Catalyst for change: Psilocybin’s antidepressant mechanisms—A systematic reviewLiebnau, Joshua; Betzler, Felix; Kerber, André
doi: 10.1177/02698811241312866pmid: 39829391
Background:Recent clinical trials suggest promising antidepressant effects of psilocybin, despite methodological challenges. While various studies have investigated distinct mechanisms and proposed theoretical opinions, a comprehensive understanding of psilocybin’s neurobiological and psychological antidepressant mechanisms is lacking.Aims:Systematically review potential antidepressant neurobiological and psychological mechanisms of psilocybin.Methods:Search terms were generated based on existing evidence of psilocybin’s effects related to antidepressant mechanisms. Following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines, 15 studies were systematically reviewed, exploring various therapeutic change principles such as brain dynamics, emotion regulation, cognition, self-referential processing, connectedness, and interpersonal functioning.Results:Within a supportive setting, psilocybin promoted openness, cognitive and neural flexibility, and greater ability and acceptance of emotional experiences. A renewed sense of connectedness to the self, others, and the world emerged as a key experience. Imaging studies consistently found altered brain dynamics, characterized by reduced global and within default mode network connectivity, alongside increased between-network connectivity.Conclusions:Together, these changes may create a fertile yet vulnerable window for change, emphasizing the importance of a supportive set, setting, and therapeutic guidance. The results suggest that psilocybin, within a supportive context, may induce antidepressant effects by leveraging the interplay between neurobiological mechanisms and common psychotherapeutic factors. This complements the view of purely pharmacological effects, supporting a multileveled approach that reflects various relevant dimensions of therapeutic change, including neurobiological, psychological, and environmental factors.
Hemispheric annealing and lateralization under psychedelics (HEALS): A novel hypothesis of psychedelic action in the brainLevin, Adam W
doi: 10.1177/02698811241303599pmid: 39704335
Current models of psychedelic action in the brain propose changes along the dorsal–ventral and anterior–posterior axes but neglect to address the lateral axis. This article proposes a novel model of psychedelic action called HEALS (Hemispheric Annealing and Lateralization Under Psychedelics) which involves the reversal of the typical hierarchical relationship between the two hemispheres of the brain. In typical modes of consciousness, the hemispheres act in parallel process with the left predominating. Under psychedelics, as well as in other altered states of consciousness (ASCs), this hierarchy is reversed, with the right hemisphere released from inhibition by the left. In support of this model, the available neuroimaging evidence for lateralization under psychedelics is reviewed. Then, various cognitive and emotional changes observed under psychedelics are contrasted with those same functions in each hemisphere. These include attention; social and emotional intelligence; creativity and insight; and language. The article concludes with a review of laterality in other ASCs, such as meditative and trance states, and suggests that many phenomena associated with psychedelics, and other ASCs, might be explained by an atypical annealing between the hemispheres toward right hemisphere predominance.
Commentary: A framework for assessment of adverse events in psychedelic researchCheung, Katherine; Ehrenkranz, Rebecca; Hinkle, Jared T; Yaden, David B
doi: 10.1177/02698811241309623pmid: 40411403
Recent discussions about the methodological rigor of psychedelic clinical trials have focused on potential underreporting or misreporting of adverse events (AEs), with many calling for their systematic assessment to help mitigate these issues. In their recent paper, Palitsky et al. offer a comprehensive framework for the assessment of AEs in psychedelic-assisted therapies, with consideration of the spiritual, existential, religious, and theological impacts that psychedelics can have. In this commentary, we respond to Palitsky et al.’s proposal, discussing the framework, its feasibility, and various assessment methods. We emphasize the need to ensure that AE assessment in psychedelic clinical trials is held to the same rigor and standard as research in other areas, in addition to maintaining and improving transparency and accessibility in AE reporting.
Psychedelic risks and benefits: A cross-sectional survey studyGoldy, Sean P; Du, Benjamin A; Rohde, Julia S; Nayak, Sandeep M; Strickland, Justin C; Ehrenkranz, Rebecca; Levine, Michael; Barrett, Frederick S; Yaden, David B
doi: 10.1177/02698811241292951pmid: 39610363
Background:As classic psychedelics’ therapeutic potential is studied and their popularity continues to rise, it is important to establish their relative risks and benefits. Previous surveys have tended to use convenience sampling on social media, select participants who have had either extremely positive or negative effects, and have not compared the risk/benefit profile of psychedelics to other substances.Aims:To address these limitations, we gathered samples from an opt-in panel service using quota-based sampling to approximate demographics representing US Census data, did not pre-specify positive or negative experiences, and compared experiences with psychedelics to those with cannabis.Methods:We conducted two studies, one using a between-subjects design (n = 743) and one using a within-subjects design (n = 514), in which participants recruited from an opt-in panel service reflected on prior experience with psychedelics or cannabis and indicated self-reported risks and benefits associated with their experience.Results:Results indicated that first or most memorable psychedelic experiences were associated with greater acute challenging effects and persisting negative effects than first or most memorable cannabis experiences, but psychedelic experiences were also associated with greater positive acute and persisting effects. Common predictors of negative and positive acute and persisting effects with psychedelics included various experience qualities (e.g., dose level, presence of others) and individual differences (e.g., religiosity, personality), though only to a small degree.Conclusions:These findings on psychedelic experiences provide a more nuanced characterization of risks and benefits and their predictors.
Co-use of psychedelics with other substances: Findings from the global psychedelic surveyLake, Stephanie; Lucas, Philippe
doi: 10.1177/02698811241292956pmid: 39468747
Background/Aims:While most psychedelic substances are considered to carry a relatively low risk of acute or long-term harm, co-use with other psychoactive substances may increase health and social harm. Using a large international survey of adults who use psychedelics, we sought to comprehensively characterize psychedelic co-use.Methods:We used data from the 2023 Global Psychedelic Survey, a web-based survey of adults ⩾21 with lifetime use of psychedelics. We explored patterns of co-use (prevalence, secondary substances used, timing, and motives of co-use) and examined sociodemographic and psychedelic use-related characteristics associated with co-use overall and by specific psychedelics.Results:In total, 5370 respondents were included in this analysis, of whom 3228 (56.3%) reported typically co-using at least one of the 11 psychedelic substances of interest, with co-use lowest for ayahuasca (14.8%) and highest for nitrous oxide (54.5%). Cannabis and alcohol were the most common secondary substances. Depressants were the only secondary substance class that increased in use following psychedelic experiences. Greater experience with psychedelics was significantly associated with co-use, as was using for recreational purposes or to reduce/substitute the use of other substances. Personal exploration and therapeutic purposes for psychedelic use were negatively associated with co-use.Conclusions:In this detailed analysis of psychedelic co-use, we observed high rates of co-use with certain psychedelics, specifically when used recreationally. Our findings highlight psychedelic-specific consumers for whom harm reduction messaging around co-use practices may be best tailored. Further research is justified to assess whether specific patterns of co-use might reduce or increase potential harms.
The Afterglow Inventory (AGI): Validation of a new instrument for measuring subacute effects of classic serotonergic psychedelicsMajić, Tomislav; Schmidt, Timo Torsten; Gröticke, Anna; Gasser, Peter; Richards, William A; Riemer, Thomas G; Evens, Ricarda
doi: 10.1177/02698811251326937pmid: 40165350
Background:Classic psychedelics such as psilocybin and lysergic acid diethylamide are anecdotally associated with the phenomenon of “psychedelic afterglow,” a set of predominantly pleasant, temporary psychological effects reported after the acute effects have subsided. Since post-acute effects are crucial for the therapeutic use of psychedelics, an instrument to systematically assess subacute “afterglow” effects is needed.Aims:To create and validate a questionnaire to quantify the subacute “afterglow” effects of psychedelics.Methods:An international online survey was conducted in English and German. Participants who had consumed a psychedelic (N = 1323) or another non-psychedelic substance (control group, N = 157) within the past 4 weeks were included. An initial list of 97 items was progressively reduced to 24 items.Results:A 5-factor structure best fit the data and showed high internal consistency. The factors included (1) vitality, (2) transpersonal aspects, (3) inspiration/creativity, (4) interpersonal relationships, and (5) relationship to nature. The final 24-item version of the Afterglow Inventory (AGI) effectively differentiated between the psychedelic group and the control group. The overall AGI score positively correlated with the intensity (r = 0.165; p < 0.001) and positive valence (r = 0.251; p < 0.001) of the acute psychedelic effects.Conclusions:The AGI is a novel scale for quantifying positive subacute (“afterglow”) effects of psychedelics. The use of the AGI could lead to a better understanding of the interplay between acute, subacute, and long-term effects of psychedelics. Insights could also be gained into how different substances, dosages, and extra-pharmacological factors, such as psychotherapy, might influence outcomes.