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K. Kuypers

Out of the box: A psychedelic model to study the creative mind

March 23, 2018 / Anxiety Disorders / PTSD, Depressive Disorders, Mushrooms / Psilocybin, Neuroscience, Papers, Psychiatry & Medicine, Publications / By /

Abstract

Our creativity is challenged daily when facing new situations asking for novel solutions. Creativity, a multicomponent construct includes flexible divergent and rigid convergent thinking. Psychedelic drugs like psilocybin can enhance creativity and affect state of mind (mood, empathy, openness). Of note, flexible thinking is disturbed in psychopathological conditions like anxiety disorders and depression and preliminary findings have shown psychedelics to be efficacious in the treatment of those conditions. The question how psychedelics induce this state of enhanced flexible thinking remains to be answered and investigating the neurobiology underlying this phenomenon will not only help in understanding why psychedelics are of use in the therapeutic setting but also in other settings where flexible thinking is challenged. A model including neuronal networks, neurotransmitters and personal factors playing a role in this process will be proposed which can be put to the test by means of placebo-controlled pharmaco-imaging studies in healthy volunteers.

Kuypers, K. P. C. (2018). Out of the box: A psychedelic model to study the creative mind. Medical hypotheses, 115, 13-16.,  10.1016/j.mehy.2018.03.010

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Depressive mood ratings are reduced by MDMA in female polydrug ecstasy users homozygous for the l-allele of the serotonin transporter

January 18, 2018 / MDMA, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

MDMA exerts its main effects via the serotonergic system and the serotonin transporter. The gene coding for this transporter determines the expression rate of the transporter. Previously it was shown that healthy individuals with the short allelic variant (‘s-group’) of the 5-HTTLPR-polymorphism displayed more anxiety and negative mood, and had a lower transcriptional efficiency compared to individuals who are homozygous for the l-allele (‘l-group’). The present study aimed to investigate the role of the 5-HTTLPR polymorphism in MDMA-induced mood effects. Four placebo-controlled, within-subject studies were pooled, including in total 63 polydrug ecstasy users (Ns-group = 48; Nl-group = 15) receiving MDMA 75 mg and placebo on two test days, separated by minimally 7 days. Mood was assessed by means of the Profile of Mood States. Findings showed that MDMA induced -independent of sex- a positive mood state, and as a side effect also increased two negative affect states, anxiety and confusion. Anxiety ratings were higher in the l-group and independent of treatment or sex. Depression ratings were lowered by MDMA in the female l-group. Findings indicate that the MDMA-induced reduction in self-rated depressive feelings is sex- and genotype-dependent, with females homozygous for the l-allele showing this beneficial effect.
Kuypers, K. P. C., de la Torre, R., Farre, M., Xicota, L., Perna, E. D. S. F., Theunissen, E. L., & Ramaekers, J. G. (2018). Depressive mood ratings are reduced by MDMA in female polydrug ecstasy users homozygous for the l-allele of the serotonin transporter. Scientific reports, 8(1), 1061. 10.1038/s41598-018-19618-1
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MDMA-induced indifference to negative sounds is mediated by the 5-HT2A receptor

July 22, 2017 / MDMA, Papers, Psychology / By / , , , ,

Abstract

BACKGROUND:
MDMA has been shown to induce feelings of sociability, a positive emotional bias and enhanced empathy. While previous research has used only visual emotional stimuli, communication entails more than that single dimension and it is known that auditory information is also crucial in this process. In addition, it is, however, unclear what the neurobiological mechanism underlying these MDMA effects on social behaviour is. Previously, studies have shown that MDMA-induced emotional excitability and positive mood are linked to the action on the serotonin (5-HT) 2A receptor.
AIM:
The present study aimed at investigating the effect of MDMA on processing of sounds (Processing of Affective Sounds Task (PAST)) and cognitive biases (Approach-Avoidance Task (AAT)) towards emotional and social stimuli and the role of 5-HT2A receptor in these effects.
METHODS:
Twenty healthy recreational users entered a 2 × 2, placebo-controlled, within-subject study with ketanserin (40 mg) as pre-treatment and MDMA (75 mg) as treatment. Behavioural (PAST, AAT) measures were conducted 90 min after treatment with MDMA, respectively, 120 min after ketanserin. Self-report mood measures and oxytocin concentrations were taken at baseline and before and after behavioural tests.
RESULTS:
Findings showed that MDMA reduced arousal elicited by negative sounds. This effect was counteracted by ketanserin pre-treatment, indicating involvement of the 5-HT2 receptor in this process. MDMA did not seem to induce a bias towards emotional and social stimuli. It increased positive and negative mood ratings and elevated oxytocin plasma concentrations. The reduction in arousal levels when listening to negative sounds was not related to the elevated subjective arousal.
CONCLUSION:
It is suggested that this decrease in arousal to negative stimuli reflects potentially a lowering of defences, a process that might play a role in the therapeutic process.
Kuypers, K. P. C., de la Torre, R., Pizarro, N., Xicota, L., & Ramaekers, J. G. MDMA-induced indifference to negative sounds is mediated by the 5-HT2A receptor. Psychopharmacology, 1-10. 10.1007/s00213-017-4699-1
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MDMA-Induced Dissociative State not Mediated by the 5-HT2A Receptor

July 11, 2017 / MDMA, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Previous research has shown that a single dose of MDMA induce a dissociative state, by elevating feelings of depersonalization and derealization. Typically, it is assumed that action on the 5-HT2A receptor is the mechanism underlying these psychedelic experiences. In addition, other studies have shown associations between dissociative states and biological parameters (heart rate, cortisol), which are elevated by MDMA. In order to investigate the role of the 5-HT2 receptor in the MDMA-induced dissociative state and the association with biological parameters, a placebo-controlled within-subject study was conducted including a single oral dose of MDMA (75 mg), combined with placebo or a single oral dose of the 5-HT2 receptor blocker ketanserin (40 mg). Twenty healthy recreational MDMA users filled out a dissociative states scale (CADSS) 90 min after treatments, which was preceded and followed by assessment of a number of biological parameters (cortisol levels, heart rate, MDMA blood concentrations). Findings showed that MDMA induced a dissociative state but this effect was not counteracted by pre-treatment with ketanserin. Heart rate was the only biological parameter that correlated with the MDMA-induced dissociative state, but an absence of correlation between these measures when participants were pretreated with ketanserin suggests an absence of directional effects of heart rate on dissociative state. It is suggested that the 5-HT2 receptor does not mediate the dissociative effects caused by a single dose of MDMA. Further research is needed to determine the exact neurobiology underlying this effect and whether these effects contribute to the therapeutic potential of MDMA.
Puxty, D. J., Ramaekers, J. G., de la Torre, R., Farré, M., Pizarro, N., Pujadas, M., & Kuypers, K. P. (2017). MDMA-induced dissociative state not mediated by the 5-HT2A receptor. Frontiers in pharmacology, 8, 455. 10.3389/fphar.2017.00455
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Multifaceted empathy of healthy volunteers after single doses of MDMA: A pooled sample of placebo-controlled studies

April 3, 2017 / MDMA, Papers, Psychology, Publications / By / , , ,

Abstract

Previous placebo-controlled experimental studies have shown that a single dose of MDMA can increase emotional empathy in the multifaceted empathy test (MET) without affecting cognitive empathy. Although sufficiently powered to detect main effects of MDMA, these studies were generally underpowered to also validly assess contributions of additional parameters, such as sex, drug use history, trait empathy and MDMA or oxytocin plasma concentrations. The present study examined the robustness of the MDMA effect on empathy and investigated the moderating role of these additional parameters. Participants ( n = 118) from six placebo-controlled within-subject studies and two laboratories were included in the present pooled analysis. Empathy (MET), MDMA and oxytocin plasma concentrations were assessed after oral administration of MDMA (single dose, 75 or 125 mg). Trait empathy was assessed using the interpersonal reactivity index. We confirmed that MDMA increased emotional empathy at both doses without affecting cognitive empathy. This MDMA-related increase in empathy was most pronounced during presentation of positive emotions as compared with negative emotions. MDMA-induced empathy enhancement was positively related to MDMA blood concentrations measured before the test, but independent of sex, drug use history and trait empathy. Oxytocin concentrations increased after MDMA administration but were not associated with behavioral effects. The MDMA effects on emotional empathy were stable across laboratories and doses. Sex did not play a moderating role in this effect, and oxytocin levels, trait empathy and drug use history were also unrelated. Acute drug exposure was of significant relevance in the MDMA-induced emotional empathy elevation.
Kuypers, K. P., Dolder, P. C., Ramaekers, J. G., & Liechti, M. E. (2017). Multifaceted empathy of healthy volunteers after single doses of MDMA: A pooled sample of placebo-controlled studies. Journal of Psychopharmacology, 31(5), 589-598. 10.1177/0269881117699617
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Ayahuasca enhances creative divergent thinking while decreasing conventional convergent thinking

July 19, 2016 / Ayahuasca, Papers, Psychology, Publications / By / , , , , ,

Abstract

Introduction: Ayahuasca is a South American psychotropic plant tea traditionally used in Amazonian shamanism. The tea contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT), plus β-carboline alkaloids with monoamine oxidase-inhibiting properties. Increasing evidence from anecdotal reports and open-label studies indicates that ayahuasca may have therapeutic effects in treatment of substance use disorders and depression. A recent study on the psychological effects of ayahuasca found that the tea reduces judgmental processing and inner reactivity, classic goals of mindfulness psychotherapy. Another psychological facet that could potentially be targeted by ayahuasca is creative divergent thinking. This mode of thinking can enhance and strengthen psychological flexibility by allowing individuals to generate new and effective cognitive, emotional, and behavioral strategies. The present study aimed to assess the potential effects of ayahuasca on creative thinking.

Methods: We visited two spiritual ayahuasca workshops and invited participants to conduct creativity tests before and during the acute effects of ayahuasca. In total, 26 participants consented. Creativity tests included the “pattern/line meanings test” (PLMT) and the “picture concept test” (PCT), both assessing divergent thinking and the latter also assessing convergent thinking.

Results: While no significant effects were found for the PLMT, ayahuasca intake significantly modified divergent and convergent thinking as measured by the PCT. While convergent thinking decreased after intake, divergent thinking increased.

Conclusions: The present data indicate that ayahuasca enhances creative divergent thinking. They suggest that ayahuasca increases psychological flexibility, which may facilitate psychotherapeutic interventions and support clinical trial initiatives.

Kuypers, K. P. C., Riba, J., de la Fuente Revenga, M., Barker, S., Theunissen, E. L., & Ramaekers, J. G. (2016). Ayahuasca enhances creative divergent thinking while decreasing conventional convergent thinking. Psychopharmacology, 1-9. 10.1007/s00213-016-4377-8

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Verbal Memory Impairment in Polydrug Ecstasy Users: A Clinical Perspective

February 23, 2016 / MDMA, Papers, Psychology, Publications / By / , , , , , ,

Abstract

BACKGROUND:

Ecstasy use has been associated with short-term and long-term memory deficits on a standard Word Learning Task (WLT). The clinical relevance of this has been debated and is currently unknown. The present study aimed at evaluating the clinical relevance of verbal memory impairment in Ecstasy users. To that end, clinical memory impairment was defined as decrement in memory performance that exceeded the cut-off value of 1.5 times the standard deviation of the average score in the healthy control sample. The primary question was whether being an Ecstasy user (E-user) was predictive of having clinically deficient memory performance compared to a healthy control group.

METHODS:

WLT data were pooled from four experimental MDMA studies that compared memory performance during placebo and MDMA intoxication. Control data were taken from healthy volunteers with no drug use history who completed the WLT as part of a placebo-controlled clinical trial. This resulted in a sample size of 65 E-users and 65 age- and gender-matched healthy drug-naïve controls. All participants were recruited by similar means and were tested at the same testing facilities using identical standard operating procedures. Data were analyzed using linear mixed-effects models, Bayes factor, and logistic regressions.

RESULTS:

Findings were that verbal memory performance of placebo-treated E-users did not differ from that of controls, and there was substantial evidence in favor of the null hypothesis. History of use was not predictive of memory impairment. During MDMA intoxication of E-users, verbal memory was impaired.

CONCLUSION:

The combination of the acute and long-term findings demonstrates that, while clinically relevant memory impairment is present during intoxication, it is absent during abstinence. This suggests that use of Ecstasy/MDMA does not lead to clinically deficient memory performance in the long term. Additionally, it has to be investigated whether the current findings apply to more complex cognitive measures in diverse ‘user categories’ using a combination of genetics, imaging techniques and neuropsychological assessments.

Kuypers, K. P., Theunissen, E. L., van Wel, J. H., Perna, E. B. D. S. F., Linssen, A., Sambeth, A., … & Ramaekers, J. G. (2016). Verbal Memory Impairment in Polydrug Ecstasy Users: A Clinical Perspective. PloS one, 11(2), e0149438. http://dx.doi.org/10.1371/journal.pone.0149438

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MDMA, cannabis, and cocaine produce acute dissociative symptoms

August 30, 2015 / MDMA, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Some drugs of abuse may produce dissociative symptoms, but this aspect has been understudied. We explored the dissociative potential of three recreational drugs (3,4-methylenedioxymethamphetamine (MDMA), cannabis, and cocaine) during intoxication and compared their effects to literature reports of dissociative states in various samples. Two placebo-controlled studies were conducted. In Study 1 (N=16), participants received single doses of 25, 50, and 100 mg of MDMA, and placebo. In Study 2 (N=21), cannabis (THC 300 µg/kg), cocaine (HCl 300 mg), and placebo were administered. Dissociative symptoms as measured with the Clinician-Administered Dissociative States Scale (CADSS) significantly increased under the influence of MDMA and cannabis. To a lesser extent, this was also true for cocaine. Dissociative symptoms following MDMA and cannabis largely exceeded those observed in schizophrenia patients, were comparable with those observed in Special Forces soldiers undergoing survival training, but were lower compared with ketamine-induced dissociation. Cocaine produced dissociative symptoms that were comparable with those observed in schizophrenia patients, but markedly less than those in Special Forces soldiers and ketamine users. Thus, MDMA and cannabis can produce dissociative symptoms that resemble dissociative pathology. The study of drug induced dissociation is important, because it may shed light on the mechanisms involved in dissociative psychopathology.

van Heugten-Van der Kloet, D., Giesbrecht, T., van Wel, J., Bosker, W. M., Kuypers, K. P., Theunissen, E. L., … & Ramaekers, J. G. (2015). MDMA, cannabis, and cocaine produce acute dissociative symptoms. Psychiatry research, 228(3), 907-912. http://dx.doi.org/10.1016/j.psychres.2015.04.028

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Acute dose of MDMA (75 mg) impairs spatial memory for location but leaves contextual processing of visuospatial information unaffected

March 1, 2006 / MDMA, Papers, Psychology, Publications / By / ,

Abstract

Rationale: Research concerning spatial memory in 3,4-methylenedioxymethamphetamine (MDMA) users has presented conflicting results showing either the presence or absence of spatial memory deficits. Two factors may have confounded results in abstinent users: memory task characteristics and polydrug use.

Objectives: The present study aims to assess whether a single dose of MDMA affects spatial memory performance during intoxication and withdrawal phase and whether spatial memory performance after MDMA is task dependent.

Materials and methods: Eighteen recreational MDMA users participated in a double-blind, placebo-controlled, three-way crossover design. They were treated with placebo, MDMA 75 mg, and methylphenidate 20 mg. Memory tests were conducted between 1.5 and 2 h (intoxication phase) and between 25.5 and 26 h (withdrawal phase) post-dosing. Two spatial memory tasks of varying complexity were used that required either storage of stimulus location alone (spatial memory task) or memory for location as well as processing of content or contextual information (change blindness task).

Results: After a single dose of MDMA, the subjects made larger localization errors and responded faster compared to placebo in the simple spatial memory task during intoxication phase. Inaccuracy was not due to increased response speed, as determined by regression analysis. Performance in the change blindness task was not affected by MDMA. Methylphenidate did not affect performance on any of the tasks.

Conclusion: It is concluded that a single dose of MDMA impairs spatial memory for location but leaves processing of contextual information intact.

Kuypers, K. P., & Ramaekers, J. G. (2007). Acute dose of MDMA (75 mg) impairs spatial memory for location but leaves contextual processing of visuospatial information unaffected. Psychopharmacology, 189(4), 557-563. 10.1007/s00213-006-0321-7

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Transient memory impairment after acute dose of 75mg 3.4-Methylene-dioxymethamphetamine

November 1, 2005 / MDMA, Papers, Psychology, Publications / By / ,

Abstract

A range of studies has indicated that users of 3.4-Methylene-dioxymethamphetamine (MDMA, ‘Ecstasy’) display cognitive deficits, particularly memory impairment, as compared to non-drug using controls. Yet it is difficult to determine whether these deficits are caused by MDMA or some other confounding factor, such as polydrug use. The present study was designed to establish the direct relation between MDMA and memory impairment under placebo-controlled conditions. Eighteen recreational MDMA users participated in a double blind, placebo controlled, 3-way crossover design. They were treated with placebo, MDMA 75mg and methylphenidate 20mg. Memory tests were conducted between 1.5-2h (intoxication phase) and between 25.5-26h (withdrawal phase) post dosing. Results showed that a single dose of MDMA caused impairment of immediate and delayed recall on a verbal learning task during the intoxication phase. However, there was no residual memory impairment during the withdrawal phase. Subjects reported more fatigue and less vigour, but no symptoms of depression during the withdrawal phase of MDMA treatment.

Methylphenidate did not affect memory or mood at any time of testing. A single dose of MDMA produces transient memory impairment.

Kuypers, K. P., & Ramaekers, J. G. (2005). Transient memory impairment after acute dose of 75mg 3.4-Methylene-dioxymethamphetamine. Journal of Psychopharmacology, 19(6), 633-639. 10.1177/0269881105056670
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