OPEN Foundation

Mushrooms / Psilocybin

Truffle therapy in the Netherlands is running ahead of the science

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

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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Harnessing psilocybin: antidepressant-like behavioral and synaptic actions of psilocybin are independent of 5-HT2R activation in mice

Abstract

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

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Trial of Psilocybin versus Escitalopram for Depression

Abstract

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

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Spontaneous and deliberate creative cognition during and after psilocybin exposure

Abstract

Creativity is an essential cognitive ability linked to all areas of our everyday functioning. Thus, finding a way to enhance it is of broad interest. A large number of anecdotal reports suggest that the consumption of psychedelic drugs can enhance creative thinking; however, scientific evidence is lacking. Following a double-blind, placebo-controlled, parallel-group design, we demonstrated that psilocybin (0.17 mg/kg) induced a time- and construct-related differentiation of effects on creative thinking. Acutely, psilocybin increased ratings of (spontaneous) creative insights, while decreasing (deliberate) task-based creativity. Seven days after psilocybin, number of novel ideas increased. Furthermore, we utilized an ultrahigh field multimodal brain imaging approach, and found that acute and persisting effects were predicted by within- and between-network connectivity of the default mode network. Findings add some support to historical claims that psychedelics can influence aspects of the creative process, potentially indicating them as a tool to investigate creativity and subsequent underlying neural mechanisms. Trial NL6007; psilocybin as a tool for enhanced cognitive flexibility; https://www.trialregister.nl/trial/6007 .

Mason, N. L., Kuypers, K., Reckweg, J. T., Müller, F., Tse, D., Da Rios, B., Toennes, S. W., Stiers, P., Feilding, A., & Ramaekers, J. G. (2021). Spontaneous and deliberate creative cognition during and after psilocybin exposure. Translational psychiatry, 11(1), 209. https://doi.org/10.1038/s41398-021-01335-5

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Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action

Abstract

Major depressive disorder (MDD) is among the most prevalent mental health disorders worldwide, and it is associated with a reduced quality of life and enormous costs to health care systems. Available drug treatments show low-to-moderate response in most patients, with almost a third of patients being non-responders (treatment-resistant). Furthermore, most currently available medications need several weeks to achieve therapeutic effects, and the long-term use of these drugs is often associated with significant unwanted side effects and resultant reductions in treatment compliance. Therefore, more effective, safer, and faster-acting antidepressants with enduring effects are needed. Together with ketamine, psychedelics (or classic or serotoninergic hallucinogens) such as lysergic acid diethylamide (LSD), psilocybin, and ayahuasca are among the few compounds with recent human evidence of fast-acting antidepressant effects. Several studies in the 1950s to 1970s reported antidepressive and anxiolytic effects of these drugs, which are being confirmed by modern trials (LSD, one trial; psilocybin, five trials; ayahuasca, two trials). The effects of these drugs appear to be produced primarily by their agonism at serotonin (5-hydroxytryptamine, 5-HT) receptors, especially the 5-HT2A receptor. Considering the overall burden of MDD and the necessity of new therapeutic options, the promising (but currently limited) evidence of safety and efficacy of psychedelics has encouraged the scientific community to explore more fully their beneficial effects in MDD.

Dos Santos, R. G., Hallak, J. E., Baker, G., & Dursun, S. (2021). Hallucinogenic/psychedelic 5HT2A receptor agonists as rapid antidepressant therapeutics: Evidence and mechanisms of action. Journal of psychopharmacology (Oxford, England), 35(4), 453–458. https://doi.org/10.1177/0269881120986422

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Acute and Sustained Reductions in Loss of Meaning and Suicidal Ideation Following Psilocybin-Assisted Psychotherapy for Psychiatric and Existential Distress in Life-Threatening Cancer

Abstract

People with advanced cancer are at heightened risk of desire for hastened death (DHD), suicidal ideation (SI), and completed suicide. Loss of Meaning (LoM), a component of demoralization, can be elevated by a cancer diagnosis and predicts DHD and SI in this population. We completed a randomized controlled trial in which psilocybin-assisted psychotherapy (PAP) produced rapid and sustained improvements in depression, demoralization, and hopelessness in people with cancer. Converging epidemiologic and clinical trial findings suggests a potential antisuicidal effect of this treatment. To probe our hypothesis that PAP relieves SI through its beneficial impacts on depression and demoralization (LoM in particular), we performed secondary analyses assessing within- and between-group differences with regard to LoM and an SI composite score. Among participants with elevated SI at baseline, PAP was associated with within-group reductions in SI that were apparent as early as 8 h and persisted for 6.5 months postdosing. PAP also produced large reductions in LoM from baseline that were apparent 2 weeks after treatment and remained significant and robust at the 6.5 month and 3.2 and 4.5 year follow-ups. Exploratory analyses support our hypothesis and suggest that PAP may be an effective antisuicidal intervention following a cancer diagnosis due to its positive impact on hopelessness and demoralization and its effects on meaning-making in particular. These preliminary results implicate psilocybin treatment as a potentially effective alternative to existing antidepressant medications in patients with cancer that are also suicidal, and warrant further investigation in participants with elevated levels of depression and suicidality.

Ross, S., Agin-Liebes, G., Lo, S., Zeifman, R. J., Ghazal, L., Benville, J., Franco Corso, S., Bjerre Real, C., Guss, J., Bossis, A., & Mennenga, S. E. (2021). Acute and Sustained Reductions in Loss of Meaning and Suicidal Ideation Following Psilocybin-Assisted Psychotherapy for Psychiatric and Existential Distress in Life-Threatening Cancer. ACS pharmacology & translational science, 4(2), 553–562. https://doi.org/10.1021/acsptsci.1c00020

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Chemoenzymatic Synthesis of 5-Methylpsilocybin: A Tryptamine with Potential Psychedelic Activity

Abstract

A novel analogue of psilocybin was produced by hybrid chemoenzymatic synthesis in sufficient quantity to enable bioassay. Utilizing purified 4-hydroxytryptamine kinase from Psilocybe cubensis, chemically synthesized 5-methylpsilocin (2) was enzymatically phosphorylated to provide 5-methylpsilocybin (1). The zwitterionic product was isolated from the enzymatic step with high purity utilizing a solvent-antisolvent precipitation approach. Subsequently, 1 was tested for psychedelic-like activity using the mouse head-twitch response assay, which indicated activity that was more potent than the psychedelic dimethyltryptamine, but less potent than that of psilocybin.

Fricke, J., Sherwood, A. M., Halberstadt, A. L., Kargbo, R. B., & Hoffmeister, D. (2021). Chemoenzymatic Synthesis of 5-Methylpsilocybin: A Tryptamine with Potential Psychedelic Activity. Journal of natural products, 84(4), 1403–1408. https://doi.org/10.1021/acs.jnatprod.1c00087

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Dose-response relationships of psilocybin-induced subjective experiences in humans

Abstract

Background: Psilocybin is the psychoactive component in Psilocybe mushrooms (‘magic mushrooms’). Whether and how the quality of the psilocybin-induced experience might mediate beneficial health outcomes is currently under investigation, for example, in therapeutic applications. However, to date, no meta-analysis has investigated the dose-dependency of subjective experiences across available studies.

Aim: Establishing dose-response relationships of the subjective experiences induced by psilocybin in healthy study participants and a comparison of patient groups.

Method: We applied a linear meta-regression approach, based on the robust variance estimation framework, to obtain linear dose-response relationship estimates on questionnaire ratings after oral psilocybin administration. Data were obtained from the Altered States Database, which contains data extracted from MEDLINE-listed journal articles that used standardized and validated questionnaires: the Altered States of Consciousness Rating Scale, the Mystical Experience Questionnaire and the Hallucinogen Rating Scale.

Results: Psilocybin dose positively correlated with ratings on most factors and scales, mainly those referring to perceptual alterations and positively experienced ego dissolution. Measures referring to challenging experiences exhibited small effects and were barely modulated by dose.

Conclusion: Psilocybin intensified almost all characteristics of altered states of consciousness assessed with the given questionnaires. Because subjective experiences are not only determined by dose, but also by individual and environmental factors, the results may only apply to controlled laboratory experiments and not to recreational use. This paper may serve as a general literature citation for the use of psilocybin in experimental and clinical research, to compare expected and observed subjective experiences.

Hirschfeld, T., & Schmidt, T. T. (2021). Dose-response relationships of psilocybin-induced subjective experiences in humans. Journal of psychopharmacology (Oxford, England), 35(4), 384–397. https://doi.org/10.1177/0269881121992676

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Low Doses of Psilocybin and Ketamine Enhance Motivation and Attention in Poor Performing Rats: Evidence for an Antidepressant Property

Abstract

Long term benefits following short-term administration of high psychedelic doses of serotonergic and dissociative hallucinogens, typified by psilocybin and ketamine respectively, support their potential as treatments for psychiatric conditions such as major depressive disorder. The high psychedelic doses induce perceptual experiences which are associated with therapeutic benefit. There have also been anecdotal reports of these drugs being used at what are colloquially referred to as “micro” doses to improve mood and cognitive function, although currently there are recognized limitations to their clinical and preclinical investigation. In the present studies we have defined a low dose and plasma exposure range in rats for both ketamine (0.3-3 mg/kg [10-73 ng/ml]) and psilocybin/psilocin (0.05-0.1 mg/kg [7-12 ng/ml]), based on studies which identified these as sub-threshold for the induction of behavioral stereotypies. Tests of efficacy were focused on depression-related endophenotypes of anhedonia, amotivation and cognitive dysfunction using low performing male Long Evans rats trained in two food motivated tasks: a progressive ratio (PR) and serial 5-choice (5-CSRT) task. Both acute doses of ketamine (1-3 mg/kg IP) and psilocybin (0.05-0.1 mg/kg SC) pretreatment increased break point for food (PR task), and improved attentional accuracy and a measure of impulsive action (5-CSRT task). In each case, effect size was modest and largely restricted to test subjects characterized as “low performing”. Furthermore, both drugs showed a similar pattern of effect across both tests. The present studies provide a framework for the future study of ketamine and psilocybin at low doses and plasma exposures, and help to establish the use of these lower concentrations of serotonergic and dissociative hallucinogens both as a valid scientific construct, and as having a therapeutic utility.

Higgins, G. A., Carroll, N. K., Brown, M., MacMillan, C., Silenieks, L. B., Thevarkunnel, S., Izhakova, J., Magomedova, L., DeLannoy, I., & Sellers, E. M. (2021). Low Doses of Psilocybin and Ketamine Enhance Motivation and Attention in Poor Performing Rats: Evidence for an Antidepressant Property. Frontiers in pharmacology, 12, 640241. https://doi.org/10.3389/fphar.2021.640241

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