American Journal of Psychiatry
January 1, 2025
Johannes G. Ramaekers, Johannes T. Reckweg, Natasha L. Mason
25 citations
Psychedelics like psilocybin can produce a rapid antidepressant response, unlike classical antidepressants. Ultra-fast, short-acting psychedelics such as 5-MeO-DMT and DMT are being explored for their potential to induce rapid antidepressant effects after a brief, intense experience. These compounds primarily act on serotonergic receptors, including 5HT1A and 5HT2A. Early small clinical trials show that short interventions (15-30 minutes) are safe and well tolerated, leading to marked improvement in depression symptoms within 24 hours that lasts at least one week. Data on long-term efficacy are scarce but suggest a prolonged treatment response. Potential benefits include flexible dosing and independence from integrative therapy. Future challenges include establishing the duration of the antidepressant effect and optimizing treatment delivery.
Frontiers in Psychiatry
July 7, 2022
Maggie Kiraga, Kim P. C. Kuypers, Malin V. Uthaug et al.
24 citations
A single dose of psilocybin-containing truffles, taken in a supportive group setting, produced rapid and lasting reductions in both state and trait anxiety among self-reported healthy volunteers. Medium reductions in anxiety were observed the morning after the ceremony and persisted for at least one week. At one week, participants also showed increased non-judging mindfulness and decreased neuroticism. The acute experience of ego dissolution and changes in neuroticism were the strongest predictors of anxiety reduction. Average psilocin consumption was 27.1 mg. Results suggest potential anxiolytic effects for sub-clinical anxiety and support further research in clinical populations.
Cannabis and Cannabinoid Research
February 27, 2019
Eef L. Theunissen, Nadia R. P. W. Hutten, Natasha L. Mason et al.
22 citations
Synthetic cannabinoid JWH-018, inhaled by 17 healthy cannabis-experienced volunteers in a placebo-controlled crossover study, increased heart rate within the first hour and impaired critical tracking and memory performance. Participants who reported a subjective high (responders) had higher serum concentrations of JWH-018 and performed worse on reaction time tests, with increased confusion, amnesia, dissociation, derealization, depersonalization, and drug liking. Large variability in drug concentrations and subjective experience was observed, likely due to fluctuations in drug delivery, which may raise the risk of overdose among synthetic cannabinoid users.
Network Neuroscience
November 1, 2023
Juan Carlos Farah, Pablo Mallaroni, Enrico Amico et al.
21 citations
Functional connectomes become more idiosyncratic under psilocybin, with greater dissimilarity between individuals than under placebo. While idiosyncratic features in placebo subjects appear mainly in the frontoparietal network, under psilocybin they concentrate in the default mode network (DMN). A DMN-focused pattern predicts subjective psilocybin experience, marked by reduced within-DMN and DMN-limbic connectivity and increased connectivity between the DMN and attentional systems. These findings link psilocybin's brain effects to subjective experience and demonstrate the value of brain-fingerprinting in pharmacological neuroimaging.
Neuroscience of Consciousness
January 1, 2025
Christopher Timmermann, James W. Sanders, David Reydellet et al.
19 citations
The psychedelic 5-MeO-DMT can, in its most extreme cases, produce a complete absence of self-experience and other perceptual content while preserving a quality of aroused, waking awareness. In an exploratory observational study in naturalistic ceremonial settings, micro-phenomenological interviews, questionnaires, and EEG recordings revealed a dynamic progression of effects, including variable disruptions of bodily and narrative self, reduced phenomenal distinctions, and visual imagery. EEG showed global alpha and posterior beta power reductions, suggesting inhibition of top-down brain models. The findings indicate 5-MeO-DMT's potential as a pharmacological model for deconstructed consciousness, though retrospective questionnaires have limitations.
Frontiers in Pharmacology
July 6, 2018
Elizabeth B. de Sousa Fernandes Perna, Eef L. Theunissen, Patrick C. Dolder et al.
18 citations
A single 100 mg dose of 4-fluoroamphetamine (4-FA), a phenethylamine novel psychoactive substance, produced strong elevation in blood pressure for 4-5 hours followed by sustained increased heart rate in healthy volunteers. Effects on mood and neurocognitive function peaked at 1 hour, including significant elevations of vigor, friendliness, elation, arousal, and positive mood, along with improvements in attention and motor performance. Negative affect also increased during the acute and subacute phases. The 150 mg dose was canceled after an interim safety review. The findings confirm clinical observations of acute toxicity and warrant warnings about health risks.
Neuroscience & Biobehavioral Reviews
February 3, 2024
Ivana Solaja, Kate Haldane, Natasha L. Mason et al.
17 citations
A systematic review and meta-analysis of ten controlled studies involving 304 participants found no lasting changes in cognition, creativity, emotional processing, or personality from serotonergic psychedelics for most measures. However, faster reaction times were observed for recognizing disgust and sadness in active treatment groups. The authors call for larger samples and standardized methods to confirm these preliminary findings.
Neuroimage
January 1, 2024
Pablo Mallaroni, Natasha L. Mason, Lilian Kloft et al.
17 citations
Brain functional connectomes are unique fingerprints that persist across mental states, but their stability under altered states is unknown. After collective ayahuasca intake in 21 Santo Daime members, 7T fMRI showed reduced idiosyncrasy in static and dynamic functional connectivity, with a spatiotemporal reallocation of keypoint edges. Interindividual differences in higher-order connectivity motifs predicted perceptual drug effects, demonstrating that individualized connectivity markers can trace a subject's functional connectome across altered states of consciousness.
Translational Psychiatry
July 15, 2024
Nadia R. P. W. Hutten, Conny W E M Quaedflieg, Natasha L. Mason et al.
16 citations
Repeated low doses of LSD (15 mcg) affect arousal, attention, and memory depending on a person's baseline cognitive state. In a randomized placebo-controlled trial with 53 healthy participants, LSD reduced resting-state EEG delta, theta, and alpha power (indicating stimulation) and enhanced pre-attentive processing during acute dosing sessions. LSD also blunted visual long-term potentiation (a marker of perceptual learning and memory) by the fourth dosing session. Stimulatory effects were strongest in individuals with low baseline arousal and attention, while inhibitory effects on memory were strongest in those with high baseline memory performance. Some EEG changes persisted at a one-week follow-up, suggesting possible neuroadaptations from repeated low-dose LSD.
Journal of Psychedelic Studies
August 26, 2021
Kim van Oorsouw, Malin V. Uthaug, Natasha L. Mason et al.
16 citations
A single ayahuasca ceremony reduced self-reported stress, anxiety, and somatization, and increased non-judging awareness four weeks later in 73 ceremony attendants. Satisfaction with life and awareness improved the day after the ceremony but returned to baseline after four weeks. No reduction in depression was found, contrary to earlier work. The intensity of ego dissolution during the ceremony predicted sub-acute mental health improvements. Effects were similar for first-time and experienced users. The authors call for placebo-controlled trials to confirm ayahuasca's therapeutic potential.
European Neuropsychopharmacology
February 25, 2021
Natasha L. Mason, Kim P. C. Kuypers, Johannes T. Reckweg et al.
16 citations
No Summary
Biological psychiatry. Cognitive neuroscience and neuroimaging
July 1, 2024
Sepehr Mortaheb, Larry D. Fort, Natasha L. Mason et al.
15 citations
Psilocybin produces profound alterations in both brain connectivity and subjective experience. In a randomized study, healthy volunteers received psilocybin or placebo and underwent ultrahigh field 7T fMRI scanning during the peak drug effect. Psilocybin caused widespread increases in averaged brain functional connectivity and a recurrent hyperconnected brain pattern with low blood oxygen level-dependent signal amplitude, suggesting heightened cortical arousal. This hyperconnected pattern was linked to feelings of oceanic boundlessness and visionary restructuralization. The brain's tendency to enter this hyperconnected-hyperarousal state may underlie the variant mental associations characteristic of the psychedelic experience.
Journal of Cognitive Neuroscience
January 1, 2023
Johannes G. Ramaekers, Pablo Mallaroni, Lilian Kloft et al.
15 citations
In members of the Santo Daime church who regularly consume ayahuasca in a ritual setting, the brew's main psychoactive compound DMT drives feelings of oceanic boundlessness, visual restructuring, and ego dissolution, with these effects correlating with peak DMT concentration in the blood. However, measures of mental imagery—including visual perspective shifting, vividness of imagery, and associative thinking—did not noticeably differ between sober and ayahuasca conditions, though subjective cognitive flexibility was lower under ayahuasca. Two mental imagery measures (perspective shifts and cognitive flexibility) correlated with peak DMT levels. Long-term ayahuasca use may produce compensatory or neuroadaptive effects that dampen the acute impact on mental imagery.
Journal of Psychedelic Studies
December 15, 2021
Malin V. Uthaug, Natasha L. Mason, Martha N. Havenith et al.
15 citations
A naturalistic observational study of 58 Czech-speaking adults found that a single session of Holotropic Breathwork (a breathing technique intended to produce altered states of consciousness) was associated with lasting improvements in non-judgment, satisfaction with life, and reductions in stress-related symptoms. Although participants reported only low levels of psychedelic-like experience (averaging 0–34% on a 100% scale), the increase in non-judgment appeared sub-acutely and persisted for four weeks. Satisfaction with life increased and stress symptoms decreased at the four-week follow-up.
Drug Science Policy and Law
January 1, 2020
Natasha L. Mason, Patrick C. Dolder, Kim P. C. Kuypers
15 citations
Psychedelics like LSD and psilocybin are most often used at home, while MDMA is more common at parties or festivals. Most people take these substances when already in a positive mood, and their mood stays positive or shifts to positive afterward. Individuals with low psychological well-being are more likely to experience a positive mood change after using LSD, psilocybin, or MDMA compared to those with normal well-being. Higher neuroticism scores are linked to both a greater likelihood of positive mood change and a greater likelihood of negative side effects. The findings suggest that psychedelic use can yield positive outcomes even in people with lower well-being and higher neuroticism.
Biomedicine & Pharmacotherapy
March 24, 2022
Francisco Madrid-Gambin, Alex Gomez-Gomez, Arnau Busquets-García et al.
14 citations
Consumption of ayahuasca increases N-acyl-ethanolamine endocannabinoids, decreases 2-acyl-glycerol endocannabinoids, and alters several large-neutral amino acids (LNAAs) in human plasma. Most LNAAs were inversely associated with nine of eleven subscales of the 5-Dimension Altered States of Consciousness Rating Scale, except tryptophan, which was positively associated. Several endocannabinoids and hexosylceramides were directly associated with ayahuasca alkaloids. Enrichment analysis confirmed dysregulation in pathways involved in serotonin and dopamine synthesis. A crosstalk between circulating LNAAs and subjective effects is suggested, independent of alkaloid concentrations, providing insights into the metabolic fingerprint and mechanism of action underlying ayahuasca experiences.
June 10, 2021
Drummond E-Wen Mcculloch, Gitte M. Knudsen, Frederick S. Barrett et al.
14 citations
preprint
Research into psychedelic drugs like psilocybin, LSD, and DMT is growing, with clinical trials showing promise for psychiatric conditions. Resting-state fMRI is a common method to study brain mechanisms in these contexts. A review of 42 articles from 17 datasets found high heterogeneity in methods and analyses; two datasets underlie over half the publications, and terms like "entropy" are used inconsistently. The authors suggest that the field needs greater methodological consistency and replicability to identify stable neural markers of psychedelic effects, and encourage development of new models and quantification methods.
Psychopharmacology
May 31, 2018
Kim P. C. Kuypers, E. B. de Sousa Fernandes Perna, Patrick C. Dolder et al.
14 citations
A single 100 mg dose of the new psychoactive substance 4-fluoroamphetamine (4-FA) increased self-reported drug liking, wanting, and good drug effect one hour after administration in 12 healthy poly-drug users, but these effects were absent 11 hours later. Impulsive behavior was not affected by 4-FA. The increase in liking and wanting suggests a potential for abuse, but the lack of effect on impulsivity and the small sample size limit the conclusions.
International Journal of Environmental Research and Public Health
July 21, 2023
Guido Huisman, Maximilian Menke, Oliver Grundmann et al.
13 citations
Kratom, a Southeast Asian plant containing alkaloids that affect humans, is sold online in strains marketed as having distinct effects. A survey of 644 current kratom users compared self-reported effects of red, green, and white strains. Respondents reported distinct subjective experiences matching marketing claims, but independent laboratory analysis of the products found no significant differences in alkaloid content across strains. This suggests marketing narratives and anecdotal reports may disproportionately influence perceived effects. Future work should include more diverse populations and vendors, and blinded experiments could determine whether reported differences stem from placebo or other factors like minor alkaloids or terpenes.
Journal of Psychoactive Drugs
January 24, 2019
Kim P. C. Kuypers, E. B. de Sousa Fernandes Perna, Eef L. Theunissen et al.
13 citations
4-Fluoroamphetamine (4-FA), a novel psychoactive substance with a chemical structure similar to amphetamine and MDMA, induces a mild psychedelic state. In a placebo-controlled crossover study of 12 healthy poly-drug users, the psychedelic state peaked one hour after administration, coinciding with highest serum concentrations, and declined over time as concentrations fell. No change in creative (flexible) thinking occurred. The intensity of the 4-FA-induced psychedelic state falls between that produced by amphetamine and MDMA, consistent with user reports. More research is needed to determine whether 4-FA can alter creative thinking.
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie
December 31, 2023
Francisco Madrid-Gambin, David Fabregat-Safont, Alex Gomez-Gomez et al.
12 citations
Psychedelics like LSD, mescaline, DMT, ayahuasca, 5-methoxy-DMT, and psilocybin induce altered states of consciousness and are being studied for treating mental health disorders. This review examines metabolic and metabolomics studies in humans after administration of these drugs. The main metabolites for classical psychedelics have been robustly established, but the metabolic alterations they induce need further exploration. Integrating metabolomics with pharmacokinetics may help understand the therapeutic role of psychedelics by revealing molecular interactions with multiple targets.
Nature Medicine
April 1, 2026
Manesh Girn, Manoj K. Doss, Leor Roseman et al.
8 citations
Psychedelic drugs are being studied again for their therapeutic potential, but how they change brain function is not well understood. By combining 11 brain-scanning datasets from five different psychedelics (psilocybin, LSD, mescaline, DMT, and ayahuasca) across three continents, researchers found a common pattern: increased communication between brain networks that handle high-level thinking (default, frontoparietal, and limbic) and those that handle sensory input (visual and somatomotor). Key deep-brain regions (thalamus, caudate, putamen) and the cerebellum also changed how they connect with sensorimotor networks. Contrary to some earlier studies, reductions in within-network connectivity were weak to moderate and varied by drug. These findings help resolve previous inconsistencies and provide a comprehensive map of how psychedelics alter large-scale brain organization.
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
June 1, 2025
Johannes G. Ramaekers, Johannes T. Reckweg, Natasha L. Mason et al.
8 citations
In a first-in-human trial, low to moderate doses of the synthetic cathinone 3-MMC were well tolerated and safe, with potential health risks only at high or excessive doses. 3-MMC caused dose-dependent increases in heart rate and blood pressure that were not clinically significant, along with feelings of subjective high. It also enhanced performance on several neurocognitive tasks, including processing speed, cognitive flexibility, psychomotor function, attention, and memory, while impulse control was unaffected. Participants reported mild dissociative and psychedelic effects, decreased appetite, and transient liking and wanting for the drug. The cardiovascular, psychostimulant, and psychotomimetic profile resembles that of amphetamine-related compounds.
Frontiers in Neuroscience
October 5, 2023
Pablo Mallaroni, Lilian Kloft, Natasha L. Mason et al.
8 citations
Repeated ayahuasca use is associated with a spatially distributed pattern of brain structural changes: sensorimotor areas become more distinct from surrounding regions while transmodal areas become less distinct. These changes correlate with the expression of genes for 5-HT2A receptors and other targets of ayahuasca, as well as with genes for transcription factors and immediate early genes previously linked to psychedelic-induced neuroplasticity in animal studies. The findings suggest that molecular mechanisms of psychedelic action may scale up to large-scale brain organization in living humans, potentially helping to explain behavioral differences in experienced users.
Biological psychiatry. Cognitive neuroscience and neuroimaging
October 1, 2024
Manoj K. Doss, Pablo Mallaroni, Natasha L. Mason et al.
7 citations
Two psychedelics, psilocybin and 2C-B, impair the encoding of detailed recollections and distort feelings of familiarity for emotional memories. In a double-blind, placebo-controlled study with 20 participants, both drugs reduced estimates of recollection and familiarity the next day, but increased false alarms based on familiarity, especially for negative and positive images. The drugs also tended to impair metamemory for negative and neutral memories while enhancing it for positive ones, though these effects were less reliable. The similar pattern across both substances suggests a shared neurocognitive mechanism among psychedelics that may underlie other phenomena.