Psychopharmacology
August 13, 2018
Malin V. Uthaug, Kim van Oorsouw, Kim P. C. Kuypers et al.
213 citations
Ayahuasca, a psychotropic plant tea used ceremonially in South America, produces sub-acute and long-term improvements in affect and cognitive thinking style. In 57 ceremony attendees in the Netherlands and Colombia, ratings of depression and stress significantly decreased the day after the ceremony and these changes persisted for 4 weeks. Convergent thinking also improved post-ceremony and was maintained at 4 weeks. Satisfaction with life and several aspects of mindfulness increased the day after but were not significantly different from baseline at 4 weeks. Changes in affect, satisfaction with life, and mindfulness correlated with the degree of ego dissolution experienced during the ceremony, not with prior ayahuasca experience. These findings highlight ayahuasca's therapeutic potential for mental health disorders like depression.
Psychopharmacology
October 30, 2010
Johannes G. Ramaekers, Eef L. Theunissen, Marjolein de Brouwer et al.
168 citations
Heavy cannabis users develop tolerance to the impairing effects of THC on neurocognitive tasks, but they do not develop cross-tolerance to the impairing effects of alcohol. In a double-blind study, 21 heavy cannabis users received alcohol at three levels (targeting blood alcohol concentrations of 0, 0.5, and 0.7 mg/ml) and smoked a THC cigarette (400 μg/kg) 3 hours after drinking began. Alcohol alone impaired performance on tests of perceptual motor control, divided attention, and motor inhibition, while THC alone generally did not affect performance. However, combining THC and alcohol produced greater impairments in divided attention than alcohol alone, indicating that alcohol can potentiate THC effects in tolerant users.
Translational Psychiatry
April 8, 2021
Natasha L. Mason, Kim P. C. Kuypers, Johannes T. Reckweg et al.
132 citations
A double-blind, placebo-controlled experiment with 0.17 mg/kg psilocybin shows that the drug affects creative thinking in time-dependent and task-specific ways. Immediately after consumption, psilocybin increased spontaneous creative insights but decreased deliberate, task-based creativity. Seven days later, participants generated more novel ideas. Brain imaging revealed that both acute and persisting effects were predicted by connectivity within and between networks of the default mode network. These results support historical claims that psychedelics can influence aspects of the creative process and may serve as tools for investigating creativity and its neural basis.
Psychopharmacology
March 10, 2021
Malin V. Uthaug, Natasha L. Mason, Stefan W. Toennes et al.
116 citations
Ayahuasca, a plant mixture containing DMT and β-carboline alkaloids, has been linked to mental health improvements in naturalistic settings, but prior studies lacked placebo controls. In this observational study, 30 experienced participants at ayahuasca retreats in the Netherlands, Spain, and Germany were assessed before and after sessions; 14 consumed ayahuasca and 16 a placebo. Symptoms of depression, anxiety, and stress reduced over time in both groups, independent of treatment. However, ayahuasca specifically increased implicit emotional empathy to negative stimuli. The findings indicate that mental health improvements can arise from both placebo effects and pharmacological actions of ayahuasca, highlighting the need for placebo-controlled designs.
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.
Psychopharmacology
October 5, 2011
Eef L. Theunissen, Gerold F. Kauert, Stefan W. Toennes et al.
82 citations
Heavy cannabis users develop tolerance to some impairing effects of cannabis, observable both in behavior and in brain electrical activity. In a double-blind, placebo-controlled crossover study, 12 occasional and 12 heavy cannabis users smoked a joint containing either 0 or 500 μg/kg body weight THC. During a divided attention task, THC reduced P100 amplitude in occasional users but not in heavy users, indicating tolerance at the neural level. P300 amplitude decreased in both groups. Performance on the stop signal task was impaired in both groups after THC, while divided attention task performance was impaired only in occasional users. Tolerance was evident in event-related potentials, suggesting it is not solely due to behavioral compensation.
Scientific Reports
May 26, 2016
Johannes G. Ramaekers, J. H. van Wel, Desirée Spronk et al.
81 citations
Acute cannabis intoxication impairs executive function, impulse control, attention, and psychomotor function, and increases subjective intoxication, regardless of how frequently a person uses cannabis. In a study of 122 drug users with cannabis use histories ranging from infrequent to daily, cannabis (300 μg/kg THC) produced these deficits compared to placebo, while cocaine (300 mg) improved psychomotor function and attention but impaired impulse control. The absence of tolerance to cannabis's neurocognitive effects suggests that frequent use and intoxication can interfere with performance in daily environments such as school, work, or traffic.
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.
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.
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.
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.
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.
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.
Journal of Ethnopharmacology
May 8, 2013
Alexander Paulke, Christian Kremer, Cora Wunder et al.
31 citations
Lysergic acid amide (LSA) from Argyreia nervosa seeds, often considered a natural substitute for LSD, shows weak psychedelic activity and should not be regarded as LSD-like. Computer models predicted LSA has highest affinity for α1A and α1B receptors, with clear affinity for several serotonin and dopamine receptors. In lab tests, LSA had lower binding affinities than LSD for all tested receptor subtypes, but showed clear affinity for 5-HT1A, 5-HT2, and α2 receptors. Other ergotalkaloids in the plant also prefer serotonin and dopamine receptors. Vegetative and psychotropic effects may arise from serotonin or dopamine receptor activation, but the psychedelic effect is weak.
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.
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.
Psychopharmacology
January 26, 2021
Eef L. Theunissen, Johannes T. Reckweg, Nadia R. P. W. Hutten et al.
20 citations
A moderate dose of the synthetic cannabinoid JWH-018, inhaled by 24 healthy adults with no history of mental illness, produced pronounced psychedelic and dissociative effects, including altered perception, amnesia, derealization, depersonalization, and confusion. The average dose administered was 5.52 mg. These findings indicate that synthetic cannabinoids pose a serious risk for public health by inducing psychotomimetic symptoms even in people without prior mental health issues.
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.
European Neuropsychopharmacology
February 3, 2022
Lilian Kloft, Henry Otgaar, Arjan Blokland et al.
17 citations
A double-blind, placebo-controlled trial with 60 healthy volunteers who had previously used MDMA examined the drug's effects on false memory. Participants received 75 mg of MDMA or a placebo and were tested using a word list task and two misinformation tasks involving a virtual reality crime scene. Memory was tested immediately and one week later. MDMA caused small impairments in true memory on the word list task at both time points. It increased false memory for related but non-critical lures immediately but decreased false memory for critical lures after a week. Episodic memory in the misinformation tasks was not consistently affected. The findings suggest no heightened vulnerability to external suggestion during MDMA intoxication.
Biomedicine & Pharmacotherapy
March 24, 2022
Francisco Madrid-Gambin, Àlex Gomez‐gómez, 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.
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.
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.
Drug Testing and Analysis
March 26, 2019
Stefan W. Toennes, David J. Schneider, Werner Pogoda et al.
9 citations
The pharmacokinetics of 4-fluoroamphetamine (4-FA) in humans resemble those of amphetamine, with peak serum concentrations occurring about 2 hours after ingestion and an elimination half-life of roughly 8-9 hours, though this varies widely (5.5-16.8 hours). After a 100 mg dose, median maximum serum concentration was 195 ng/mL (range 155-316 ng/mL). Concentrations in oral fluid were higher than in serum, especially during the first 3 hours, likely due to oral contamination. Serum concentrations observed in forensic cases matched those in the study, suggesting recreational doses are similar, but such doses may already cause prominent adverse effects and life-threatening consequences.
Human Psychopharmacology Clinical and Experimental
October 25, 2018
Patrick C. Dolder, Elizabeth B. de Sousa Fernandes Perna, Natasha L. Mason et al.
6 citations
4-Fluoroamphetamine (4-FA), a novel psychoactive substance with effects between MDMA and amphetamine, reduced cognitive empathy while leaving emotional empathy unaffected in healthy poly-drug users. Plasma oxytocin levels increased one hour after a 100 mg dose compared with placebo, but this hormonal change was unrelated to the behavioral effects on empathy. The findings indicate that 4-FA affects empathy differently from MDMA and amphetamine, and confirm that drug-induced changes in peripheral oxytocin are not associated with empathy.