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What is the clinical evidence on psilocybin for the treatment of psychiatric disorders? A systematic review

June 17, 2022 / Depressive Disorders, Mushrooms / Psilocybin, Papers, Substance Use Disorder / Leave a Comment / By / ,

Abstract

Background: Psilocybin is a predominant agonist of 5HT1A and 5HT2A/C receptors and was first isolated in 1958, shortly before it became a controlled substance. Research on the potential therapeutic effects of this compound has recently re-emerged alongside what is being addressed as a psychedelic renaissance.

Methods: In this paper we performed a systematic review of the clinical trials conducted so far regarding the therapeutic effects of psilocybin on psychiatric disorders. The eligibility criteria included clinical trials that assessed psilocybin’s potential therapeutic effects on patients with psychiatric disorders. Nine hundred seven articles were found and screened in regard to the title, from which 94 were screened through abstract and 9 met the eligibility criteria and were included.

Results: The papers published focused on 3 disorders: depression, obsessive-compulsive disorder (OCD) and substance use disorder (namely tobacco and alcohol). Psilocybin has shown a relatively safe profile and very promising results, with reductions found on most of the psychiatric rating scales’ scores. Research on depression showed the most solid evidence, supported by 3 randomized controlled trials. Studies on OCD and substance use disorder showed more limitations due to their open-label design.

Conclusions: Altogether, the results from the studies reviewed in this paper suggest a substantial therapeutic potential. This calls for further research to confirm the results observed so far and further explain the underlying mechanisms.

Castro Santos, H., & Gama Marques, J. (2021). What is the clinical evidence on psilocybin for the treatment of psychiatric disorders? A systematic review. Porto biomedical journal, 6(1), e128. https://doi.org/10.1097/j.pbj.0000000000000128

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Neural and subjective effects of inhaled N,N-dimethyltryptamine in natural settings

February 6, 2022 / DMT, Neuroscience, Papers / Leave a Comment / By / , , , , , , , , , ,

Abstract

Background: N,N-dimethyltryptamine is a short-acting psychedelic tryptamine found naturally in many plants and animals. Few studies to date have addressed the neural and psychological effects of N,N-dimethyltryptamine alone, either administered intravenously or inhaled in freebase form, and none have been conducted in natural settings.

Aims: Our primary aim was to study the acute effects of inhaled N,N-dimethyltryptamine in natural settings, focusing on questions tuned to the advantages of conducting field research, including the effects of contextual factors (i.e. “set” and “setting”), the possibility of studying a comparatively large number of subjects, and the relaxed mental state of participants consuming N,N-dimethyltryptamine in familiar and comfortable settings.

Methods: We combined state-of-the-art wireless electroencephalography with psychometric questionnaires to study the neural and subjective effects of naturalistic N,N-dimethyltryptamine use in 35 healthy and experienced participants.

Results: We observed that N,N-dimethyltryptamine significantly decreased the power of alpha (8-12 Hz) oscillations throughout all scalp locations, while simultaneously increasing power of delta (1-4 Hz) and gamma (30-40 Hz) oscillations. Gamma power increases correlated with subjective reports indicative of some features of mystical-type experiences. N,N-dimethyltryptamine also increased global synchrony and metastability in the gamma band while decreasing those measures in the alpha band.

Conclusions: Our results are consistent with previous studies of psychedelic action in the human brain, while at the same time the results suggest potential electroencephalography markers of mystical-type experiences in natural settings, thus highlighting the importance of investigating these compounds in the contexts where they are naturally consumed.

Pallavicini, C., Cavanna, F., Zamberlan, F., de la Fuente, L. A., Ilksoy, Y., Perl, Y. S., Arias, M., Romero, C., Carhart-Harris, R., Timmermann, C., & Tagliazucchi, E. (2021). Neural and subjective effects of inhaled N,N-dimethyltryptamine in natural settings. Journal of psychopharmacology (Oxford, England), 35(4), 406–420. https://doi.org/10.1177/0269881120981384

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Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects

February 6, 2022 / Papers, Salvia / Salvinorin A / Leave a Comment / By / , , , ,

Abstract

Salvia divinorum Epling and Játiva is a perennial mint from the Lamiaceae family, endemic to Mexico, predominantly from the state of Oaxaca. Due to its psychoactive properties, S. divinorum had been used for centuries by Mazatecans for divinatory, religious, and medicinal purposes. In recent years, its use for recreational purposes, especially among adolescents and young adults, has progressively increased. The main bioactive compound underlying the hallucinogenic effects, salvinorin A, is a non-nitrogenous diterpenoid with high affinity and selectivity for the k-opioid receptor. The aim of this work is to comprehensively review and discuss the toxicokinetics and toxicodynamics of S. divinorum and salvinorin A, highlighting their psychological, physiological, and toxic effects. Potential therapeutic applications and forensic aspects are also covered in this review. The leaves of S. divinorum can be chewed, drunk as an infusion, smoked, or vaporised. Absorption of salvinorin A occurs through the oral mucosa or the respiratory tract, being rapidly broken down in the gastrointestinal system to its major inactive metabolite, salvinorin B, when swallowed. Salvinorin A is rapidly distributed, with accumulation in the brain, and quickly eliminated. Its pharmacokinetic parameters parallel well with the short-lived psychoactive and physiological effects. No reports on toxicity or serious adverse outcomes were found. A variety of therapeutic applications have been proposed for S. divinorum which includes the treatment of chronic pain, gastrointestinal and mood disorders, neurological diseases, and treatment of drug dependence. Notwithstanding, there is still limited knowledge regarding the pharmacology and toxicology features of S. divinorum and salvinorin A, and this is needed due to its widespread use. Additionally, the clinical acceptance of salvinorin A has been hampered, especially due to the psychotropic side effects and misuse, turning the scientific community to the development of analogues with better pharmacological profiles.

Brito-da-Costa, A. M., Dias-da-Silva, D., Gomes, N., Dinis-Oliveira, R. J., & Madureira-Carvalho, Á. (2021). Pharmacokinetics and Pharmacodynamics of Salvinorin A and Salvia divinorum: Clinical and Forensic Aspects. Pharmaceuticals (Basel, Switzerland), 14(2), 116. https://doi.org/10.3390/ph14020116

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Trends in the Top-Cited Articles on Classic Psychedelics

February 6, 2022 / Papers / Leave a Comment / By / , , ,

Abstract

This study was designed to identify trends in the top-cited classic psychedelic publications. The top 50 publications on classic psychedelics with the greatest total of number of citations and annual citation rate were identified and pooled. Unique articles (n = 76) were dichotomized by median year of publication (2010.5); the differential distribution of study characteristics between the “Recent Cohort” (n = 38) and “Older Cohort” (n = 38) were documented. The Recent Cohort had a greater annual citation rate (median 76.0, IQR 38.5 to 101.5) compared to the Older Cohort (median10.0, IQR 5.2 to 19.3, p < .001). The Recent Cohort included a greater number of clinical studies (n = 26 [68.4%] vs. n = 9 [23.7%]) while the Older Cohort included more basic science and preclinical studies (n = 21 [55.3%] vs. n = 2 [5.3%], p < .001). Psilocybin was the predominant psychedelic studied in the Recent Cohort (n = 25 [65.8%] vs. n = 9 [23.7%]) while lysergic acid diethylamide (LSD) was predominantly studied in the Older Cohort (n = 25 [65.8%] vs. n = 18 [47.4%], p = .013). The Recent Cohort included more studies examining affective disorders (n = 15 [39.5%] vs. n = 3 [7.9%]) and substance use disorders (n = 6 [15.8%] vs. n = 0 [0.0%]), while the Older Cohort included a greater number of pharmacological outcomes (n = 29 [76.3%] vs. n = 6 [15.8%], p < .001). This study identified and documented trends in the top-cited classic psychedelic publications. The field is continuing to form a foundational understanding of the pharmacological effects of psychedelics and is now advancing with the identification of therapeutic uses within clinical populations.

Lawrence, D. W., Sharma, B., Griffiths, R. R., & Carhart-Harris, R. (2021). Trends in the Top-Cited Articles on Classic Psychedelics. Journal of psychoactive drugs, 53(4), 283–298. https://doi.org/10.1080/02791072.2021.1874573

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Development and Evaluation of a Therapist Training Program for Psilocybin Therapy for Treatment-Resistant Depression in Clinical Research

February 21, 2022 / Depressive Disorders, Mushrooms / Psilocybin, Papers / Leave a Comment / By / , , , , , , , , ,

Abstract

Introduction: Psychological support throughout psilocybin therapy is mandated by regulators as an essential part of ensuring participants’ physical and psychological safety. There is an increased need for specially trained therapists who can provide high-quality care to participants in clinical studies. This paper describes the development and practical implementation of a therapist training program of psychological support within a current phase IIb international, multicenter, randomized controlled study of psilocybin therapy for people experiencing treatment-resistant depression. Description of Training Program: This new and manualized approach, based on current evidence-based psychotherapeutic approaches, was developed in partnership with different mental health researchers, practitioners, and experts; and has been approved by the FDA. Training consists of four components: an online learning platform; in-person training; applied clinical training; and ongoing individual mentoring and participation in webinars.This paper provides a brief overview of the method of support, the rationale and methodology of the training program, and describes each stage of training. The design and implementation of fidelity procedures are also outlined. Lessons Learned: As part of the phase IIb study of psilocybin therapy for treatment-resistant depression, 65 health care professionals have been fully trained as therapists and assisting therapists, across the US, Canada and Europe. Therapists provided informal feedback on the training program. Feedback indicates that the didactic and experiential interactive learning, delivered through a combination of online and in-person teaching, helped therapists build conceptual understanding and skill development in the therapeutic approach. Clinical training and engagement in participant care, under the guidance of experienced therapists, were considered the most beneficial and challenging aspects of the training. Conclusions: Clinical training for therapists is essential for ensuring consistently high-quality psilocybin therapy. Development of a rigorous, effective and scalable training methodology has been possible through a process of early, active and ongoing collaborations between mental health experts. To maximize impact and meet phase III and post-approval need, enhanced online learning and establishing pathways for clinical training are identified as critical points for quality assurance. This will require close public, academic and industry collaboration.

Tai, S. J., Nielson, E. M., Lennard-Jones, M., Johanna Ajantaival, R. L., Winzer, R., Richards, W. A., Reinholdt, F., Richards, B. D., Gasser, P., & Malievskaia, E. (2021). Development and Evaluation of a Therapist Training Program for Psilocybin Therapy for Treatment-Resistant Depression in Clinical Research. Frontiers in psychiatry, 12, 586682. https://doi.org/10.3389/fpsyt.2021.586682

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Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission

February 6, 2022 / LSD, Neuroscience, Papers, Psychology / Leave a Comment / By / , , , , , , , , , , , , , ,

Abstract

Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT2A, but not N-methyl-D-aspartate (NMDA) and 5-HT1A, synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons (Raptor f/f :Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC (Raptor f/f :Gad2-Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.

De Gregorio, D., Popic, J., Enns, J. P., Inserra, A., Skalecka, A., Markopoulos, A., Posa, L., Lopez-Canul, M., Qianzi, H., Lafferty, C. K., Britt, J. P., Comai, S., Aguilar-Valles, A., Sonenberg, N., & Gobbi, G. (2021). Lysergic acid diethylamide (LSD) promotes social behavior through mTORC1 in the excitatory neurotransmission. Proceedings of the National Academy of Sciences of the United States of America, 118(5), e2020705118. https://doi.org/10.1073/pnas.2020705118

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Psychedelics, placebo effects, and set and setting: Insights from common factors theory of psychotherapy

February 6, 2022 / Papers / Leave a Comment / By / ,

Abstract

Psychedelic-assisted treatment is at first glance markedly different in structure and approach from mainstream forms of psychotherapy in the West. A major criticism of clinical psychedelic research rests on the difficulty of executing placebo-controlled studies and distinguishing drug effects from those of the psychotherapeutic container in which psychedelics are typically presented. Detractors also tend to find fault in spiritual or mystical themes that often arise in the context of psychedelic use. Common factors theory of psychotherapy is a useful and extensively studied framework that can help make sense of these issues, and has much to contribute to our understanding of contextual effects that are often discussed in psychedelic literature as “set and setting.” In this article, we examine four major contextual “common factors” shared by various healing traditions: 1) the therapeutic relationship; 2) the healing setting; 3) the rationale, conceptual scheme, or myth; and 4) the ritual. We explain how these factors show up in psychedelic-assisted treatment and how they may contribute to therapeutic effects. Lastly, we discuss the implications of these factors for the concept of placebo, and for future research.

Gukasyan, N., & Nayak, S. M. (2021). Psychedelics, placebo effects, and set and setting: Insights from common factors theory of psychotherapy. Transcultural psychiatry, 1363461520983684. Advance online publication. https://doi.org/10.1177/1363461520983684

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Harmine inhibits the proliferation and migration of glioblastoma cells via the FAK/AKT pathway

March 14, 2022 / Papers, Psychiatry & Medicine / Leave a Comment / By / , , , , , , ,

Abstract

Aims: Glioblastoma is one of the most invasive tumors of the central nervous system, and has a high degree of malignancy and poor prognosis. Harmine, an active ingredient extracted from perennial herbs, has been reported to have obvious antitumor effects on various tumors. However, the effects of harmine on glioblastoma growth remain unknown. We here explored the effects of harmine on glioblastoma and its underlying molecular mechanisms related to tumorigenesis.

Materials and methods: CCK-8 and immunofluorescent assay were performed to measure anti-proliferative effect of harmine on U251-MG and U373-MG cells. Wound healing assay was performed to measure the effects of harmine on cell migration. qRT-PCR and western blot were performed to detect the protein/gene expression. BALB/c nude mice bearing U251-MG xenografts was used to measure the effects of harmine on the growth of glioblastoma in vivo.

Key findings: Harmine treatment significantly suppressed the proliferation of U251-MG and U373-MG cells in a dose and time-dependent way. Mechanistically, harmine reduced the basal and EGF-enhanced the phosphorylation level of FAK and AKT. Moreover, harmine inhibited the cell viability of U251-MG and U373-MG cells by downregulating the phosphorylation of the FAK/AKT pathway. Besides, harmine significantly suppressed the migration of U251-MG cells by suppressing the expression of MMP2, MMP9 and VEGF. Subsequently, orthotopic xenograft models revealed that harmine treatment dramatically inhibited the growth of glioblastoma in vivo.

Significance: In conclusion, these results suggest that harmine suppresses the proliferation and migration of U251-MG and U373-MG cells by inhibiting the FAK/AKT signaling pathway. Our findings elucidate harmine could be a promising drug for glioblastoma therapy.

Zhu, Y. G., Lv, Y. X., Guo, C. Y., Xiao, Z. M., Jiang, Q. G., Kuang, H., Zhang, W. H., & Hu, P. (2021). Harmine inhibits the proliferation and migration of glioblastoma cells via the FAK/AKT pathway. Life sciences, 270, 119112. https://doi.org/10.1016/j.lfs.2021.119112

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Within-treatment changes in a novel addiction treatment program using traditional Amazonian medicine

March 14, 2022 / Ayahuasca, Papers, Psychology, Substance Use Disorder / Leave a Comment / By / , , , ,

Abstract

Aims: The therapeutic use of psychedelics is regaining scientific momentum, but similarly psychoactive ethnobotanical substances have a long history of medical (and other) uses in indigenous contexts. Here we aimed to evaluate patient outcomes in a residential addiction treatment center that employs a novel combination of Western and traditional Amazonian methods.

Methods: The study was observational, with repeated measures applied throughout treatment. All tests were administered in the center, which is located in Tarapoto, Peru. Data were collected between 2014 and 2015, and the study sample consisted of 36 male inpatients who were motivated to seek treatment and who entered into treatment voluntarily. Around 58% of the sample was from South America, 28% from Europe, and the remaining 14% from North America. We primarily employed repeated measures on a psychological test battery administered throughout treatment, measuring perceived stress, craving frequency, mental illness symptoms, spiritual well-being, and physical and emotional health. Addiction severity was measured on intake, and neuropsychological performance was assessed in a subsample from intake to at least 2 months into treatment.

Results: Statistically significant and clinically positive changes were found across all repeated measures. These changes appeared early in the treatment and were maintained over time. Significant improvements were also found for neuropsychological functioning.

Conclusion: These results provide evidence for treatment safety in a highly novel addiction treatment setting, while also suggesting positive therapeutic effects.

O’Shaughnessy, D. M., Berlowitz, I., Rodd, R., Sarnyai, Z., & Quirk, F. (2021). Within-treatment changes in a novel addiction treatment program using traditional Amazonian medicine. Therapeutic advances in psychopharmacology, 11, 2045125320986634. https://doi.org/10.1177/2045125320986634

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Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression

March 14, 2022 / Depressive Disorders, Ketamine, Neuroscience, Papers / Leave a Comment / By / , , , , , , , , ,

Abstract

Ketamine produces a rapid antidepressant response in over 50% of adults with treatment-resistant depression. A long infusion of ketamine may provide durable remission of depressive symptoms, but the safety, efficacy, and neurobiological correlates are unknown. In this open-label, proof-of-principle study, adults with treatment-resistant depression (N = 23) underwent a 96-h infusion of intravenous ketamine (0.15 mg/kg/h titrated toward 0.6 mg/kg/h). Clonidine was co-administered to reduce psychotomimetic effects. We measured clinical response for 8 weeks post-infusion. Resting-state functional magnetic resonance imaging was used to assess functional connectivity in patients pre- and 2 weeks post-infusion and in matched non-depressed controls (N = 27). We hypothesized that responders to therapy would demonstrate response-dependent connectivity changes while all subjects would show treatment-dependent connectivity changes. Most participants completed infusion (21/23; mean final dose 0.54 mg/kg/h, SD 0.13). The infusion was well tolerated with minimal cognitive and psychotomimetic side effects. Depressive symptoms were markedly reduced (MADRS 29 ± 4 at baseline to 9 ± 8 one day post-infusion), which was sustained at 2 weeks (13 ± 8) and 8 weeks (15 ± 8). Imaging demonstrated a response-dependent decrease in hyperconnectivity of the subgenual anterior cingulate cortex to the default mode network, and a treatment-dependent decrease in hyperconnectivity within the limbic system (hippocampus, amygdala, medial thalamus, nucleus accumbens). In exploratory analyses, connectivity was increased between the limbic system and frontal areas, and smaller right hippocampus volume at baseline predicted larger MADRS change. A single prolonged infusion of ketamine provides a tolerated, rapid, and sustained response in treatment-resistant depression and normalizes depression-related hyperconnectivity in the limbic system and frontal lobe. ClinicalTrials.gov : Treatment Resistant Depression (Pilot), NCT01179009.

Siegel, J. S., Palanca, B., Ances, B. M., Kharasch, E. D., Schweiger, J. A., Yingling, M. D., Snyder, A. Z., Nicol, G. E., Lenze, E. J., & Farber, N. B. (2021). Prolonged ketamine infusion modulates limbic connectivity and induces sustained remission of treatment-resistant depression. Psychopharmacology, 238(4), 1157–1169. https://doi.org/10.1007/s00213-021-05762-6

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