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S. Borgwardt

A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A) or Early Growth Response Genes (EGR1-3) in Healthy Subjects

June 28, 2017 / LSD, Neuroscience, Papers / By / , , , ,

Abstract

Rationale: Renewed interest has been seen in the use of lysergic acid diethylamide (LSD) in psychiatric research and practice. The repeated use of LSD leads to tolerance that is believed to result from serotonin (5-HT) 5-HT2A receptor downregulation. In rats, daily LSD administration for 4 days decreased frontal cortex 5-HT2A receptor binding. Additionally, a single dose of LSD acutely increased expression of the early growth response genes EGR1 and EGR2 in rat and mouse brains through 5-HT2A receptor stimulation. No human data on the effects of LSD on gene expression has been reported. Therefore, we investigated the effects of single-dose LSD administration on the expression of the 5-HT2A receptor gene (HTR2A) and EGR1-3 genes. Methods: mRNA expression levels were analyzed in whole blood as a peripheral biomarker in 15 healthy subjects before and 1.5 and 24 h after the administration of LSD (100 μg) and placebo in a randomized, double-blind, placebo-controlled, cross-over study. Results: LSD did not alter the expression of the HTR2A or EGR1-3 genes 1.5 and 24 h after administration compared with placebo. Conclusion: No changes were observed in the gene expression of LSD’s primary target receptor gene or genes that are implicated in its downstream effects. Remaining unclear is whether chronic LSD administration alters gene expression in humans.
Dolder, P. C., Grünblatt, E., Müller, F., Borgwardt, S. J., & Liechti, M. E. (2017). A Single Dose of LSD Does Not Alter Gene Expression of the Serotonin 2A Receptor Gene (HTR2A) or Early Growth Response Genes (EGR1-3) in Healthy Subjects. Frontiers in Pharmacology, 8. 10.3389/fphar.2017.00423
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Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects

May 27, 2017 / MDMA, Papers, Psychology / By / , , , ,

Abstract

Rationale

3,4-Methylenedioxymethamphetamine (MDMA) is used recreationally and investigated as an adjunct to psychotherapy. Methylphenidate and modafinil are psychostimulants that are used to treat attention-deficit/hyperactivity disorder and narcolepsy, respectively, but they are also misused as cognitive enhancers. Little is known about differences in the acute effects of equally cardiostimulant doses of these stimulant-type substances compared directly within the same subjects.

Methods

We investigated the acute autonomic, subjective, endocrine, and emotional effects of single doses of MDMA (125 mg), methylphenidate (60 mg), modafinil (600 mg), and placebo in a double-blind, cross-over study in 24 healthy participants. Acute drug effects were tested using psychometric scales, the Facial Emotion Recognition Task (FERT), and the Sexual Arousal and Desire Inventory (SADI).

Results

All active drugs produced comparable hemodynamic and adverse effects. MDMA produced greater increases in pupil dilation, subjective good drug effects, drug liking, happiness, trust, well-being, and alterations in consciousness than methylphenidate or modafinil. Only MDMA reduced subjective anxiety and impaired fear recognition and led to misclassifications of emotions as happy on the FERT. On the SADI, only MDMA produced sexual arousal-like effects. Only MDMA produced marked increases in cortisol, prolactin, and oxytocin. In contrast to MDMA, methylphenidate increased subjective anxiety, and methylphenidate and modafinil increased misclassifications of emotions as angry on the FERT. Modafinil had no significant subjective drug effects but significant sympathomimetic and adverse effects.

Conclusions

MDMA induced subjective, emotional, sexual, and endocrine effects that were clearly distinct from those of methylphenidate and modafinil at the doses used.

Dolder, P. C., Müller, F., Schmid, Y., Borgwardt, S. J., & Liechti, M. E. (2017). Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects. Psychopharmacology, 1-13. 10.1007/s00213-017-4650-5
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Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects

April 4, 2017 / LSD, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

Lysergic acid diethylamide (LSD) induces profound changes in various mental domains, including perception, self-awareness and emotions. We used functional magnetic resonance imaging (fMRI) to investigate the acute effects of LSD on the neural substrate of emotional processing in humans. Using a double-blind, randomised, cross-over study design, placebo or 100 μg LSD were orally administered to 20 healthy subjects before the fMRI scan, taking into account the subjective and pharmacological peak effects of LSD. The plasma levels of LSD were determined immediately before and after the scan. The study (including the a priori-defined study end point) was registered at ClinicalTrials.gov before study start (NCT02308969). The administration of LSD reduced reactivity of the left amygdala and the right medial prefrontal cortex relative to placebo during the presentation of fearful faces (P<0.05, family-wise error). Notably, there was a significant negative correlation between LSD-induced amygdala response to fearful stimuli and the LSD-induced subjective drug effects (P<0.05). These data suggest that acute administration of LSD modulates the engagement of brain regions that mediate emotional processing.

Mueller, F., Lenz, C., Dolder, P. C., Harder, S., Schmid, Y., Lang, U. E., … & Borgwardt, S. (2017). Acute effects of LSD on amygdala activity during processing of fearful stimuli in healthy subjects. Translational Psychiatry, 7(4), e1084. 10.1038/tp.2017.54
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LSD Acutely Impairs Fear Recognition and Enhances Emotional Empathy and Sociality

June 1, 2016 / LSD, Papers, Psychology, Publications / By / , , , ,

Abstract

Lysergic acid diethylamide (LSD) is used recreationally and has been evaluated as an adjunct to psychotherapy to treat anxiety in patients with life-threatening illness. LSD is well-known to induce perceptual alterations, but unknown is whether LSD alters emotional processing in ways that can support psychotherapy. We investigated the acute effects of LSD on emotional processing using the Face Emotion Recognition Task (FERT) and Multifaceted Empathy Test (MET). The effects of LSD on social behavior were tested using the Social Value Orientation (SVO) test. Two similar placebo-controlled, double-blind, random-order, cross-over studies were conducted using 100 μg LSD in 24 subjects and 200 μg LSD in 16 subjects. All of the subjects were healthy and mostly hallucinogen-naive 25- to 65-year-old volunteers (20 men, 20 women). LSD produced feelings of happiness, trust, closeness to others, enhanced explicit and implicit emotional empathy on the MET, and impaired the recognition of sad and fearful faces on the FERT. LSD enhanced the participants’ desire to be with other people and increased their prosocial behavior on the SVO test. These effects of LSD on emotion processing and sociality may be useful for LSD-assisted psychotherapy.

Dolder, P. C., Schmid, Y., Müller, F., Borgwardt, S., & Liechti, M. E. (2016). Lsd acutely impairs fear recognition and enhances emotional empathy and sociality. Neuropsychopharmacology. http://dx.doi.org/10.1038/npp.2016.82
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Neuroimaging in moderate MDMA use: A systematic review

December 30, 2015 / MDMA, Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

MDMA (“ecstasy”) is widely used as a recreational drug, although there has been some debate about its neurotoxic effects in humans. However, most studies have investigated subjects with heavy use patterns, and the effects of transient MDMA use are unclear. In this review, we therefore focus on subjects with moderate use patterns, in order to assess the evidence for harmful effects. We searched for studies applying neuroimaging techniques in man. Studies were included if they provided at least one group with an average of <50 lifetime episodes of ecstasy use or an average lifetime consumption of <100 ecstasy tablets. All studies published before July 2015 were included. Of the 250 studies identified in the database search, 19 were included.

There is no convincing evidence that moderate MDMA use is associated with structural or functional brain alterations in neuroimaging measures. The lack of significant results was associated with high methodological heterogeneity in terms of dosages and co-consumption of other drugs, low quality of studies and small sample sizes.

Mueller, F., Lenz, C., Steiner, M., Dolder, P. C., Walter, M., Lang, U. E., … & Borgwardt, S. (2016). Neuroimaging in moderate MDMA use: A systematic review. Neuroscience & Biobehavioral Reviews, 62, 21-34. http://dx.doi.org/10.1016/j.neubiorev.2015.12.010
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