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Phenomenology

The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects

Abstract

Classic psychedelics produce altered states of consciousness that individuals often interpret as meaningful experiences. Across a number of human studies, when the participant-rated intensity of the overall drug effects are statistically controlled for, certain subjective effects predict therapeutic and other desirable outcomes. Underlying neurobiological mechanisms are likely necessary but not sufficient to confer full and enduring beneficial effects. We propose that the subjective effects of psychedelics are necessary for their enduring beneficial effects and that these subjective effects account for the majority of their benefit.

Yaden, D. B., & Griffiths, R. R. (2020). The Subjective Effects of Psychedelics Are Necessary for Their Enduring Therapeutic Effects. ACS pharmacology & translational science, 4(2), 568–572. https://doi.org/10.1021/acsptsci.0c00194

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LSD and ketanserin and their impact on the human autonomic nervous system

Abstract

The interest in lysergic acid diethylamide (LSD) has sparked again due to its supposed positive effects on psychopathological conditions. Yet, most research focuses on the actions of LSD on the central nervous system. The interaction with the autonomic nervous system (ANS) has been neglected so far. Therefore, the aim was to assess the effects of LSD and the serotonin 2A receptor antagonist ketanserin on the ANS as assessed by heart rate variability (HRV) measures and their correlation with subjective drug-induced effects in a randomized, placebo-controlled crossover trial. Thus, ANS activity was derived from electrocardiogram recordings after intake of placebo, LSD or ketanserin, and LSD by calculating R-peak-based measures of sympathetic and parasympathetic activity. Repeated measure ANOVA and partial correlation for HRV measures and subjective experience questionnaires were performed. LSD predominantly increased sympathetic activity, while ketanserin counteracted this effect on the ANS via an increase of parasympathetic tone. Sympathetic activity was positively and parasympathetic activity negatively associated with psychedelic effects of LSD. Furthermore, Placebo HRV measures predicted subjective experiences after LSD intake. The association between trait ANS activity and LSD-induced subjective experiences may serve as a candidate biomarker set for the effectiveness of LSD in the treatment of psychopathological conditions.

Olbrich, S., Preller, K. H., & Vollenweider, F. X. (2021). LSD and ketanserin and their impact on the human autonomic nervous system. Psychophysiology, 58(6), e13822. https://doi.org/10.1111/psyp.13822

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Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes

Abstract

Mescaline is a naturally occurring psychoactive alkaloid that has been used as a sacrament by Indigenous populations in spiritual ritual and healing ceremonies for millennia. Despite promising early preliminary research and favorable anecdotal reports, there is limited research investigating mescaline’s psychotherapeutic potential. We administered an anonymous online questionnaire to adults (N = 452) reporting use of mescaline in naturalistic settings about mental health benefits attributed to mescaline. We assessed respondents’ self-reported improvements in depression, anxiety, post-traumatic stress disorder (PTSD), and alcohol and drug use disorders (AUD and DUD). Of the respondents reporting histories of these clinical conditions, most (68-86%) reported subjective improvement following their most memorable mescaline experience. Respondents who reported an improvement in their psychiatric conditions reported significantly higher ratings of acute psychological factors including mystical-type, psychological insight, and ego dissolution effects compared to those who did not report improvements (Cohen’s d range 0.7 – 1.5). Many respondents (35-50%) rated the mescaline experience as the single or top five most spiritually significant or meaningful experience(s) of their lives. Acute experiences of psychological insight during their mescaline experience were associated with increased odds of reporting improvement in depression, anxiety, AUD and DUD. Additional research is needed to corroborate these preliminary findings and to rigorously examine the efficacy of mescaline for psychiatric treatment in controlled, longitudinal clinical trials.

Agin-Liebes, G., Haas, T. F., Lancelotta, R., Uthaug, M. V., Ramaekers, J. G., & Davis, A. K. (2021). Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes. ACS pharmacology & translational science, 4(2), 543–552. https://doi.org/10.1021/acsptsci.1c00018

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Clinical and biological predictors of psychedelic response in the treatment of psychiatric and addictive disorders: A systematic review

Abstract

Background: The use of psychedelic treatments has shown very promising results in some psychiatric and addictive disorders, but not all patients achieved a response.

Aim: The aim of this review is to explore the clinical and biological factors which could predict the response to psychedelics in psychiatric and addictive disorders.

Methods: A systematic research was performed on MEDLINE, PsycInfo, Web of science, and Scopus databases from January 1990 to May 2020. All studies investigating the predictive factors of response to psychedelics regardless of psychiatric or addictive disorders, were included.

Results: Twenty studies investigating addictive disorder, treatment-resistant depression, obsessive-compulsive disorder and depressive and anxiety symptoms in patients with life-threatening cancer were included in this review. We found that, in all indications, the main predictive factor of response to psychedelics is the intensity of the acute psychedelic experience. Indeed, we found this factor for alcohol and tobacco use disorders, treatment-resistant depression, and anxiety and depressive symptoms in patients with life-threatening cancer, but not for obsessive-compulsive disorder.

Conclusion: The intensity of the acute psychedelic experience was the main predicting factor of response. The action mechanism of this experience was not clear, but some hypotheses could be made, such as a modulation of serotoninergic system by 5-HT2A receptors agonism, a modulation of the default mode network (DMN) with an acute modular disintegration of the DMN followed by a re-integration of this network with a normal functioning, or an anti-inflammatory effect of this treatment.

Romeo, B., Hermand, M., Pétillion, A., Karila, L., & Benyamina, A. (2021). Clinical and biological predictors of psychedelic response in the treatment of psychiatric and addictive disorders: A systematic review. Journal of psychiatric research, 137, 273–282. https://doi.org/10.1016/j.jpsychires.2021.03.002

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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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The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects

Abstract

Psychedelics represent one of the most promising classes of experimental medicines for the treatment of neuropsychiatric disorders due to their ability to promote neural plasticity and produce both rapid and sustained therapeutic effects following a single administration. Conventional wisdom holds that peak mystical experiences induced by psychedelics are a critical component of their therapeutic mechanisms of action, though evidence supporting that claim is largely correlational. Here, I present data suggesting that the subjective effects induced by psychedelics may not be necessary to produce long-lasting changes in mood and behavior. Understanding the role of subjective effects in the therapeutic mechanisms of psychedelics will have important implications for both basic neuroscience and for increasing patient access to the next generation of medicines developed as a result of psychedelic research.

Olson D. E. (2020). The Subjective Effects of Psychedelics May Not Be Necessary for Their Enduring Therapeutic Effects. ACS pharmacology & translational science, 4(2), 563–567. https://doi.org/10.1021/acsptsci.0c00192

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Hallucinations Under Psychedelics and in the Schizophrenia Spectrum: An Interdisciplinary and Multiscale Comparison

Abstract

The recent renaissance of psychedelic science has reignited interest in the similarity of drug-induced experiences to those more commonly observed in psychiatric contexts such as the schizophrenia-spectrum. This report from a multidisciplinary working group of the International Consortium on Hallucinations Research (ICHR) addresses this issue, putting special emphasis on hallucinatory experiences. We review evidence collected at different scales of understanding, from pharmacology to brain-imaging, phenomenology and anthropology, highlighting similarities and differences between hallucinations under psychedelics and in the schizophrenia-spectrum disorders. Finally, we attempt to integrate these findings using computational approaches and conclude with recommendations for future research.

Leptourgos, P., Fortier-Davy, M., Carhart-Harris, R., Corlett, P. R., Dupuis, D., Halberstadt, A. L., Kometer, M., Kozakova, E., LarØi, F., Noorani, T. N., Preller, K. H., Waters, F., Zaytseva, Y., & Jardri, R. (2020). Hallucinations Under Psychedelics and in the Schizophrenia Spectrum: An Interdisciplinary and Multiscale Comparison. Schizophrenia bulletin, 46(6), 1396–1408. https://doi.org/10.1093/schbul/sbaa117

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Making “bad trips” good: How users of psychedelics narratively transform challenging trips into valuable experiences

Abstract

Background: We study the significance of stories about bad trips among users of psychedelics. Drawing on narrative theory, we describe the characteristics of such stories and explore the work they do.

Methods: In-depth qualitative interviews with 50 Norwegian users of psychedelics.

Results: Almost all participants had frightening experiences when using psychedelics and many described these as bad trips. The key feature of a bad trip was a feeling of losing oneself or going crazy, or ego dissolution. Most users said that these experiences could be avoided by following certain rules, based on tacit knowledge in the subcultures of users. Possessing such knowledge was part of symbolic boundary work that distinguished between drug culture insiders and outsiders. Some also rejected the validity of the term bad trip altogether, arguing that such experiences reflected the lack of such competence. Finally, and most importantly, most participants argued that unpleasant experiences during bad trips had been beneficial and had sometimes given them deep existential and life-altering insights.

Conclusion: Bad trip experiences are common among users of psychedelics. Such experiences are often transformed into valuable experiences through storytelling. Bad trip narratives may be a potent coping mechanism for users of psychedelics in non-controlled environments, enabling them to make sense of frightening experiences and integrate these into their life stories. Such narrative sense-making, or narrative work, facilitates the continued use of psychedelics, even after unpleasant experiences with the drugs.

Gashi, L., Sandberg, S., & Pedersen, W. (2021). Making “bad trips” good: How users of psychedelics narratively transform challenging trips into valuable experiences. The International journal on drug policy, 87, 102997. https://doi.org/10.1016/j.drugpo.2020.102997

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Mood and cognition after administration of low LSD doses in healthy volunteers: A placebo controlled dose-effect finding study

Abstract

There is a popular interest in microdosing with psychedelics such as LSD. This practice of using one-tenth of a full psychedelic dose according to a specific dosing schedule, anecdotally enhances mood and performance. Nonetheless, controlled research on the efficacy of microdosing is scarce. The main objective of the present dose-finding study was to determine the minimal dose of LSD needed to affect mood and cognition. A placebo-controlled within-subject study including 24 healthy participants, was conducted to assess the acute effects of three LSD doses (5, 10, and 20 mcg) on measures of cognition, mood, and subjective experience, up until 6 h after administration. Cognition and subjective experience were assessed using the Psychomotor Vigilance Task, Digit Symbol Substitution Test, Cognitive Control Task, Profile of Mood States, and 5-Dimensional Altered States of Consciousness rating scale. LSD showed positive effects in the majority of observations by increasing positive mood (20 mcg), friendliness (5, 20 mcg), arousal (5 mcg), and decreasing attentional lapses (5, 20 mcg). Negative effects manifested as an increase in confusion (20 mcg) and anxiety (5, 20 mcg). Psychedelic-induced changes in waking consciousness were also present (10, 20 mcg). Overall, the present study demonstrated selective, beneficial effects of low doses of LSD on mood and cognition in the majority of observations. The minimal LSD dose at which subjective and performance effects are notable is 5 mcg and the most apparent effects were visible after 20 mcg.

Hutten, N., Mason, N. L., Dolder, P. C., Theunissen, E. L., Holze, F., Liechti, M. E., Feilding, A., Ramaekers, J. G., & Kuypers, K. (2020). Mood and cognition after administration of low LSD doses in healthy volunteers: A placebo controlled dose-effect finding study. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 41, 81–91. https://doi.org/10.1016/j.euroneuro.2020.10.002

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Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects

Abstract

Growing interest has been seen in using lysergic acid diethylamide (LSD) in psychiatric research and therapy. However, no modern studies have evaluated subjective and autonomic effects of different and pharmaceutically well-defined doses of LSD. We used a double-blind, randomized, placebo-controlled, crossover design in 16 healthy subjects (eight women, eight men) who underwent six 25 h sessions and received placebo, LSD (25, 50, 100, and 200 µg), and 200 µg LSD 1 h after administration of the serotonin 5-hydroxytryptamine-2A (5-HT2A) receptor antagonist ketanserin (40 mg). Test days were separated by at least 10 days. Outcome measures included self-rating scales that evaluated subjective effects, autonomic effects, adverse effects, plasma brain-derived neurotrophic factor levels, and pharmacokinetics up to 24 h. The pharmacokinetic-subjective response relationship was evaluated. LSD showed dose-proportional pharmacokinetics and first-order elimination and dose-dependently induced subjective responses starting at the 25 µg dose. A ceiling effect was observed for good drug effects at 100 µg. The 200 µg dose of LSD induced greater ego dissolution than the 100 µg dose and induced significant anxiety. The average duration of subjective effects increased from 6.7 to 11 h with increasing doses of 25-200 µg. LSD moderately increased blood pressure and heart rate. Ketanserin effectively prevented the response to 200 µg LSD. The LSD dose-response curve showed a ceiling effect for subjective good effects, and ego dissolution and anxiety increased further at a dose above 100 µg. These results may assist with dose finding for future LSD research. The full psychedelic effects of LSD are primarily mediated by serotonin 5-HT2A receptor activation.

Holze, F., Vizeli, P., Ley, L., Müller, F., Dolder, P., Stocker, M., Duthaler, U., Varghese, N., Eckert, A., Borgwardt, S., & Liechti, M. E. (2021). Acute dose-dependent effects of lysergic acid diethylamide in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 46(3), 537–544. https://doi.org/10.1038/s41386-020-00883-6

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