Frontiers in Pharmacology
January 17, 2018
Leor Roseman, David Nutt, Robin Carhart‐Harris
814 citations
In patients with treatment-resistant depression given psilocybin, the quality of the acute psychedelic experience—specifically the intensity of oceanic boundlessness (a mystical-type experience) and dread of ego dissolution (anxiety-like experience)—predicted improvements in depressive symptoms at 5 weeks. Sensory perceptual effects had negligible predictive value. The findings support the view that the subjective quality of the psychedelic experience is a key mediator of long-term mental health changes, suggesting that therapeutic approaches should aim to enhance mystical-type experiences and reduce anxiety.
Frontiers in Pharmacology
November 2, 2018
Adam D. G. Hampshire, Christopher Timmermann, Christopher Timmermann et al.
422 citations
Psychological well-being increased two weeks after a psychedelic experience and remained elevated at four weeks. Higher ratings of a 'mystical-type experience' positively influenced this change in well-being, while 'challenging experience' and 'visual effects' did not. Having 'clear intentions' for the experience fostered mystical-type experiences. A positive 'set' and recreational intentions reduced the likelihood of a challenging experience. The trait 'absorption' and higher drug doses amplified all aspects of the acute experience. Baseline traits had the strongest effect on well-being change, underscoring the importance of extra-pharmacological factors in shaping responses to psychedelics.
Frontiers in Pharmacology
July 5, 2018
Eduardo Ekman Schenberg
242 citations
Psychedelic-assisted psychotherapy (PAP), involving professionally supervised use of ketamine, MDMA, psilocybin, LSD, and ibogaine within structured therapy programs, has shown safety and efficacy in clinical trials, even for treatment-resistant conditions. Beyond offering new treatments, PAP challenges the current psychiatric paradigm by questioning discrete diagnostic categories and advancing explanations for mental disorders that incorporate social and cultural factors, including adversity, trauma, and the therapeutic potential of non-ordinary states of consciousness. This model addresses the stalled innovation in psychiatric medications and the broader crisis in psychiatric diagnostics and explanations.
Frontiers in Pharmacology
March 31, 2022
Roberta Murphy, Roberta Murphy, Hannes Kettner et al.
229 citations
In a trial comparing psilocybin-assisted therapy to escitalopram for moderate-to-severe depression, a stronger therapeutic alliance with the therapist predicted greater emotional breakthrough and mystical-type experiences during psilocybin sessions, and these experiences in turn predicted larger reductions in depression symptoms six weeks after treatment. Emotional breakthrough during the first session strengthened the alliance before the second session, while a weaker alliance before the second session directly predicted higher depression scores at the endpoint, independent of the acute psychedelic experience. The findings suggest the therapeutic relationship plays a key role in shaping both the quality of the psychedelic experience and clinical outcomes.
Frontiers in Pharmacology
March 2, 2018
Link Swanson
185 citations
Psychedelic drugs produce acute effects on perception, emotion, cognition, and sense of self. This review traces theories of these effects over 125 years, from model psychoses, filtration, and psychoanalytic theories in the late 19th and early 20th centuries to modern frameworks like entropic brain theory, integrated information theory, and predictive processing. A common principle across theories is that psychedelics perturb brain processes that normally constrain neural systems central to perception, emotion, cognition, and self. Investigating these mechanisms offers a powerful way to develop and test unifying theories of brain function.
Frontiers in Pharmacology
April 3, 2018
Tara C. Malone, Sarah E. Mennenga, Jeffrey Guss et al.
128 citations
Cancer patients who receive psilocybin-assisted psychotherapy often have personalized experiences that extend beyond their diagnosis, centering on self-compassion, love, acceptance of death, and past trauma. In a double-blind trial, 29 patients with cancer-related anxiety and depression received either psilocybin or niacin with psychotherapy. Psilocybin produced rapid and lasting reductions in anxiety and depression. Detailed accounts of four participants show that while the content of each psilocybin session was unique, common themes emerged. The findings highlight how the subjective effects of psilocybin can address individual spiritual and psychological needs.
Frontiers in Pharmacology
February 20, 2018
Michael P. Bogenschutz, Samantha K. Podrebarac, Jessie H. Duane et al.
125 citations
After a 40-year pause, clinical research on classic hallucinogens for addiction has resumed. An ongoing double-blind placebo-controlled trial tests psilocybin-assisted treatment for alcohol use disorder, building on a small open-label feasibility study. Descriptive case studies of three participants illustrate treatment trajectories. Pivotal moments during psilocybin sessions are individualized, vivid, and memorable, often extending beyond the clinical problem. Participants experienced lasting shifts in self-perception, consciousness, and relationship with alcohol. Experiences of catharsis, forgiveness, self-compassion, and love were as salient as mystical content. Feelings of increased mindfulness, spaciousness, and control over choices and behavior were reported. The treatment elicits highly variable experiences that appear to meet individual needs.
Frontiers in Pharmacology
November 8, 2017
Rainer Kraehenmann, Dan Pokorný, Helena Aicher et al.
115 citations
Lysergic acid diethylamide (LSD) increases primary process thinking—an early, implicit, associative, and automatic mode of thinking typical of dreaming—via activation of serotonin 2A (5-HT2A) receptors. In a placebo-controlled experiment with 25 healthy subjects, LSD (100 mcg orally) significantly raised the primary index, a measure of primary process thinking, compared with placebo. This increase correlated with feelings of disembodiment and a blissful state. Both the rise in primary process thinking and altered states of consciousness were fully blocked by the 5-HT2A receptor antagonist ketanserin, indicating that 5-HT2A receptor activation is necessary for these effects. Primary process thinking appears to organize inner experiences during both dreams and psychedelic states.
Frontiers in Pharmacology
February 21, 2018
Elizabeth M. Nielson, Darrick G. May, Alyssa A. Forcehimes et al.
111 citations
In an open-label pilot study of psilocybin-assisted treatment for alcohol dependence, researchers analyzed 17 debriefing sessions conducted the day after psilocybin medication sessions. Participants described key phenomena related to changes in their drinking behavior and the acute subjective effects of psilocybin. The findings illuminate change processes in patients' own words during clinical sessions, shedding light on potential therapeutic mechanisms and how participants express the effects of psilocybin. This study is unique in analyzing actual clinical sessions rather than interviews conducted separately from treatment.
Frontiers in Pharmacology
March 20, 2018
Joaquim Soler, Matilde Elices, Elisabet Domínguez‐clavé et al.
104 citations
A single weekend of four ayahuasca sessions improved the capacity for non-judgmental acceptance as much as an eight-week mindfulness-based stress reduction (MBSR) course, though MBSR produced larger overall gains in mindfulness. Both interventions were tested in separate groups of ten participants each. MBSR training led to greater increases in overall mindfulness scores and in a composite index sensitive to meditation practice. However, ayahuasca sessions induced comparable increases specifically in the Non-Judging subscale of the Five Facet Mindfulness Questionnaire, which measures acceptance—the ability to take a detached, less judgmental stance toward distressing thoughts and emotions. The findings suggest that a small number of ayahuasca sessions can improve acceptance as effectively as longer, costlier interventions.
Frontiers in Pharmacology
March 9, 2022
Drummond E-Wen Mcculloch, Maria Zofia Grzywacz, Martin Bruun Madsen et al.
91 citations
Psilocybin, a psychedelic drug, can produce lasting positive psychological changes in healthy people. In 28 healthy volunteers who received 35 medium-high doses, the intensity of the acute mystical experience, measured by the Mystical Experience Questionnaire, predicted positive persisting effects three months later. Specifically, the subscales for positive mood and mysticality were linked to later benefits, while transcendence of time/space and ineffability were not. Qualitative reports described themes of connection with the Universe, familial love, and profound beauty. The type of acute experience appears important for predicting enduring positive outcomes.
Frontiers in Pharmacology
April 5, 2018
Antonio Inserra
91 citations
Ayahuasca ingestion may help retrieve and reprocess traumatic memories in PTSD by activating sigma-1 receptors and monoamine oxidase inhibitors, which reverse amnesic deficits and enhance synaptic plasticity, neurogenesis, and dopaminergic neurotransmission. This process could destabilize traumatic memories, allowing fear responses to be reprogrammed or extinguished through reconsolidation. The hypothesis suggests that DMT-mediated sigma-1 receptor activation and MAOI effects facilitate memory retrieval and updating, potentially offering a unique pharmacological treatment for PTSD. The mechanisms may also apply to other conditions with dysregulated cellular memory, such as cancer, diabetes, autoimmune diseases, and addiction.
Frontiers in Pharmacology
October 1, 2021
Maggie Kiraga, Natasha L. Mason, Malin V. Uthaug et al.
83 citations
A single ayahuasca ceremony is associated with lasting improvements in cognitive empathy, satisfaction with life, and the ability to take a non-judgmental stance toward oneself (decentering), while decreasing neuroticism and divergent thinking. In a naturalistic study of 43 ceremony attendees, 20 completed the morning-after assessment and 19 completed the one-week follow-up. Compared to baseline, cognitive empathy, satisfaction with life, and decentering increased at both one day and one week post-ceremony; implicit emotional empathy increased only at one week; and trait neuroticism decreased. Divergent thinking (fluency corrected for originality) decreased. The findings suggest ayahuasca may enhance well-being and social cognition, but clinical trials are needed to confirm therapeutic potential.
Frontiers in Pharmacology
November 19, 2019
Richard J. Zeifman, Fernanda Palhano-Fontes, Jaime E. C. Hallak et al.
79 citations
A single dose of ayahuasca, compared with placebo, was associated with medium-to-large reductions in suicidality among 29 adults with treatment-resistant depression. Suicidality was assessed by a psychiatrist before the intervention and at one, two, and seven days afterward. The between-group effect sizes (ayahuasca versus placebo) were medium at each time point (Cohen's d = 0.58, 0.56, and 0.67), and the within-group effect sizes for those receiving ayahuasca were large (Cohen's d = 1.33, 1.42, and 1.19). The group-by-time interaction was not statistically significant, suggesting the findings should be interpreted cautiously. The authors conclude that ayahuasca may hold potential as an intervention for suicidality, while noting important limitations and the need for further research.
Frontiers in Pharmacology
September 8, 2015
Mary Jeanne Kreek, Eduardo R. Butelman
77 citations
Salvinorin A, a hallucinogen from the plant Salvia divinorum, selectively activates kappa-opioid receptors (KOPr) in the brain, which are normally stimulated by endogenous dynorphins. This activation counterbalances dopamine-driven reward and mood systems, producing aversion and anhedonia in animal models. Unlike other opioid ligands, salvinorin A is a non-nitrogenous neoclerodane, offering a novel chemical scaffold for drug development. Ongoing research aims to create semi-synthetic analogs with partial or biased KOPr agonism to achieve therapeutic effects—such as for pain or mood disorders—while reducing the undesirable effects seen with salvinorin A itself.
Frontiers in Pharmacology
February 26, 2021
Guy A. Higgins, Nicole K. Carroll, Matthew A. Brown et al.
67 citations
Low doses of the hallucinogens ketamine and psilocybin, too small to cause perceptual effects, modestly improved motivation, attention, and impulse control in low-performing male rats. In two food-rewarded tasks, acute doses of ketamine (1–3 mg/kg) and psilocybin (0.05–0.1 mg/kg) increased break point for food and improved attentional accuracy. The benefits were small and mainly seen in rats that initially performed poorly. Both drugs produced similar patterns of effect. These findings support the idea that low, sub-perceptual doses of these drugs may have therapeutic potential for depression-related symptoms like anhedonia and cognitive dysfunction, though further research is needed.
Frontiers in Pharmacology
July 13, 2021
Friederike Holze, Isidora Avedisian, Nimmy Varghese et al.
66 citations
Lysergic acid diethylamide (LSD) dose-dependently increased both implicit and explicit emotional empathy in 16 healthy subjects, with the highest 200 µg dose producing a significant effect compared with placebo. The 200 µg dose also moderately increased plasma oxytocin levels. Blocking the serotonin 5-HT2A receptor with ketanserin reduced the LSD-induced oxytocin release but did not reduce the increases in emotional empathy. These results indicate that LSD enhances empathy through mechanisms that may be partially independent of its primary action on 5-HT2A receptors, whereas the oxytocin release depends on 5-HT2A receptor stimulation and aligns with the psychedelic effect of LSD.
Frontiers in Pharmacology
February 23, 2021
Michael Winkelman
62 citations
Psychedelics, particularly psilocybin, may have influenced hominin evolution by acting as exogenous neurotransmitter sources that shaped selection for features of human psychology. The review argues that shamanism, an empirical phenomenon in foraging societies, integrates innate modular thought processes—self-awareness, other awareness, mind reading, spatial and visual intelligences—that psychedelics stimulate through effects on serotonin and dopamine systems and ancient brain structures. Differences between chimpanzee displays and shamanic rituals indicate a zone of proximal development in evolution, with mimetic capacities for dance, music, and imitation underlying shamanic performances. A shamanic-informed psychedelic therapy includes preparatory practices, a relational animistic worldview, focus on internal imagery, and incorporation of animal spirits, aiming to optimize set, setting, and ritual frameworks.
Frontiers in Pharmacology
March 13, 2018
Esther Papaseit, Marta Torrens, Mireia Ventura et al.
61 citations
2C-B, a psychedelic similar to mescaline, acts on serotonin receptors and produces mild psychedelic and stimulant-like effects. In an observational study, 16 healthy experienced users took 10–20 mg orally. The drug increased blood pressure and heart rate, elevated scores on scales for euphoria, liking, and stimulation, and altered perceptions of distances, colors, shapes, and lights. Five participants reported mild hallucinations. Peak 2C-B levels in saliva occurred at 1 hour, and peak cortisol at 3 hours. The effects resemble those of other serotonin-acting drugs.
Frontiers in Pharmacology
April 29, 2024
Jan Thomann, Oliver V Stoeckmann, Deborah Rudin et al.
52 citations
Psilocybin is rapidly converted to psilocin in the body, which causes psychedelic effects by binding to the 5-HT2A receptor. Psilocin is mainly broken down by glucuronidation or conversion to 4-hydroxyindole-3-acetic acid (4-HIAA). In laboratory experiments with human liver microsomes, about 29% of psilocin was metabolized, while specific enzymes CYP2D6 and CYP3A4 metabolized nearly 100% and 40%, respectively. Monoamine oxidase A produced small amounts of 4-HIAA and 4-hydroxytryptophol (4-HTP), but 4-HTP appeared only in lab tests and neither metabolite showed activity at serotonin receptors. Two new potential metabolites were found: norpsilocin in mice and an oxidized form in humans, though CYP2D6 genotype did not affect psilocin levels in people. These findings help understand drug interactions and psilocybin's therapeutic use.
Frontiers in Pharmacology
July 7, 2022
Songbai Xu, Xiaoxiao Yao, Bingjin Li et al.
50 citations
Ketamine, a drug that blocks N-methyl-D-aspartate receptors, produces rapid and lasting antidepressant effects in people with major depressive disorder and in animal models, but its use is limited by side effects like dissociation and psychosis-like experiences. The drug may work by enhancing signaling through another receptor type, AMPA receptors, in brain cells, possibly by reducing inhibition or blocking spontaneous NMDAR activity. It also activates pathways linked to brain plasticity and synapse formation, such as BDNF/TrkB and mTOR signaling. These processes may help restore the balance of excitatory and inhibitory signals in brain circuits disrupted in depression. Understanding these mechanisms could guide development of safer, more effective treatments.
Frontiers in Pharmacology
May 29, 2018
Elisangela Gouveia Cata-Preta, Yasmim A. Serra, Eliseu Da Cruz Moreira-Junior et al.
50 citations
Ayahuasca, a hallucinogenic beverage containing DMT and β-carbolines, can reduce ethanol reward in male mice without itself being rewarding at certain doses. An intermediate dose of ayahuasca induced conditioned place preference (CPP), while higher doses and its plant components Banisteriopsis caapi (Bc) and Psychotria viridis (Pv) did not. Pretreatment with ayahuasca blocked the development of ethanol-induced CPP, whereas Bc and Pv alone had no effect. Post-conditioning treatment with ayahuasca, Bc, or Pv in the ethanol-paired environment blocked expression of ethanol-induced CPP; treatment in the saline-paired compartment also blocked expression for intermediate ayahuasca and Bc doses, and for Pv. The environment influences these therapeutic effects.
Frontiers in Pharmacology
May 4, 2021
Ido Hartogsohn
49 citations
The psychedelic experience is profoundly shaped by psychological, social, and cultural factors—a concept known as set and setting. The Santo Daime religion in Brazil uses a rich tapestry of ordering principles, techniques, symbology, aesthetics, and music to direct the effects of the hallucinogenic brew ayahuasca. This paper systematically describes these elements and the mechanics of entheogenic initiation within the tradition, providing a template for future studies on how context influences psychedelic experimentation.
Frontiers in Pharmacology
October 7, 2022
Katarzyna Stachowicz, Magdalena Sowa-Kućma
48 citations
Depression is a severe mental health problem that affects people regardless of social status or education, is associated with changes in mood and behavior, and can result in suicide attempts. Current therapy relies mainly on drugs discovered in the 1960s and early 1970s, with SSRIs and SNRIs as frontline treatments. Esketamine, approved by the FDA in 2019, is an important compound for suicide and drug-resistant depression, acting as an NMDA receptor antagonist with additional effects on AMPA receptors, HCN channels, L-VDCC, opioid receptors, and monoaminergic receptors. However, treatment is burdened with severe side effects and often ineffective. This review discusses new research directions and proposes a new perspective on depressive therapies, emphasizing the need for antidepressants with different mechanisms of action.
Frontiers in Pharmacology
January 27, 2022
Athanasios Markopoulos, Antonio Inserra, Danilo de Gregorio et al.
44 citations
Psychedelic compounds such as LSD, psilocybin, and DMT show empathogenic and prosocial effects, suggesting potential therapeutic benefit for behavioral traits in autism spectrum disorder (ASD), including reduced social behavior and co-occurring anxiety and depression. The review examines dysregulated neurobiological systems in ASD—synaptic function, serotonergic signaling, prefrontal cortex activity, and thalamocortical signaling—that may underlie or limit these effects. Clinical studies from the 1960s and 70s using psychedelics in children with ASD reported positive outcomes like enhanced mood and social behavior, but also adverse effects including increased aggression, dissociation, and psychosis. Further studies are needed to weigh benefits against risks and determine if the 5-HT 2A receptor could be a target for social-behavioral disorders.