OPEN Foundation

M. Liechti

LSD Acutely Impairs Fear Recognition and Enhances Emotional Empathy and Sociality

June 1, 2016 / LSD, Papers, Psychiatry, Psychology, Psychotherapy, 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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Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens

May 20, 2016 / Neuroscience, New substances, Other substances, Papers, Psychopharmacology, Publications / By / , , ,

Abstract

The present study investigated interactions between the novel psychoactive tryptamines DiPT, 4-OH-DiPT, 4-OH-MET, 5-MeO-AMT, and 5-MeO-MiPT at monoamine receptors and transporters compared with the classic hallucinogens lysergic acid diethylamide (LSD), psilocin, N,N-dimethyltryptamine (DMT), and mescaline. We investigated binding affinities at human monoamine receptors and determined functional serotonin (5-hydroxytryptamine [5-HT]) 5-HT2A and 5-HT2B receptor activation. Binding at and the inhibition of human monoamine uptake transporters and transporter-mediated monoamine release were also determined. All of the novel tryptamines interacted with 5-HT2A receptors and were partial or full 5-HT2A agonists. Binding affinity to the 5-HT2A receptor was lower for all of the tryptamines, including psilocin and DMT, compared with LSD and correlated with the reported psychoactive doses in humans. Several tryptamines, including psilocin, DMT, DiPT, 4-OH-DiPT, and 4-OH-MET, interacted with the serotonin transporter and partially the norepinephrine transporter, similar to 3,4-methylenedioxymethamphetamine but in contrast to LSD and mescaline. LSD but not the tryptamines interacted with adrenergic and dopaminergic receptors. In conclusion, the receptor interaction profiles of the tryptamines predict hallucinogenic effects that are similar to classic serotonergic hallucinogens but also MDMA-like psychoactive properties.

Rickli, A., Moning, O. D., Hoener, M. C., & Liechti, M. E. (2016). Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. European Neuropsychopharmacology. http://dx.doi.org/10.1016/j.euroneuro.2016.05.001

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Acute effects of LSD on circulating steroid levels in healthy subjects.

February 6, 2016 / LSD, Other subjects, Papers, Psychiatry, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Lysergic acid diethylamide (LSD) is a serotonin 5-hydroxytryptamine-2A (5-HT2A ) receptor agonist that is used recreationally worldwide. Interest in LSD research in humans waned after the 1970s, but the use of LSD in psychiatric research and practice has recently gained increasing attention. LSD produces pronounced acute psychedelic effects, but its influence on plasma steroid levels over time have not yet been characterized in humans. The effects of LSD (200μg) or placebo on plasma steroid levels were investigated in 16 healthy subjects using a randomized, double-blind, placebo-controlled cross-over study design. Plasma concentration-time profiles were determined for 15 steroids using liquid-chromatography tandem mass-spectrometry. LSD increased plasma concentrations of the glucocorticoids cortisol, cortisone, corticosterone, and 11-dehydrocorticosterone compared with placebo. The mean maximum concentration of LSD was reached at 1.7h. Mean peak psychedelic effects were reached at 2.4h, with significant alterations in mental state from 0.5h to >10h. Mean maximal concentrations of cortisol and corticosterone were reached at 2.5h and 1.9h, and significant elevations were observed 1.5-6h and 1-3h after drug administration, respectively. LSD also significantly increased plasma concentrations of the androgen dehydroepiandrosterone but not other androgens, progestogens, or mineralocorticoids compared with placebo. A close relationship was found between plasma LSD concentrations and changes in plasma cortisol and corticosterone and the psychotropic response to LSD, and no clockwise hysteresis was observed. In conclusion, LSD produces significant acute effects on circulating steroids, especially glucocorticoids. LSD-induced changes in circulating glucocorticoids were associated with plasma LSD concentrations over time and showed no acute pharmacological tolerance.

Strajhar, P., Schmid, Y., Liakoni, E., Dolder, P. C., Rentsch, K. M., Kratschmar, D. V., … & Liechti, M. E. (2016). Acute effects of LSD on circulating steroid levels in healthy subjects. Journal of Neuroendocrinology. http://dx.doi.org/10.1111/jne.12374

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Pharmacokinetics and concentration-effect relationship of oral LSD in humans

June 24, 2015 / LSD, Medicine, Neuroscience, Other subjects, Papers, Psychopharmacology, Publications / By / , , , ,

Abstract

Background: The pharmacokinetics of oral lysergic acid diethylamide (LSD) are unknown, despite its common recreational use and renewed interest in its use in psychiatric research and practice.

Methods: We characterized the pharmacokinetic profile, pharmacokinetic-pharmacodynamic relationship, and urine recovery of LSD and its main metabolite after administration of a single oral dose of LSD (200 μg) in eight male and eight female healthy subjects.

Results: Plasma LSD concentrations were quantifiable (> 0.1 ng/ml) in all of the subjects up to 12 h after administration. Maximal concentrations of LSD (mean ± SD: 4.5 ± 1.4 ng/ml) were reached (median, range) 1.57 (0.5-4) h after administration. Concentrations then decreased following first-order kinetics with a half-life of 3.6 ± 0.9 h up to 12 h and slower elimination thereafter with a terminal half-life of 8.9 ± 5.9 h. One percent of the orally administered LSD was eliminated in urine as LSD, and 14% was eliminated as 2-oxo-3-hydroxy-LSD within 24 h. No sex differences were observed in the pharmacokinetic profiles of LSD. The acute subjective and sympathomimetic responses to LSD lasted up to 12 h and were closely associated with the concentrations in plasma over time and exhibited no acute tolerance.

Conclusions: These first data on the pharmacokinetics and concentration-effect relationship of oral LSD are relevant for further clinical studies and serve as a reference for the assessment of intoxication with LSD.

Dolder, P. C., Schmid, Y., Haschke, M., Rentsch, K. M., & Liechti, M. E. (2015). Pharmacokinetics and concentration-effect relationship of oral LSD in humans. International Journal of Neuropsychopharmacology, pyv072.

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Development and validation of a rapid turboflow LC-MS/MS method for the quantification of LSD and 2-oxo-3-hydroxy LSD in serum and urine samples of emergency toxicological cases

December 27, 2014 / LSD, Medicine, Other subjects, Papers, Publications, Toxicology / By / , ,

Abstract

Lysergic acid diethylamide (LSD) is a widely used recreational drug. The aim of the present study is to develop a quantitative turboflow LC-MS/MS method that can be used for rapid quantification of LSD and its main metabolite 2-oxo-3-hydroxy LSD (O-H-LSD) in serum and urine in emergency toxicological cases without time-consuming extraction steps. The method was developed on an ion-trap LC-MS/MS instrument coupled to a turbulent-flow extraction system. The validation data showed no significant matrix effects and no ion suppression has been observed in serum and urine. Mean intraday accuracy and precision for LSD were 101 and 6.84 %, in urine samples and 97.40 and 5.89 % in serum, respectively. For O-H-LSD, the respective values were 97.50 and 4.99 % in urine and 107 and 4.70 % in serum. Mean interday accuracy and precision for LSD were 100 and 8.26 % in urine and 101 and 6.56 % in serum, respectively. For O-H-LSD, the respective values were 101 and 8.11 % in urine and 99.8 and 8.35 % in serum, respectively. The lower limit of quantification for LSD was determined to be 0.1 ng/ml. LSD concentrations in serum were expected to be up to 8 ng/ml. 2-Oxo-3-hydroxy LSD concentrations in urine up to 250 ng/ml. The new method was accurate and precise in the range of expected serum and urine concentrations in patients with a suspected LSD intoxication. Until now, the method has been applied in five cases with suspected LSD intoxication where the intake of the drug has been verified four times with LSD concentrations in serum in the range of 1.80–14.70 ng/ml and once with a LSD concentration of 1.25 ng/ml in urine. In serum of two patients, the O-H-LSD concentration was determined to be 0.99 and 0.45 ng/ml. In the urine of a third patient, the O-H-LSD concentration was 9.70 ng/ml.

Dolder, P. C., Liechti, M. E., & Rentsch, K. M. (2015). Development and validation of a rapid turboflow LC-MS/MS method for the quantification of LSD and 2-oxo-3-hydroxy LSD in serum and urine samples of emergency toxicological cases. Analytical and bioanalytical chemistry, 407(6), 1577-1584. http://dx.doi.org/10.1007/s00216-014-8388-1

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Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects

November 29, 2014 / LSD, Neuroscience, Other subjects, Papers, Psychology, Psychopharmacology, Psychosis, Publications, Safety / By / , , , , , ,

Abstract

Background

After no research in humans for >40 years, there is renewed interest in using lysergic acid diethylamide (LSD) in clinical psychiatric research and practice. There are no modern studies on the subjective and autonomic effects of LSD, and its endocrine effects are unknown. In animals, LSD disrupts prepulse inhibition (PPI) of the acoustic startle response, and patients with schizophrenia exhibit similar impairments in PPI. However, no data are available on the effects of LSD on PPI in humans.

Methods

In a double-blind, randomized, placebo-controlled, crossover study, LSD (200 μg) and placebo were administered to 16 healthy subjects (8 women, 8 men). Outcome measures included psychometric scales; investigator ratings; PPI of the acoustic startle response; and autonomic, endocrine, and adverse effects.

Results

Administration of LSD to healthy subjects produced pronounced alterations in waking consciousness that lasted 12 hours. The predominant effects induced by LSD included visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization phenomena. Subjective well-being, happiness, closeness to others, openness, and trust were increased by LSD. Compared with placebo, LSD decreased PPI. LSD significantly increased blood pressure, heart rate, body temperature, pupil size, plasma cortisol, prolactin, oxytocin, and epinephrine. Adverse effects produced by LSD completely subsided within 72 hours. No severe acute adverse effects were observed.

Conclusions

In addition to marked hallucinogenic effects, LSD exerts methylenedioxymethamphetamine-like empathogenic mood effects that may be useful in psychotherapy. LSD altered sensorimotor gating in a human model of psychosis, supporting the use of LSD in translational psychiatric research. In a controlled clinical setting, LSD can be used safely, but it produces significant sympathomimetic stimulation.

Schmid, Y., Enzler, F., Gasser, P., Grouzmann, E., Preller, K. H., Vollenweider, F. X., … & Liechti, M. E. (2014). Acute Effects of Lysergic Acid Diethylamide in Healthy Subjects. Biological psychiatry. https://dx.doi.org/doi:10.1016/j.biopsych.2014.11.015
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MDMA enhances emotional empathy and prosocial behavior

October 4, 2013 / Anxiety disorders / PTSD, MDMA, Neuroscience, Papers, Psychology, Publications / By / , , , , , ,

Abstract

3,4-Methylenedioxymethamphetamine (MDMA, ‘ecstasy’) releases serotonin and norepinephrine. MDMA is reported to produce empathogenic and prosocial feelings. It is unknown whether MDMA in fact alters empathic concern and prosocial behavior. We investigated the acute effects of MDMA using the Multifaceted Empathy Test (MET), dynamic Face Emotion Recognition Task (FERT) and Social Value Orientation (SVO) test. We also assessed effects of MDMA on plasma levels of hormones involved in social behavior using a placebo-controlled, double-blind, random-order, cross-over design in 32 healthy volunteers (16 women). MDMA enhanced explicit and implicit emotional empathy in the MET and increased prosocial behavior in the SVO test in men. MDMA did not alter cognitive empathy in the MET but impaired the identification of negative emotions, including fearful, angry and sad faces, in the FERT, particularly in women. MDMA increased plasma levels of cortisol and prolactin, which are markers of serotonergic and noradrenergic activity, and of oxytocin, which has been associated with prosocial behavior. In summary, MDMA sex-specifically altered the recognition of emotions, emotional empathy and prosociality. These effects likely enhance sociability when MDMA is used recreationally and may be useful when MDMA is administered in conjunction with psychotherapy in patients with social dysfunction or post-traumatic stress disorder.

Hysek, C. M., Schmid, Y., Simmler, L. D., Domes, G., Heinrichs, M., Eisenegger, C., … Liechti, M. E. (2013). MDMA enhances emotional empathy and prosocial behavior. Social Cognitive & Affective Neuroscience, 9(11), 1645-1652. http://dx.doi.org/10.1093/scan/nst161
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30 April - Q&A with Rick Strassman

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