Psychopharmacology
July 19, 2016
Kim P. C. Kuypers, Jordi Riba, Mario de la Fuente Revenga et al.
204 citations
Ayahuasca, a psychedelic plant tea used in Amazonian shamanism, may enhance creative divergent thinking—the ability to generate new ideas and strategies—while decreasing convergent thinking, which focuses on a single correct answer. In a study of 26 participants at two spiritual workshops, creativity tests before and during the acute effects of ayahuasca showed that the tea significantly increased divergent thinking and decreased convergent thinking, as measured by the picture concept test. No significant effects were found on the pattern/line meanings test. These results suggest ayahuasca increases psychological flexibility, potentially aiding psychotherapeutic interventions.
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.
ACS Pharmacology & Translational Science
August 31, 2020
Nadia R. P. W. Hutten, Natasha L. Mason, Patrick C. Dolder et al.
134 citations
Low doses of LSD (5, 10, and 20 μg) increase brain-derived neurotrophic factor (BDNF) levels in blood plasma, a marker of neuroplasticity. In a placebo-controlled within-subject study with healthy volunteers, BDNF levels rose at 4 hours after 5 μg and at 6 hours after both 5 and 20 μg, compared to placebo. This suggests that even low doses of LSD can acutely enhance neuroplasticity, supporting further research in patient populations for psychiatric conditions.
European Neuropsychopharmacology
October 17, 2020
Nadia R. P. W. Hutten, Natasha L. Mason, Patrick C. Dolder et al.
121 citations
Taking very low doses of LSD, known as microdosing, can selectively improve mood and cognition. In a placebo-controlled experiment with 24 healthy adults, doses of 5, 10, and 20 micrograms of LSD were tested. The 20 mcg dose increased positive mood, while 5 mcg and 20 mcg increased friendliness and reduced attentional lapses. Arousal increased at 5 mcg. Negative effects included increased confusion at 20 mcg and increased anxiety at both 5 and 20 mcg. Altered states of waking consciousness occurred at 10 and 20 mcg. The minimal dose producing noticeable effects was 5 mcg, with the clearest effects at 20 mcg.
PLoS ONE
July 10, 2012
Janelle H. P. van Wel, Kim P. C. Kuypers, Eef L. Theunissen et al.
121 citations
MDMA increases both positive moods (vigor, arousal, friendliness, elation) and negative moods (anxiety, confusion) while also slowing reaction times on impulsivity tasks, indicating greater impulse control. Blocking 5-HT(2) receptors with ketanserin prevented the positive mood effects but not the negative mood or impulsivity changes. Blocking 5-HT(1) receptors with pindolol had no effect on any MDMA-related mood or impulse measures. Thus, 5-HT(2) receptors are specifically involved in MDMA's positive mood enhancement, while 5-HT(1) receptors do not appear to play a role in these effects.
Journal of Psychopharmacology
August 25, 2020
Johannes G. Ramaekers, Nadia R. P. W. Hutten, Natasha L. Mason et al.
95 citations
A low dose of LSD (20 micrograms) that does not cause a psychedelic experience can increase pain tolerance and reduce the unpleasantness of pain in healthy volunteers. In a controlled experiment with 24 participants, those given 20 µg of LSD kept their hand in cold (3°C) water longer and reported less pain than when given a placebo. Smaller doses (5 and 10 µg) did not produce the same effect. The 20 µg dose caused slight increases in blood pressure, anxiety, and dissociation, but no profound mind-altering effects. These findings suggest that very low doses of LSD may offer a new approach to pain management without the intense psychological effects of higher doses.
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.
Clinical Pharmacology & Therapeutics
September 25, 2020
Friederike Holze, Matthias E. Liechti, Nadia R. P. W. Hutten et al.
63 citations
Very low doses of LSD (5, 10, and 20 µg) were given to 23 healthy participants in a double-blind, placebo-controlled crossover trial. LSD concentrations in the blood increased in proportion to dose, with maximal levels reached after about 1.1 hours and an average elimination half-life of 2.7 hours. The 5 µg dose produced no significant subjective effects. The 10 µg dose significantly increased feelings of being under the influence and good drug effect, starting at 1.1 hours, peaking at 2.5 hours, and lasting until 5.1 hours. The 20 µg dose also increased bad drug effects. The threshold for psychotropic effects was 10 µg.
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.
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.
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.
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.
Frontiers in Pharmacology
January 28, 2020
Esther Papaseit, Clara Pérez-mañá, Elizabeth B. de Sousa Fernandes Perna et al.
27 citations
Combining mephedrone with alcohol amplifies cardiovascular effects and intensifies euphoria and well-being compared to either drug alone, while mephedrone reduces the sedative effects of alcohol. In a double-blind, placebo-controlled trial with 11 male volunteers, the combination increased blood pressure, heart rate, and subjective feelings of euphoria. Mephedrone alone and alcohol alone were also tested. The results suggest that the abuse liability of mephedrone is greater when taken with alcohol, similar to other psychostimulants like amphetamines and MDMA.
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.
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.
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.
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.