trial of Psilocybin versus Escitalopram for Depression. The New England journal of medicine, 384(15), 1402–1411. https://doi.org/10.1056/NEJMoa2032994
