OPEN Foundation

N. Mason

Spontaneous and deliberate creative cognition during and after psilocybin exposure

Abstract

Creativity is an essential cognitive ability linked to all areas of our everyday functioning. Thus, finding a way to enhance it is of broad interest. A large number of anecdotal reports suggest that the consumption of psychedelic drugs can enhance creative thinking; however, scientific evidence is lacking. Following a double-blind, placebo-controlled, parallel-group design, we demonstrated that psilocybin (0.17 mg/kg) induced a time- and construct-related differentiation of effects on creative thinking. Acutely, psilocybin increased ratings of (spontaneous) creative insights, while decreasing (deliberate) task-based creativity. Seven days after psilocybin, number of novel ideas increased. Furthermore, we utilized an ultrahigh field multimodal brain imaging approach, and found that acute and persisting effects were predicted by within- and between-network connectivity of the default mode network. Findings add some support to historical claims that psychedelics can influence aspects of the creative process, potentially indicating them as a tool to investigate creativity and subsequent underlying neural mechanisms. Trial NL6007; psilocybin as a tool for enhanced cognitive flexibility; https://www.trialregister.nl/trial/6007 .

Mason, N. L., Kuypers, K., Reckweg, J. T., Müller, F., Tse, D., Da Rios, B., Toennes, S. W., Stiers, P., Feilding, A., & Ramaekers, J. G. (2021). Spontaneous and deliberate creative cognition during and after psilocybin exposure. Translational psychiatry, 11(1), 209. https://doi.org/10.1038/s41398-021-01335-5

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A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats

Abstract

Ayahuasca is a plant concoction containing N,N-dimethyltryptamine (DMT) and certain β-carboline alkaloids from South America. Previous research in naturalistic settings has suggested that ingestion of ayahuasca can improve mental health and well-being; however, these studies were not placebo controlled and did not control for the possibility of expectation bias. This naturalistic observational study was designed to assess whether mental health changes were produced by ayahuasca or by set and setting. Assessments were made pre- and post-ayahuasca sessions in 30 experienced participants of ayahuasca retreats hosted in the Netherlands, Spain, and Germany. Participants consumed ayahuasca (N = 14) or placebo (N = 16). Analysis revealed a main effect of time on symptoms of depression, anxiety, and stress. Compared to baseline, symptoms reduced in both groups after the ceremony, independent of treatment. There was a main treatment × time interaction on implicit emotional empathy, indicating that ayahuasca increased emotional empathy to negative stimuli. The current findings suggest that improvements in mental health of participants of ayahuasca ceremonies can be driven by non-pharmacological factors that constitute a placebo response but also by pharmacological factors that are related to the use of ayahuasca. These findings stress the importance of placebo-controlled designs in psychedelic research and the need to further explore the contribution of non-pharmacological factors to the psychedelic experience.

Uthaug, M. V., Mason, N. L., Toennes, S. W., Reckweg, J. T., de Sousa Fernandes Perna, E. B., Kuypers, K., van Oorsouw, K., Riba, J., & Ramaekers, J. G. (2021). A placebo-controlled study of the effects of ayahuasca, set and setting on mental health of participants in ayahuasca group retreats. Psychopharmacology, 238(7), 1899–1910. https://doi.org/10.1007/s00213-021-05817-8

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Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants

Abstract

“Microdoses” of lysergic acid diethylamide (LSD) are used recreationally to enhance mood and cognition. Increasing interest has also been seen in developing LSD into a medication. Therefore, we performed a pharmacokinetic-pharmacodynamic study using very low doses of LSD. Single doses of LSD base (5, 10, and 20 µg) and placebo were administered in a double-blind, randomized, placebo-controlled crossover study in 23 healthy participants. Test days were separated by at least 5 days. Plasma levels of LSD and subjective effects were assessed up to 6 hours after administration. Pharmacokinetic parameters were determined using compartmental modeling. Concentration-subjective effect relationships were described using pharmacokinetic-pharmacodynamic modeling. Mean (95% confidence interval) maximal LSD concentrations were 151 pg/mL (127-181), 279 pg/mL (243-320), and 500 pg/mL (413-607) after 5, 10, and 20 µg LSD administration, respectively. Maximal concentrations were reached after 1.1 hours. The mean elimination half-life was 2.7 hours (1.5-6.2). The 5 µg dose of LSD elicited no significant acute subjective effects. The 10 µg dose of LSD significantly increased ratings of “under the influence” and “good drug effect” compared with placebo. These effects began an average of 1.1 hours after 10 µg LSD administration, peaked at 2.5 hours, and ended at 5.1 hours. The 20 µg dose of LSD significantly increased ratings of “under the influence,” “good drug effects,” and “bad drug effects.” LSD concentrations dose-proportionally increased at doses as low as 5-20 µg and decreased with a half-life of 3 hours. The threshold dose of LSD base for psychotropic effects was 10 µg.

Holze, F., Liechti, M. E., Hutten, N., Mason, N. L., Dolder, P. C., Theunissen, E. L., Duthaler, U., Feilding, A., Ramaekers, J. G., & Kuypers, K. (2021). Pharmacokinetics and Pharmacodynamics of Lysergic Acid Diethylamide Microdoses in Healthy Participants. Clinical pharmacology and therapeutics, 109(3), 658–666. https://doi.org/10.1002/cpt.2057

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Mood and cognition after administration of low LSD doses in healthy volunteers: A placebo controlled dose-effect finding study

Abstract

There is a popular interest in microdosing with psychedelics such as LSD. This practice of using one-tenth of a full psychedelic dose according to a specific dosing schedule, anecdotally enhances mood and performance. Nonetheless, controlled research on the efficacy of microdosing is scarce. The main objective of the present dose-finding study was to determine the minimal dose of LSD needed to affect mood and cognition. A placebo-controlled within-subject study including 24 healthy participants, was conducted to assess the acute effects of three LSD doses (5, 10, and 20 mcg) on measures of cognition, mood, and subjective experience, up until 6 h after administration. Cognition and subjective experience were assessed using the Psychomotor Vigilance Task, Digit Symbol Substitution Test, Cognitive Control Task, Profile of Mood States, and 5-Dimensional Altered States of Consciousness rating scale. LSD showed positive effects in the majority of observations by increasing positive mood (20 mcg), friendliness (5, 20 mcg), arousal (5 mcg), and decreasing attentional lapses (5, 20 mcg). Negative effects manifested as an increase in confusion (20 mcg) and anxiety (5, 20 mcg). Psychedelic-induced changes in waking consciousness were also present (10, 20 mcg). Overall, the present study demonstrated selective, beneficial effects of low doses of LSD on mood and cognition in the majority of observations. The minimal LSD dose at which subjective and performance effects are notable is 5 mcg and the most apparent effects were visible after 20 mcg.

Hutten, N., Mason, N. L., Dolder, P. C., Theunissen, E. L., Holze, F., Liechti, M. E., Feilding, A., Ramaekers, J. G., & Kuypers, K. (2020). Mood and cognition after administration of low LSD doses in healthy volunteers: A placebo controlled dose-effect finding study. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 41, 81–91. https://doi.org/10.1016/j.euroneuro.2020.10.002

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Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers

Abstract

Despite preclinical evidence for psychedelic-induced neuroplasticity, confirmation in humans is grossly lacking. Given the increased interest in using low doses of psychedelics for psychiatric indications and the importance of neuroplasticity in the therapeutic response, this placebo-controlled within-subject study investigated the effect of single low doses of LSD (5, 10, and 20 μg) on circulating BDNF levels in healthy volunteers. Blood samples were collected every 2 h over 6 h, and BDNF levels were determined afterward in blood plasma using ELISA. The findings demonstrated an increase in BDNF blood plasma levels at 4 h (5 μg) and 6 h (5 and 20 μg) compared to that for the placebo. The finding that LSD acutely increases BDNF levels warrants studies in patient populations.

Hutten, N., Mason, N. L., Dolder, P. C., Theunissen, E. L., Holze, F., Liechti, M. E., Varghese, N., Eckert, A., Feilding, A., Ramaekers, J. G., & Kuypers, K. (2020). Low Doses of LSD Acutely Increase BDNF Blood Plasma Levels in Healthy Volunteers. ACS pharmacology & translational science, 4(2), 461–466. https://doi.org/10.1021/acsptsci.0c00099

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Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin

Abstract

There is growing interest in the therapeutic utility of psychedelic substances, like psilocybin, for disorders characterized by distortions of the self-experience, like depression. Accumulating preclinical evidence emphasizes the role of the glutamate system in the acute action of the drug on brain and behavior; however this has never been tested in humans. Following a double-blind, placebo-controlled, parallel group design, we utilized an ultra-high field multimodal brain imaging approach and demonstrated that psilocybin (0.17 mg/kg) induced region-dependent alterations in glutamate, which predicted distortions in the subjective experience of one’s self (ego dissolution). Whereas higher levels of medial prefrontal cortical glutamate were associated with negatively experienced ego dissolution, lower levels in hippocampal glutamate were associated with positively experienced ego dissolution. Such findings provide further insights into the underlying neurobiological mechanisms of the psychedelic, as well as the baseline, state. Importantly, they may also provide a neurochemical basis for therapeutic effects as witnessed in ongoing clinical trials.

Mason, N. L., Kuypers, K. P. C., Müller, F., Reckweg, J., Tse, D. H. Y., Toennes, S. W., … & Ramaekers, J. G. (2020). Me, myself, bye: regional alterations in glutamate and the experience of ego dissolution with psilocybin. Neuropsychopharmacology, 1-11., https://doi.org/10.1038/s41386-020-0718-8
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Self-Rated Effectiveness of Microdosing With Psychedelics for Mental and Physical Health Problems Among Microdosers

Abstract

Background: There is a growing interest in the use of psychedelic substances for health related purposes, including symptom relief for disorders like anxiety, depression, and pain. Although the focus of recent clinical trials has been on high doses of these substances, anecdotal evidence suggests that low (micro) doses are also effective, and may be more suitable for certain conditions. Nonetheless, empirical evidence regarding the efficacy of microdosing with psychedelics for symptomatic relief is lacking. The present study aimed to investigate, by means of an online questionnaire, the self-rated effectiveness (SRE) of microdosing with psychedelics (MDP) for mental and physiological disorders compared to the conventional prescribed treatment and to regular doses of psychedelics. Methods: An online questionnaire was launched on several websites and fora between March and July 2018. Respondents who had consented, were 18 years of age or older, had experience with microdosing and were diagnosed with at least one mental or physiological disorder by a medical doctor or therapist (N = 410; 7.2%) were included in the analyses. Odds ratio were calculated to compare the SRE of MDP with conventional treatment, and regular psychedelic doses for mental and physiological diagnoses for each of the three effectiveness questions (“Did it work,” “Symptom disappear,” “Quality of life improved”). Results: Odds ratio showed that SRE of MDP was significantly higher compared to that of conventional treatments for both mental and physiological diagnoses; and that these effects were specific for ADHD/ADD and anxiety disorders. In contrast, SRE of MDP was lower compared to that of higher, regular psychedelic doses for mental disorders such as anxiety and depression, while for physiological disorders no difference was shown. Conclusion: This study demonstrates that SRE of MDP to alleviate symptoms of a range of mental or physiological diagnoses is higher compared to conventionally offered treatment options, and lower than regular (‘full’) psychedelic doses. Future RCTs in patient populations should objectively assess the effectivity claims of psychedelics, and whether these are dose related, disorder specific, and superior to conventional treatments.

Hutten, N. R., Mason, N. L., Dolder, P. C., & Kuypers, K. P. (2019). Self-rated effectiveness of microdosing with psychedelics for mental and physical health problems amongst microdosers. Frontiers in psychiatry10, 672. 10.3389/fpsyt.2019.00672

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A single inhalation of vapor from dried toad secretion containing 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms

Abstract

BACKGROUND: 5-methoxy-N,N-dimethyltryptamine (hereinafter referred to as 5-MeO-DMT) is a psychedelic substance found in the secretion from the parotoid glands of the Bufo alvarius toad. Inhalation of vapor from toad secretion containing 5-MeO-DMT has become popular in naturalistic settings as a treatment of mental health problems or as a means for spiritual exploration. However, knowledge of the effects of 5-MeO-DMT in humans is limited.
AIMS: The first objective of this study was to assess sub-acute and long-term effects of inhaling vapor from dried toad secretion containing 5-MeO-DMT on affect and cognition. The second objective was to assess whether any changes were associated with the psychedelic experience.
METHODS: Assessments at baseline, within 24 h and 4 weeks following intake, were made in 42 individuals who inhaled vapor from dried toad secretion at several European locations.
RESULTS: Relative to baseline, ratings of satisfaction with life and convergent thinking significantly increased right after intake and were maintained at follow-up 4 weeks later. Ratings of mindfulness also increased over time and reached statistical significance at 4 weeks. Ratings of depression, anxiety, and stress decreased after the session, and reached significance at 4 weeks. Participants that experienced high levels of ego dissolution or oceanic boundlessness during the session displayed higher ratings of satisfaction with life and lower ratings of depression and stress.
CONCLUSION: A single inhalation of vapor from dried toad secretion containing 5-MeO-DMT produces sub-acute and long-term changes in affect and cognition in volunteers. These results warrant exploratory research into therapeutic applications of 5-MeO-DMT.
Uthaug, M. V., Lancelotta, R., van Oorsouw, K., Kuypers, K. P. C., Mason, N., Rak, J., … & Ramaekers, J. G. (2019). A single inhalation of vapor from dried toad secretion containing 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms. Psychopharmacology236(9), 2653-2666., https://doi.org/10.1007/s00213-019-05236-w
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A single inhalation of vapor from dried toad secretion containing 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms.

Abstract

BACKGROUND:
5-methoxy-N,N-dimethyltryptamine (hereinafter referred to as 5-MeO-DMT) is a psychedelic substance found in the secretion from the parotoid glands of the Bufo alvarius toad. Inhalation of vapor from toad secretion containing 5-MeO-DMT has become popular in naturalistic settings as a treatment of mental health problems or as a means for spiritual exploration. However, knowledge of the effects of 5-MeO-DMT in humans is limited.
AIMS:
The first objective of this study was to assess sub-acute and long-term effects of inhaling vapor from dried toad secretion containing 5-MeO-DMT on affect and cognition. The second objective was to assess whether any changes were associated with the psychedelic experience.
METHODS:
Assessments at baseline, within 24 h and 4 weeks following intake, were made in 42 individuals who inhaled vapor from dried toad secretion at several European locations.
RESULTS:
Relative to baseline, ratings of satisfaction with life and convergent thinking significantly increased right after intake and were maintained at follow-up 4 weeks later. Ratings of mindfulness also increased over time and reached statistical significance at 4 weeks. Ratings of depression, anxiety, and stress decreased after the session, and reached significance at 4 weeks. Participants that experienced high levels of ego dissolution or oceanic boundlessness during the session displayed higher ratings of satisfaction with life and lower ratings of depression and stress.
CONCLUSION:
A single inhalation of vapor from dried toad secretion containing 5-MeO-DMT produces sub-acute and long-term changes in affect and cognition in volunteers. These results warrant exploratory research into therapeutic applications of 5-MeO-DMT.

 
Uthaug, M. V., Lancelotta, R., van Oorsouw, K., Kuypers, K. P. C., Mason, N., Rak, J., … & Páleníček, T. (2019). A single inhalation of vapor from dried toad secretion containing 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) in a naturalistic setting is related to sustained enhancement of satisfaction with life, mindfulness-related capacities, and a decrement of psychopathological symptoms. Psychopharmacology, 1-14., https://doi.org/10.1007/s00213-019-05236-w
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Sub-Acute Effects of Psilocybin on Empathy, Creative Thinking, and Subjective Well-Being

Abstract

Creative thinking and empathy are crucial for everyday interactions and subjective well-being. This is emphasized by studies showing a reduction in these skills in populations where social interaction and subjective well-being are significantly compromised (e.g., depression). Anecdotal reports and recent studies suggest that a single administration of psilocybin can enhance such processes and could therefore be a potential treatment. However, it has yet to be assessed whether effects outlast acute intoxication. The present study aimed to assess the sub-acute effects of psilocybin on creative thinking, empathy, and well-being. Participants attending a psilocybin retreat completed tests of creative (convergent and divergent) thinking and empathy, and the satisfaction with life scale on three occasions: before ingesting psilocybin (N = 55), the morning after (N = 50), and seven days after (N = 22). Results indicated that psilocybin enhanced divergent thinking and emotional empathy the morning after use. Enhancements in convergent thinking, valence-specific emotional empathy, and well-being persisted seven days after use. Sub-acute changes in empathy correlated with changes in well-being. The study demonstrates that a single administration of psilocybin in a social setting may be associated with sub-acute enhancement of creative thinking, empathy, and subjective well-being. Future research should test whether these effects contribute to the therapeutic effects in clinical populations.

Mason, N. L., Mischler, E., Uthaug, M. V., & Kuypers, K. P. (2019). Sub-Acute Effects of Psilocybin on Empathy, Creative Thinking, and Subjective Well-Being. Journal of psychoactive drugs, 1-12., 10.1080/02791072.2019.1580804
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