OPEN Foundation

J. Ramaekers

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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Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes

Abstract

Mescaline is a naturally occurring psychoactive alkaloid that has been used as a sacrament by Indigenous populations in spiritual ritual and healing ceremonies for millennia. Despite promising early preliminary research and favorable anecdotal reports, there is limited research investigating mescaline’s psychotherapeutic potential. We administered an anonymous online questionnaire to adults (N = 452) reporting use of mescaline in naturalistic settings about mental health benefits attributed to mescaline. We assessed respondents’ self-reported improvements in depression, anxiety, post-traumatic stress disorder (PTSD), and alcohol and drug use disorders (AUD and DUD). Of the respondents reporting histories of these clinical conditions, most (68-86%) reported subjective improvement following their most memorable mescaline experience. Respondents who reported an improvement in their psychiatric conditions reported significantly higher ratings of acute psychological factors including mystical-type, psychological insight, and ego dissolution effects compared to those who did not report improvements (Cohen’s d range 0.7 – 1.5). Many respondents (35-50%) rated the mescaline experience as the single or top five most spiritually significant or meaningful experience(s) of their lives. Acute experiences of psychological insight during their mescaline experience were associated with increased odds of reporting improvement in depression, anxiety, AUD and DUD. Additional research is needed to corroborate these preliminary findings and to rigorously examine the efficacy of mescaline for psychiatric treatment in controlled, longitudinal clinical trials.

Agin-Liebes, G., Haas, T. F., Lancelotta, R., Uthaug, M. V., Ramaekers, J. G., & Davis, A. K. (2021). Naturalistic Use of Mescaline Is Associated with Self-Reported Psychiatric Improvements and Enduring Positive Life Changes. ACS pharmacology & translational science, 4(2), 543–552. https://doi.org/10.1021/acsptsci.1c00018

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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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A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers

Abstract

Background: Lysergic acid diethylamide (LSD) is an ergot alkaloid derivative with psychedelic properties that has been implicated in the management of persistent pain. Clinical studies in the 1960s and 1970s have demonstrated profound analgesic effects of full doses of LSD in terminally ill patients, but this line of research evaporated after LSD was scheduled worldwide.

Aim: The present clinical study is the first to revisit the potential of LSD as an analgesic, and at dose levels which are not expected to produce profound mind-altering effects.

Methods: Twenty-four healthy volunteers received single doses of 5, 10 and 20 µg LSD as well as placebo on separate occasions. A Cold Pressor Test was administered at 1.5 and 5 h after treatment administration to assess pain tolerance to experimentally evoked pain. Ratings of dissociation and psychiatric symptoms as well as assessments of vital signs were included to monitor mental status as well as safety during treatments.

Results: LSD 20 µg significantly increased the time that participants were able to tolerate exposure to cold (3°C) water and decreased their subjective levels of experienced pain and unpleasantness. LSD elevated mean blood pressure within the normal range and slightly increased ratings of dissociation, anxiety and somatization.

Conclusion: The present study provides evidence of a protracted analgesic effect of LSD at a dose that is low enough to avoid a psychedelic experience. The present data warrant further research into the analgesic effects of low doses of LSD in patient populations.

Ramaekers, J. G., Hutten, N., Mason, N. L., Dolder, P., Theunissen, E. L., Holze, F., … & Kuypers, K. P. (2020). A low dose of lysergic acid diethylamide decreases pain perception in healthy volunteers. Journal of Psychopharmacology, 0269881120940937; 10.1177/0269881120940937
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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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Prospective examination of synthetic 5-methoxy-N,N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment

Abstract

Rationale

5-methoxy-N,N-dimethyltryptamine is a psychotropic substance found in various plant and animal species and is synthetically produced. 5-methoxy-N,N-dimethyltryptamine is used in naturalistic settings for spiritual exploration, recreation, or to address negative affect and mood problems. However, scientific knowledge on the effects of 5-methoxy-N,N-dimethyltryptamine in humans is scarce.

Objectives

The first objective was to assess the effects of inhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine on neuroendocrine markers. The second objective was to assess effects of the substance on affect and mindfulness. In addition, we assessed whether ratings of subjective measures were associated with changes in stress biomarkers (i.e., cortisol) and immune response (i.e., IL-6, CRP, IL-1β), as well as the acute psychedelic experience.

Methods

Assessments (baseline, immediately post-session, and 7-day follow-up) were made in 11 participants. Salivary samples were collected at baseline and post-session and analyzed by high-sensitivity enzyme-linked immunosorbent assay (ELISA).

Results

5-methoxy-N,N-dimethyltryptamine significantly increased cortisol levels and decreased IL-6 concentrations in saliva immediately post-session. These changes were not correlated to ratings of mental health or the psychedelic experience. Relative to baseline, ratings of non-judgment significantly increased, and ratings of depression decreased immediately post-session and at follow-up. Ratings of anxiety and stress decreased from baseline to 7-day follow-up. Participant ratings of the psychedelic experience correlated negatively with ratings of affect and positively with ratings of non-judgment.

Conclusion

Inhalation of vaporized synthetic 5-methoxy-N,N-dimethyltryptamine produced significant changes in inflammatory markers, improved affect, and non-judgment in volunteers. Future research should examine the effect of 5-methoxy-N,N-dimethyltryptamineamine with healthy volunteers in a controlled laboratory setting.

Uthaug, M. V., Lancelotta, R., Szabo, A., Davis, A. K., Riba, J., & Ramaekers, J. G. (2019). Prospective examination of synthetic 5-methoxy-N, N-dimethyltryptamine inhalation: effects on salivary IL-6, cortisol levels, affect, and non-judgment. Psychopharmacology, 1-13., 10.1007/s00213-019-05414-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., … & 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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