健康成年志愿者舌下微剂量麦角酸二乙胺的药代动力学和药效学。

IF 4.5 3区 医学 Q1 CLINICAL NEUROLOGY
James D Morse, Soo Hee Jeong, Robin J Murphy, Suresh D Muthukumaraswamy, Rachael L Sumner
{"title":"健康成年志愿者舌下微剂量麦角酸二乙胺的药代动力学和药效学。","authors":"James D Morse, Soo Hee Jeong, Robin J Murphy, Suresh D Muthukumaraswamy, Rachael L Sumner","doi":"10.1177/02698811251330747","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Microdosing is the practice of taking psychedelic drugs at doses that produce no or minimal perceptible subjective or behavioural effects. This study investigated the pharmacokinetics and pharmacodynamics of microdosed lysergic acid diethylamide (LSD).</p><p><strong>Methods: </strong>This was a Phase 1 double-blind placebo-controlled parallel-groups trial with 80 healthy male volunteers (four withdrawals due to anxiety). Plasma samples were taken at 0.5, 1, 2, 4 and 6 h after 10 µg sublingual LSD and analysed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). LSD pharmacokinetics were modelled. Population analyses were performed using nonlinear mixed effects models. Heart rate and a visual analogue scale ('feel effect') were used to describe LSD pharmacodynamics. The effect of the relevant cytochrome P450 (CYP) genotype on LSD pharmacokinetics was qualitatively assessed. Plasma and serum levels of brain-derived neurotrophic factor (BDNF) were evaluated.</p><p><strong>Results: </strong>A one-compartment model best described LSD pharmacokinetics. Mean (95% confidence interval): elimination clearance = 7.78 L/h/70 kg (6.75-8.77), central volume of distribution = 32.9 L/70 kg (30.1, 36.0). Maximal concentration (0.20 µg/L), time to maximal concentration (1.51 h) and elimination half-life (3.08 h). The maximal increase in heart rate and visual analogue scale was small (<15%) compared to baseline estimates limiting the modelling. Two of the participants withdrawn from the study due to anxiety had intermediate-weak CYP2D6 activity. CYP2D6, CYP1A6, CYP2B6 and CYP2C9 qualitatively appeared to influence concentration. No evidence of alterations of peripheral BDNF with microdosing was found.</p><p><strong>Conclusion: </strong>This study provides a population pharmacokinetic model and LC-MS/MS assay that can inform clinical and bioequivalence studies. Relevant CYP genotypes should be studied in larger samples as combined potential biomarkers of response. Microdose-sensitive and reliable pharmacodynamic measures are needed.</p>","PeriodicalId":16892,"journal":{"name":"Journal of Psychopharmacology","volume":" ","pages":"2698811251330747"},"PeriodicalIF":4.5000,"publicationDate":"2025-04-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Pharmacokinetics and pharmacodynamics of sublingual microdosed lysergic acid diethylamide in healthy adult volunteers.\",\"authors\":\"James D Morse, Soo Hee Jeong, Robin J Murphy, Suresh D Muthukumaraswamy, Rachael L Sumner\",\"doi\":\"10.1177/02698811251330747\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Microdosing is the practice of taking psychedelic drugs at doses that produce no or minimal perceptible subjective or behavioural effects. This study investigated the pharmacokinetics and pharmacodynamics of microdosed lysergic acid diethylamide (LSD).</p><p><strong>Methods: </strong>This was a Phase 1 double-blind placebo-controlled parallel-groups trial with 80 healthy male volunteers (four withdrawals due to anxiety). Plasma samples were taken at 0.5, 1, 2, 4 and 6 h after 10 µg sublingual LSD and analysed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). LSD pharmacokinetics were modelled. Population analyses were performed using nonlinear mixed effects models. Heart rate and a visual analogue scale ('feel effect') were used to describe LSD pharmacodynamics. The effect of the relevant cytochrome P450 (CYP) genotype on LSD pharmacokinetics was qualitatively assessed. Plasma and serum levels of brain-derived neurotrophic factor (BDNF) were evaluated.</p><p><strong>Results: </strong>A one-compartment model best described LSD pharmacokinetics. Mean (95% confidence interval): elimination clearance = 7.78 L/h/70 kg (6.75-8.77), central volume of distribution = 32.9 L/70 kg (30.1, 36.0). Maximal concentration (0.20 µg/L), time to maximal concentration (1.51 h) and elimination half-life (3.08 h). The maximal increase in heart rate and visual analogue scale was small (<15%) compared to baseline estimates limiting the modelling. Two of the participants withdrawn from the study due to anxiety had intermediate-weak CYP2D6 activity. CYP2D6, CYP1A6, CYP2B6 and CYP2C9 qualitatively appeared to influence concentration. No evidence of alterations of peripheral BDNF with microdosing was found.</p><p><strong>Conclusion: </strong>This study provides a population pharmacokinetic model and LC-MS/MS assay that can inform clinical and bioequivalence studies. Relevant CYP genotypes should be studied in larger samples as combined potential biomarkers of response. Microdose-sensitive and reliable pharmacodynamic measures are needed.</p>\",\"PeriodicalId\":16892,\"journal\":{\"name\":\"Journal of Psychopharmacology\",\"volume\":\" \",\"pages\":\"2698811251330747\"},\"PeriodicalIF\":4.5000,\"publicationDate\":\"2025-04-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Psychopharmacology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1177/02698811251330747\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CLINICAL NEUROLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Psychopharmacology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1177/02698811251330747","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CLINICAL NEUROLOGY","Score":null,"Total":0}
引用次数: 0

摘要

微剂量是服用致幻剂的做法,其剂量不产生或只有很小的可察觉的主观或行为影响。研究了微剂量麦角酸二乙胺(LSD)的药代动力学和药效学。方法:这是一项一期双盲安慰剂对照平行组试验,共有80名健康男性志愿者(4名因焦虑而停药)。分别于10µg舌下LSD后0.5、1、2、4和6 h取血浆样品,采用液相色谱-串联质谱(LC-MS/MS)分析。建立LSD药代动力学模型。总体分析采用非线性混合效应模型。心率和视觉模拟量表(“感觉效应”)被用来描述LSD的药效学。定性评价相关细胞色素P450 (CYP)基因型对LSD药代动力学的影响。评估血浆和血清脑源性神经营养因子(BDNF)水平。结果:单室模型最能描述LSD的药代动力学。平均值(95%置信区间):消除清除率= 7.78 L/h/70 kg(6.75-8.77),中心分布容积= 32.9 L/70 kg(30.1, 36.0)。最大浓度(0.20µg/L),达到最大浓度的时间(1.51 h)和消除半衰期(3.08 h)。结论:本研究提供了一个群体药代动力学模型和LC-MS/MS分析,为临床和生物等效性研究提供了信息。相关的CYP基因型应该在更大的样本中作为联合潜在的生物标志物进行研究。需要微剂量敏感和可靠的药效学测量。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Pharmacokinetics and pharmacodynamics of sublingual microdosed lysergic acid diethylamide in healthy adult volunteers.

Introduction: Microdosing is the practice of taking psychedelic drugs at doses that produce no or minimal perceptible subjective or behavioural effects. This study investigated the pharmacokinetics and pharmacodynamics of microdosed lysergic acid diethylamide (LSD).

Methods: This was a Phase 1 double-blind placebo-controlled parallel-groups trial with 80 healthy male volunteers (four withdrawals due to anxiety). Plasma samples were taken at 0.5, 1, 2, 4 and 6 h after 10 µg sublingual LSD and analysed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). LSD pharmacokinetics were modelled. Population analyses were performed using nonlinear mixed effects models. Heart rate and a visual analogue scale ('feel effect') were used to describe LSD pharmacodynamics. The effect of the relevant cytochrome P450 (CYP) genotype on LSD pharmacokinetics was qualitatively assessed. Plasma and serum levels of brain-derived neurotrophic factor (BDNF) were evaluated.

Results: A one-compartment model best described LSD pharmacokinetics. Mean (95% confidence interval): elimination clearance = 7.78 L/h/70 kg (6.75-8.77), central volume of distribution = 32.9 L/70 kg (30.1, 36.0). Maximal concentration (0.20 µg/L), time to maximal concentration (1.51 h) and elimination half-life (3.08 h). The maximal increase in heart rate and visual analogue scale was small (<15%) compared to baseline estimates limiting the modelling. Two of the participants withdrawn from the study due to anxiety had intermediate-weak CYP2D6 activity. CYP2D6, CYP1A6, CYP2B6 and CYP2C9 qualitatively appeared to influence concentration. No evidence of alterations of peripheral BDNF with microdosing was found.

Conclusion: This study provides a population pharmacokinetic model and LC-MS/MS assay that can inform clinical and bioequivalence studies. Relevant CYP genotypes should be studied in larger samples as combined potential biomarkers of response. Microdose-sensitive and reliable pharmacodynamic measures are needed.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Journal of Psychopharmacology
Journal of Psychopharmacology 医学-精神病学
CiteScore
8.60
自引率
4.90%
发文量
126
审稿时长
3-8 weeks
期刊介绍: The Journal of Psychopharmacology is a fully peer-reviewed, international journal that publishes original research and review articles on preclinical and clinical aspects of psychopharmacology. The journal provides an essential forum for researchers and practicing clinicians on the effects of drugs on animal and human behavior, and the mechanisms underlying these effects. The Journal of Psychopharmacology is truly international in scope and readership.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信