Brain Imaging and Behavior
December 14, 2015
Johannes G. Ramaekers, J. H. van Wel, Desirée Spronk et al.
61 citations
The dopamine β-hydroxylase (DβH) enzyme converts dopamine into noradrenaline. People with low-activity DBH genotypes (rs1611115 CT/TT) appear more sensitive to cannabis and cocaine's effects on cognitive impulse control and brain connectivity. In 122 regular drug users, acute doses of cannabis (450 μg/kg THC) and cocaine (300 mg) increased cognitive impulsivity and reduced functional connectivity between the nucleus accumbens and limbic, prefrontal, striatal, and thalamic areas, primarily in those with CT/TT genotypes, not in those with the CC genotype. A negative association emerged between impulsivity and subcortical connectivity. The findings suggest DBH genotype influences how these drugs affect impulse control and brain networks, potentially explaining progression to drug seeking and informing targeted pharmacotherapy.
Frontiers in Pharmacology
January 1, 2021
Johannes T. Reckweg, Natasha L. Mason, Cees van Leeuwen et al.
58 citations
Vaporized 5-MeO-DMT (GH001) produces dose-dependent increases in psychedelic experience intensity in healthy volunteers, with individualized dose escalation yielding maximal effects on peak experience, mystical experience, ego dissolution, and altered states of consciousness. Higher single doses (6, 12, 18 mg) significantly increased ratings compared to 2 mg on all measures except challenging experiences. Cognition, mood, and well-being were unaffected. Vital signs remained stable, and adverse events were mild and self-resolving. Individualized dose escalation may be preferable for clinical applications aiming to maximize the psychedelic experience for therapeutic response.
Addiction Biology
December 22, 2019
Natasha L. Mason, Eef L. Theunissen, Nadia R. P. W. Hutten et al.
58 citations
Regular cannabis users develop tolerance to the drug's impairing and rewarding effects, but the underlying brain changes are unclear. In a double-blind, placebo-controlled study, 12 occasional and 12 chronic cannabis users received acute doses of cannabis (300 μg/kg delta-9-tetrahydrocannabinol) or placebo. In occasional users, cannabis decreased functional connectivity and increased striatal glutamate levels in reward circuitry, linked to greater subjective high and worse attention performance. Chronic users showed none of these changes, indicating reduced responsiveness of reward circuitry to cannabis intoxication, suggesting a pharmacodynamic mechanism for tolerance development.
Neuropsychopharmacology
May 11, 2011
Janelle H. P. van Wel, Kim P. C. Kuypers, Eef L. Theunissen et al.
52 citations
Blocking the 5-HT(2A) receptor with ketanserin prevented MDMA-induced impairment on a word-learning task, but not on spatial or prospective memory tasks. Blocking the 5-HT(1A) receptor with pindolol had no effect on any memory task. MDMA alone significantly impaired performance in all three memory tasks. The findings indicate that MDMA-induced verbal memory impairment is mediated by 5-HT(2A) receptor stimulation.
Proceedings of the National Academy of Sciences
February 10, 2020
Lilian Kloft, Henry Otgaar, Arjan Blokland et al.
49 citations
Under the acute influence of THC, healthy volunteers showed a heightened tendency to form false memories compared to those given a placebo. In a double-blind, randomized trial, 64 participants completed memory tasks—including associative word lists and two virtual-reality misinformation scenarios—immediately while intoxicated and again one week later while sober. Intoxicated individuals exhibited a stronger false-recognition bias, especially when test items were weakly associated with studied material, and were more susceptible to misinformation in eyewitness and perpetrator scenarios. These false-memory effects were largely confined to the acute intoxication phase. The findings suggest that cannabis increases false-memory proneness and have practical implications for police interviews with suspects and eyewitnesses.
Addiction Biology
December 22, 2021
Thomas R. Arkell, Richard C. Kevin, Frederick Vinckenbosch et al.
45 citations
Males and females show few differences in their acute responses to a moderate dose of vaporized cannabis containing 13.75 mg THC, with or without 13.75 mg CBD. After controlling for body mass index and plasma THC concentrations, males performed better on a divided attention task and had higher peak plasma levels of a THC metabolite (11-COOH-THC), but no sex differences appeared in subjective drug effects, cardiovascular measures, or plasma concentrations of THC, CBD, or other metabolites. The findings suggest an absence of systematic sex differences at this dose, though differences might emerge with higher THC doses or other routes of administration.
Psychopharmacology
January 18, 2010
Wendy M. Bosker, Kim P. C. Kuypers, Silke Conen et al.
45 citations
Sleep deprivation impairs psychomotor function, and the stimulant effects of MDMA are not sufficient to compensate for this impairment. In a randomized, double-blind, placebo-controlled crossover study, 16 recreational MDMA users received single doses of 25, 50, and 100 mg. While MDMA did not generally affect performance, the highest dose improved rapid information processing in the morning after administration. In the evening, MDMA increased subjective ratings of positive mood at every dose and subjective arousal at the highest dose, but these subjective effects were no longer present after a night of sleep loss.
Journal of Psychopharmacology
February 1, 2022
Isabel Wießner, Marcelo Falchi-Carvalho, Lucas Oliveira Maia et al.
43 citations
A randomized, double-blind, placebo-controlled crossover study gave 24 healthy volunteers 50 micrograms of LSD or an inactive placebo and tested creativity near the drug's peak using multiple tasks. LSD changed creativity in three ways: it increased novelty, surprise, originality, and semantic distances (pattern break); decreased utility, convergent thinking, and marginally elaboration (disorganization); and increased symbolic thinking and ambiguity (meaning). The findings suggest LSD shifts cognitive resources away from normal patterns toward new ones, and that LSD-induced symbolic thinking might aid psychedelic-assisted therapy.
British Journal of Pharmacology
November 22, 2017
Eef L. Theunissen, Nadia R. P. W. Hutten, Natasha L. Mason et al.
38 citations
A placebo-controlled crossover study gave six healthy adults with prior cannabis experience two low doses (2 mg and 3 mg) of the synthetic cannabinoid JWH-018. Serum concentrations of the drug were highest after the 2 mg dose but remained low overall. Both doses were well tolerated with no serious side effects. Participants reported feeling more 'high' at 1 and 2 hours after administration, especially after 2 mg. Despite low serum levels, behavioral impairments emerged: the 2 mg dose impaired performance on tracking, divided attention, and stop signal tasks. Higher doses are needed to obtain a more representative risk profile.
British Journal of Pharmacology
October 11, 2013
Janelle H. P. van Wel, Kim P. C. Kuypers, Eef L. Theunissen et al.
38 citations
Heavy cannabis users show broad impairments in neuropsychological function during THC intoxication, including reduced psychomotor performance and more errors on impulsivity tasks. These impairments appear less severe in psychomotor tasks than those previously seen in occasional users, suggesting some tolerance. Cocaine temporarily improves psychomotor function and speeds reaction times but increases errors, indicating a trade-off between stimulation and impulse control. The decline in impulse control may increase the risk of repeated drug use and addiction.
Psychopharmacology
October 13, 2022
Nadia R. P. W. Hutten, Thomas R. Arkell, Frederick Vinckenbosch et al.
36 citations
Vaporized cannabis containing both THC and cannabidiol (CBD) produces less anxiety than THC alone, but this effect depends on a person's baseline anxiety level. In a placebo-controlled trial with 26 healthy recreational cannabis users, THC-dominant cannabis (13.75 mg THC) and THC/CBD-equivalent cannabis (13.75 mg each) both increased self-rated state anxiety compared to placebo, though the combination caused significantly less anxiety than THC alone. When baseline anxiety was low, CBD completely counteracted THC-induced anxiety; when baseline anxiety was high, CBD did not counteract it. Trait anxiety did not influence the results, and objective measures of attention bias showed no effects.
Clinical Pharmacology & Therapeutics
May 30, 2023
Pablo Mallaroni, Riccardo Paci, Sabrina Ritscher et al.
34 citations
2,5‐dimethoxy‐4‐bromophenethylamine (2C‐B), a hallucinogen derived from mescaline, produces psychedelic effects of moderate depth, shorter in duration than psilocybin. In a double‐blind, placebo‐controlled study of 22 healthy participants with prior psychedelic experience, 20 mg of 2C‐B elicited alterations of waking consciousness, though psilocybin (15 mg) caused greater dysphoria, subjective impairment, auditory alterations, and ego dissolution. Both compounds equally slowed psychomotor performance and impaired spatial memory compared with placebo, and neither produced empathogenic effects on the Multifaceted Empathy Test. 2C‐B raised blood pressure transiently, similar to psilocybin, and its effects largely resolved within six hours.
J Psychopharmacol
June 30, 2023
Chloé Pronovost-Morgan, Ido Hartogsohn, Johannes G. Ramaekers
33 citations
The randomized controlled trial (RCT) design assumes a drug's specific effect can be separated from nonspecific context and person effects, but ample evidence shows that physical, social, and cultural variables not only add to but also shape drug effects. Harnessing these placebo effects for patient benefit is challenging due to conceptual and normative obstacles. A new framework inspired by psychedelic science's 'set and setting' concept acknowledges that drug and nondrug factors interact synergistically, suggesting ways to reintegrate nondrug variables into biomedical practice to ethically use placebo effects for improved clinical care.
Frontiers in Pharmacology
July 11, 2017
Drew J. Puxty, Johannes G. Ramaekers, Rafael de la Torre et al.
33 citations
A single 75 mg dose of MDMA produces a dissociative state, marked by feelings of depersonalization and derealization, in healthy recreational users. Blocking the 5-HT2 receptor with ketanserin did not prevent this effect, indicating that the 5-HT2 receptor does not mediate MDMA-induced dissociation. Heart rate correlated with the dissociative state after MDMA alone, but not when ketanserin was given, suggesting heart rate changes do not directly cause dissociation. Cortisol levels and MDMA blood concentrations showed no clear relationship with dissociation. The exact neurobiological mechanism remains unknown and may be relevant to MDMA's therapeutic use.
Psychopharmacology
September 27, 2011
Wendy M. Bosker, Kim P. C. Kuypers, Silke Conen et al.
32 citations
Taking MDMA (ecstasy) during the night does not improve driving performance the next morning after sleep loss, nor does it counteract the impairing effects of sleep deprivation. In a controlled driving test, weaving (measured as standard deviation of lateral position) was significantly increased during morning drives after a night without sleep, regardless of whether participants had taken 0, 25, 50, or 100 mg of MDMA the previous evening. The degree of impairment was clinically relevant and comparable to that seen with a blood alcohol concentration above 0.8 mg/mL. MDMA cannot compensate for sleep-loss-induced driving impairment, and sleep-deprived drivers who have taken MDMA are unfit to drive.
European Journal of Pain
August 20, 2023
Mauro Cavarra, Amanda Feilding, Pamela Kryskow et al.
28 citations
A survey of people with chronic pain conditions found that, except for sciatica, those who used psychedelics (full doses or microdoses) reported better pain relief than with conventional medication. Full doses outperformed conventional medication for fibromyalgia, arthritis, migraine, and tension-type headache. Microdoses provided significantly better relief than conventional medication for migraines and comparable relief for the other conditions. The findings suggest that psychedelics may hold value for treating some chronic pain conditions.
Frontiers in Psychology
July 15, 2022
Alexandre Augusto de Deus Pontual, Alexandre Augusto de Deus Pontual, Luís Fernando Tófoli et al.
27 citations
Setting characteristics—social context, comfort, infrastructure, and decoration—moderate the intensity of challenging experiences during ayahuasca ceremonies, explaining 41% of the variance in challenging experience ratings across three traditions (União do Vegetal, Santo Daime, and neo-shamanic groups). Mystical experiences were less strongly associated with setting, with leadership and comfort explaining only 14% of the variance. Social context was rated highest among União do Vegetal members. In neo-shamanic groups, infrastructure, comfort, and decoration correlated more consistently with mystical experiences than in the other traditions. Maximizing setting quality reduces the likelihood of challenging experiences and modestly supports mystical experiences.
Nature Medicine
June 3, 2025
Chloé Pronovost-Morgan, Kyle T. Greenway, Leor Roseman et al.
26 citations
A Delphi consensus study with 89 experts from 17 countries identified 30 extra-pharmacological variables that are important or very important for reporting the setting in psychedelic clinical trials. These variables, forming the ReSPCT guidelines, cover physical environment, dosing session procedure, therapeutic framework and protocol, and subjective experiences. The findings reveal significant ambiguities in current conceptualizations of set and setting. The guidelines provide a new standard for designing and documenting contextual factors in psychedelic research.
Br J Pain
July 14, 2022
Valerie Bonnelle, Will J Smith, Natasha L. Mason et al.
26 citations
A survey of chronic pain sufferers who have used classical psychedelics reports that both macrodoses and microdoses are associated with pain relief. Among respondents, 78% reported pain reduction after macrodosing, and 55% reported pain reduction after microdosing. The findings suggest that psychedelics may have analgesic potential in this population, though the survey design cannot establish causation.
Scientific Reports
February 14, 2022
Johannes G. Ramaekers, Natasha L. Mason, Stefan W. Toennes et al.
26 citations
Acute cannabis intoxication and chronic cannabis use produce distinct patterns of altered connectivity across the whole brain, not just in isolated regions. Using ultra-high field (7T) resting state fMRI scans of 26 cannabis users under placebo and after vaporizing cannabis, two data-driven methods revealed that chronic users showed broad hyperconnectivity across major brain networks compared to occasional users, suggesting adaptive network reorganization from prolonged exposure. A separate spatial pattern—hypoconnectivity in dorsal attention, limbic, subcortical, and cerebellum networks combined with hyperconnectivity between the default mode and ventral attention network—was linked to the subjective feeling of being high during acute intoxication. These whole-brain approaches distinguish short- from long-term cannabis effects and may help probe the transition from occasional to chronic use.
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.
Journal of Psychedelic Studies
March 25, 2020
Malin V. Uthaug, Rafael Lancelotta, Ana María Ortiz Bernal et al.
25 citations
Among 27 respondents who used the psychedelic drug 5-MeO-DMT, those who received it by intramuscular injection (IM) reported a lower rate of reactivations (21%) compared to those who vaporized it (69%). The IM group also required fewer redoses, experienced release of physical tension more consistently, and had a slower onset of acute effects (1–6 minutes) versus the vaporization group (1–50 seconds). These findings suggest that the route of administration influences the frequency of reactivations, dosing patterns, physical sensations, and the timing of the drug's effects.
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.
Psychopharmacology
July 22, 2017
Kim P. C. Kuypers, Rafael de la Torre, Magı́ Farré et al.
24 citations
MDMA reduced the arousal normally elicited by negative sounds, and this effect was blocked by pre-treatment with ketanserin, a 5-HT2 receptor antagonist, indicating the involvement of the serotonin 2A receptor. The drug did not produce a bias toward emotional or social stimuli in the tasks used. MDMA increased both positive and negative mood ratings and elevated oxytocin plasma concentrations. The reduction in arousal to negative sounds was unrelated to subjective arousal levels. This decrease in defensive arousal may contribute to MDMA's therapeutic effects.
PLoS One
February 23, 2016
Kim P. C. Kuypers, Eef L. Theunissen, Janelle H. P. van Wel et al.
23 citations
Verbal memory performance in people who use Ecstasy (MDMA) does not differ from that of healthy non-users when they are not under the drug's influence, and there is substantial evidence supporting no long-term memory deficit. Clinically significant memory impairment—defined as performance more than 1.5 standard deviations below the average of healthy controls—was absent during abstinence. However, during acute MDMA intoxication, verbal memory was impaired. Pooled data from four experimental studies compared 65 Ecstasy users tested on placebo with 65 matched drug-naïve controls. History of use did not predict memory impairment. The findings suggest that Ecstasy/MDMA use does not cause clinically deficient long-term verbal memory.