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The Use of Classic Hallucinogens/Psychedelics in a Therapeutic Context: Healthcare Policy Opportunities and Challenges

Abstract

Psychedelics or serotonergic hallucinogens are a group of substances that share the agonism of serotonergic 5-HT2A receptors as their main mechanism of action. Its main effects include changes in perception, cognitive process, and mood. Despite being used for centuries by different cultures in ritual contexts, these substances have currently aroused the interest of science and industry for their promising antidepressant, anxiolytic, and anti-addictive effects. Considering this evidence, this article aims to explore some of the possible health policy challenges to integrate these therapeutic tools into broad and heterogeneous health systems. As a main benefit, these substances produce rapid and enduring effects with the administration of single or few doses, which could lead to new treatment possibilities for patients with severe mental disorders resistant to the usual medications. The main challenge is associated with the fact that these substances remain scheduled in most countries and are associated with social stigma related to their recreational use (especially LSD and psilocybin). This situation makes it exceedingly difficult to conduct clinical trials, although international conventions allow such research. Ethically, this could be interpreted as a violation of human rights since thousands of people are prevented from having access to possible benefits. Interestingly, ritual ayahuasca use is more acceptable to the public than the use of psilocybin-containing mushrooms or LSD. The controlled, clinical use of LSD and psilocybin seems to be less criticized and is being explored by the industry. Rigorous scientific evidence coupled with industrial interests (LSD and psilocybin), together with respect for traditional uses (ayahuasca) and international conventions, seems to be the best way for these drugs to be integrated into health systems in the next years. Which highlights the need for an urgent dialogue between science, health system, society, and politics.

Dos Santos, R. G., Bouso, J. C., Rocha, J. M., Rossi, G. N., & Hallak, J. E. (2021). The Use of Classic Hallucinogens/Psychedelics in a Therapeutic Context: Healthcare Policy Opportunities and Challenges. Risk management and healthcare policy, 14, 901–910. https://doi.org/10.2147/RMHP.S300656

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The Evolved Psychology of Psychedelic Set and Setting: Inferences Regarding the Roles of Shamanism and Entheogenic Ecopsychology

Abstract

This review illustrates the relevance of shamanism and its evolution under effects of psilocybin as a framework for identifying evolved aspects of psychedelic set and setting. Effects of 5HT2 psychedelics on serotonin, stress adaptation, visual systems and personality illustrate adaptive mechanisms through which psychedelics could have enhanced hominin evolution as an environmental factor influencing selection for features of our evolved psychology. Evolutionary psychology perspectives on ritual, shamanism and psychedelics provides bases for inferences regarding psychedelics’ likely roles in hominin evolution as exogenous neurotransmitter sources through their effects in selection for innate dispositions for psychedelic set and setting. Psychedelics stimulate ancient brain structures and innate modular thought modules, especially self-awareness, other awareness, “mind reading,” spatial and visual intelligences. The integration of these innate modules are also core features of shamanism. Cross-cultural research illustrates shamanism is an empirical phenomenon of foraging societies, with its ancient basis in collective hominid displays, ritual alterations of consciousness, and endogenous healing responses. Shamanic practices employed psychedelics and manipulated extrapharmacological effects through stimulation of serotonin and dopamine systems and augmenting processes of the reptilian and paleomammalian brains. Differences between chimpanzee maximal displays and shamanic rituals reveal a zone of proximal development in hominin evolution. The evolution of the mimetic capacity for enactment, dance, music, and imitation provided central capacities underlying shamanic performances. Other chimp-human differences in ritualized behaviors are directly related to psychedelic effects and their integration of innate modular thought processes. Psychedelics and other ritual alterations of consciousness stimulate these and other innate responses such as soul flight and death-and-rebirth experiences. These findings provided bases for making inferences regarding foundations of our evolved set, setting and psychology. Shamanic setting is eminently communal with singing, drumming, dancing and dramatic displays. Innate modular thought structures are prominent features of the set of shamanism, exemplified in animism, animal identities, perceptions of spirits, and psychological incorporation of spirit others. A shamanic-informed psychedelic therapy includes: a preparatory set with practices such as sexual abstinence, fasting and dream incubation; a set derived from innate modular cognitive capacities and their integration expressed in a relational animistic worldview; a focus on internal imagery manifesting a presentational intelligence; and spirit relations involving incorporation of animals as personal powers. Psychedelic research and treatment can adopt this shamanic biogenetic paradigm to optimize set, setting and ritual frameworks to enhance psychedelic effects.

Winkelman M. J. (2021). The Evolved Psychology of Psychedelic Set and Setting: Inferences Regarding the Roles of Shamanism and Entheogenic Ecopsychology. Frontiers in pharmacology, 12, 619890. https://doi.org/10.3389/fphar.2021.619890

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Trends in the Top-Cited Articles on Classic Psychedelics

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

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

Abstract

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

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

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How psychedelic researchers’ self-admitted substance use and their association with psychedelic culture affect people’s perceptions of their scientific integrity and the quality of their research

Abstract

Across three studies (total N = 952), we tested how self-admitted use of psychedelics and association with psychedelic culture affects the public’s evaluation of researchers’ scientific integrity and of the quality of their research. In Studies 1 and 2, we found that self-admitted substance use negatively affected people’s assessment of a fictitious researcher’s integrity (i.e. being unbiased, professional, and honest), but not of the quality of his research, or how much value and significance they ascribed to the findings. Study 3, however, found that an association with psychedelic culture (i.e. presenting work at a scientific conference that includes social activities stereotypically associated with psychedelic culture) negatively affected perceived research quality (e.g. less valid, true, unbiased). We further found that the latter effect was moderated by participants’ personal experience with psychedelic substances: only participants without such experience evaluated research quality more negatively when it was presented in a stereotyped context.

Forstmann, M., & Sagioglou, C. (2021). How psychedelic researchers’ self-admitted substance use and their association with psychedelic culture affect people’s perceptions of their scientific integrity and the quality of their research. Public understanding of science (Bristol, England), 30(3), 302–318. https://doi.org/10.1177/0963662520981728

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The entropic tongue: Disorganization of natural language under LSD

Abstract

Serotonergic psychedelics have been suggested to mirror certain aspects of psychosis, and, more generally, elicit a state of consciousness underpinned by increased entropy of on-going neural activity. We investigated the hypothesis that language produced under the effects of lysergic acid diethylamide (LSD) should exhibit increased entropy and reduced semantic coherence. Computational analysis of interviews conducted at two different time points after 75 μg of intravenous LSD verified this prediction. Non-semantic analysis of speech organization revealed increased verbosity and a reduced lexicon, changes that are more similar to those observed during manic psychoses than in schizophrenia, which was confirmed by direct comparison with reference samples. Importantly, features related to language organization allowed machine learning classifiers to identify speech under LSD with accuracy comparable to that obtained by examining semantic content. These results constitute a quantitative and objective characterization of disorganized natural speech as a landmark feature of the psychedelic state.

Sanz, C., Pallavicini, C., Carrillo, F., Zamberlan, F., Sigman, M., Mota, N., Copelli, M., Ribeiro, S., Nutt, D., Carhart-Harris, R., & Tagliazucchi, E. (2021). The entropic tongue: Disorganization of natural language under LSD. Consciousness and cognition, 87, 103070. https://doi.org/10.1016/j.concog.2020.103070

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The History of Psychedelics in Psychiatry

Abstract

Initial interest in the value of psychedelic drugs (“psychotomimetics”) in psychiatry began in the early 20th century, with explorations of the possibility that mescaline or peyote could produce psychosis-like effects. Over time, interest was focused on whether the effects of psychedelics could inform as to the underlying basis for psychiatric disorders. As research continued, and especially after the discovery of LSD in 1943, increasing interest in a role for psychedelics as adjuncts to psychotherapy began to evolve and became the major focus of work with psychedelics up to the present day.

Nichols, D. E., & Walter, H. (2021). The History of Psychedelics in Psychiatry. Pharmacopsychiatry, 54(4), 151–166. https://doi.org/10.1055/a-1310-3990

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Prescribing meaning: hedonistic perspectives on the therapeutic use of psychedelic-assisted meaning enhancement

Abstract

The recent renaissance in research on psychedelic-assisted psychotherapy is showing great promise for the treatment of many psychiatric conditions. Interestingly, therapeutic outcomes for patients undergoing these treatments are predicted by the occurrence of a mystical experience-an experience characterised in part by a sense of profound meaning. This has led to hypotheses that psychedelic-assisted psychotherapy is therapeutic because it enhances perception of meaning, and consequently leads to a meaning response (a therapeutic mechanism that has been well described in the philosophical literature on the placebo effect). The putative mechanism of action of psychedelics as meaning enhancers raises normative ethical questions as to whether it can be justified to pharmacologically increase the perception of meaning in order to heal patients. Using the perspectives of hedonistic moral theories, this paper argues that if psychedelics operate as meaning enhancers, psychedelic-assisted psychotherapy can be ethically justified. An anti-hedonistic objection is presented by applying Robert Nozick’s Experience Machine thought experiment to the case of psychedelic-assisted psychotherapy. However, it is argued that this objection falls short for two reasons. First, even if pleasure and pain are not the only consequences which have moral value they are not morally irrelevant, therefore, therapeutic meaning enhancement can still be justified in cases of extreme suffering. Second, it is possible that psychedelic states of consciousness do not represent a false reality, hence their therapeutic meaning enhancement is not problematic according to Nozick’s standards.

Miceli McMillan R. (2021). Prescribing meaning: hedonistic perspectives on the therapeutic use of psychedelic-assisted meaning enhancement. Journal of medical ethics, 47(10), 701–705. https://doi.org/10.1136/medethics-2020-106619

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Psychedelics and virtual reality: parallels and applications

Abstract

Psychedelic drugs and virtual reality (VR) each have the capacity to disrupt the rigidity and limitations of typical conscious experience. This article delineates the parallels among psychedelic and VR states as well as their potential synergistic applications in clinical and recreational settings. Findings indicate that, individually, psychedelics and VR are used in analogous ways to alter sensory experience and evoke awe. They are also both used in tandem with traditional therapies to treat a variety of mood disorders; their shared capacity to transiently alter perspective and disrupt rigid patterns of mental experience may underly their analogous and transdiagnostic therapeutic uses. In terms of their combined applications, a number of recreational users currently utilize psychedelics and VR together to enhance their experience. We propose that VR may be a useful tool for preparing hallucinogen-naïve participants in clinical trials for the sensory distortions experienced in psychedelic states. Given the critical role of “setting” in psychedelic treatment outcomes, we also detail how VR could be used to optimize the environment in psychedelic sessions. Finally, we provide considerations for future studies and detail how advancements in psychedelic and VR research can inform one another. Collectively, this article outlines a number of connections between psychedelics and VR, and, more broadly, is representative of growing scientific interest into the interactions among technology, psychopharmacology, and mental health.

Aday, J. S., Davoli, C. C., & Bloesch, E. K. (2020). Psychedelics and virtual reality: parallels and applications. Therapeutic advances in psychopharmacology, 10, 2045125320948356. https://doi.org/10.1177/2045125320948356

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30 April - Q&A with Rick Strassman

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