Straumann, Isabelle. Safety, pharmacology, and subjective effects of LSD, psilocybin, MDMA and its enantiomers. 2024, Doctoral Thesis, University of Basel, Faculty of Medicine.
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Abstract
Classic psychedelics such as psilocybin and lysergic acid diethylamide (LSD) and the entactogen 3,4-Methylenedioxymethamphetamine (MDMA) are being investigated for their potential in substance-assisted therapy for various psychiatric and neurological disorders. While first results propose potential in treating these conditions, there is a lack of phase I studies examining the safety, pharmacology, and subjective effects of these compounds in healthy volunteers, as usually is the case in drug development. Previous research has shown that the acute positive effects of psychedelics are linked to their therapeutic benefits, making it essential to enhance these acute subjective effects. MDMA is a racemic substance that has already been investigated more extensively in phase I studies, yet preclinical research suggests that its enantiomers may have different effects, with one potentially being more suitable for substance-assisted therapy, regarding the safety. This thesis includes three projects aimed at expanding our knowledge of the safety, pharmacology and subjective effects of LSD, psilocybin, MDMA and the enantiomers R-MDMA and S-MDMA. The first project involved a clinical study with healthy volunteers where MDMA (100 mg) was used as a pharmacological tool to enhance the psychedelic effects of LSD (100 µg). While the effects profile of the combined LSD + MDMA administration did not differ significantly from LSD alone, the duration of effects was extended by an average of 1.5 hours. This is likely due to MDMA’s strong inhibition of the Cytochrome P450 2D6 (CYP2D6) enzyme, which slowed the metabolization of LSD, resulting in higher plasma concentration and a longer elimination half-life. This finding further supports a role for CYP2D6 in the LSD metabolism. The LSD + MDMA combination induced higher blood pressure and heart rate, with similar minimal increases in body temperature compared with LSD alone. Even though the combined administration is intriguing, it probably offers no additional benefit to LSD-assisted psychotherapy in patients. The second project included three completed studies with 113 psilocybin administrations at doses from 15 to 30 mg in 85 healthy volunteers. Safety data of these studies were pooled and revealed comparable positive effects for 20, 25, and 30 mg psilocybin, while significant “anxiety” was only observed with the 25 and 30 mg doses. Increases in blood pressure (>140 mmHg), heart rate (>100 bpm), and body temperature (>38°C) were noted in 50%, 7%, and 16% of participants, respectively, after psilocybin administration. The autonomic effects of psilocybin were similar to those of LSD and less pronounced than those of MDMA. Acute adverse effects included fatigue, lack of concentration, lethargy, vertigo, feeling of weakness, and decreased appetite. Overall, single-dose administrations of psilocybin up to 30 mg were found to be safe regarding psychological and physical harm in healthy volunteers in a controlled setting. However, risk and benefits of using psilocybin in patients need further investigation. The third project examined the acute and subacute effects of MDMA (125 mg) and its enantiomers R-MDMA (125 and 250 mg) and S-MDMA (125 mg). While small differences in subjective effects were observed with MDMA, R-MDMA and S-MDMA, dose equivalence was not achieved, leaving it unclear whether these differences are due to their distinct binding profiles or the dosing. The results suggest dose equivalence regarding subjective effects with 125 mg MDMA, 300 mg R-MDMA, and 100 mg S-MDMA. The elimination half-life of R-MDMA increased dose-dependently from 11 hours with 125 mg racemic MDMA, to 12 hours with 125 mg R-MDMA, to 14 hours with 250 mg R-MDMA. In contrast, the elimination half-life of S-MDMA decreased when administered without R-MDMA. Additionally, the formation of 4-Hydroxy-3-methoxymethamphetamine (HMMA), a metabolite produced via CYP2D6, did not increase with higher doses of R-MDMA, indicating that R-MDMA dose-dependently inhibits CYP2D6. The extent to which S-MDMA inhibits CYP2D6 remains to be determined. All projects uncovered new findings about these compounds, providing valuable insights to inform and guide future clinical studies in both healthy volunteers and patients.
Advisors: | Liechti, Matthias Emanuel |
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Committee Members: | Scheurer, Eva and Quednow, Boris |
Faculties and Departments: | 03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Psychopharmacology Research (Liechti) |
UniBasel Contributors: | Liechti, Matthias Emanuel and Scheurer, Eva |
Item Type: | Thesis |
Thesis Subtype: | Doctoral Thesis |
Thesis no: | 15609 |
Thesis status: | Complete |
Number of Pages: | 138 |
Language: | English |
Identification Number: |
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edoc DOI: | |
Last Modified: | 31 Jan 2025 05:30 |
Deposited On: | 30 Jan 2025 10:17 |
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