Michigan Psychedelic Center (M-PsyC), and Chronic Pain and Fatigue Research Center (CPFRC), University of Michigan Medical School, Ann Arbor, MI, USA.
Neuroscience Graduate Program, and Program in Biomedical Sciences (PIBS), University of Michigan Medical School, 1135 Catherine Street, Box 5619, 2960 Taubman Health Science Library, Ann Arbor, MI, USA.
CNS Drugs. 2023 Dec;37(12):1027-1063. doi: 10.1007/s40263-023-01044-1. Epub 2023 Nov 24.
The renewed interest in psychedelic research provides growing evidence of potentially unique effects on various aspects of reward processing systems. Using the Research Domain Criteria (RDoC) framework, as proposed by the National Institute of Mental Health, we aim to synthesize the existing literature concerning the impact of lysergic acid diethylamide (LSD) on the RDoC's Positive Valence Systems (PVS) domain, and to identify potential avenues for further research.
Two LSD-related terms (lysergic acid diethylamide and LSD) and 13 PVS-related terms (reward, happiness, bliss, motivation, reinforcement learning, operant, conditioning, satisfaction, decision making, habit, valence, affect, mood) were used to search electronic databases such as PubMed, Scopus, PsychINFO, and Web of Science for relevant articles. A manual search of the reference list resulted in nine additional articles. After screening, articles and data were evaluated and included based on their relevance to the objective of investigating the effects of LSD on the PVS. Articles and data were excluded if they did not provide information about the PVS, were observational in nature, lacked comparators or reference groups, or were duplicates. A risk of bias assessment was performed using the National Toxicology Program's Office of Health Assessment and Translation (NTP OHAT) risk of bias (RoB) tool. Data from the included articles were collected and structured based on the RDoC bio-behavioral matrix, specifically focusing on the PVS domain and its three constituent constructs: reward responsiveness, reward learning, and reward valuation.
We reviewed 28 clinical studies with 477 participants. Lysergic acid diethylamide, assessed at self-report (23 studies), molecular (5 studies), circuit (4 studies), and paradigm (3 studies) levels, exhibited dose-dependent mood improvement (20 short-term and 3 long-term studies). The subjective and neural effects of LSD were linked to the 5-HT receptor (molecular). Animal studies (14 studies) suggested LSD could mildly reinforce conditioned place preference without aversion and reduce responsiveness to other rewards. Findings on reward learning were inconsistent but hinted at potential associative learning enhancements. Reward valuation measures indicated potential reductions in effort expenditure for other reinforcers.
Our findings are consistent with our previous work, which indicated classical psychedelics, primarily serotonin 2A receptor agonists, enhanced reward responsiveness in healthy individuals and patient populations. Lysergic acid diethylamide exhibits a unique profile in the reward learning and valuation constructs. Using the RDoC-based framework, we identified areas for future research, enhancing our understanding of the impact of LSD on reward processing. However, applying RDoC to psychedelic research faces limitations due to diverse study designs that were not initially RDoC-oriented. Limitations include subjective outcome measure selection aligned with RDoC constructs and potential bias in synthesizing varied studies. Additionally, some human studies were open-label, introducing potential bias compared to randomized, blinded studies.
对迷幻药物研究的重新关注提供了越来越多的证据，表明其对奖励处理系统的各个方面可能具有独特的影响。我们使用美国国立精神卫生研究院提出的研究领域标准（RDoC）框架，旨在综合有关麦角酰二乙胺（LSD）对 RDoC 的正价系统（PVS）领域影响的现有文献，并确定进一步研究的潜在途径。
使用两个 LSD 相关术语（麦角酰二乙胺和 LSD）和 13 个 PVS 相关术语（奖励、快乐、幸福、动机、强化学习、操作性、条件反射、满足、决策、习惯、效价、情感、情绪）在 PubMed、Scopus、PsychINFO 和 Web of Science 等电子数据库中搜索相关文章。对参考文献列表进行手动搜索，得到另外 9 篇文章。经过筛选，根据调查 LSD 对 PVS 影响的目标，评估并纳入了与目标相关的文章和数据。如果文章没有提供有关 PVS 的信息、是观察性的、缺乏对照或参考组，或者是重复的，则将其排除在外。使用国家毒理学计划的健康评估和转化办公室（NTP OHAT）风险评估（RoB）工具对文章和数据进行了风险评估。从纳入的文章中收集和构建数据，基于 RDoC 生物行为矩阵，特别是关注 PVS 领域及其三个组成结构：奖励反应性、奖励学习和奖励估值。
我们回顾了 28 项涉及 477 名参与者的临床研究。麦角酰二乙胺在自我报告（23 项研究）、分子（5 项研究）、回路（4 项研究）和范式（3 项研究）水平上评估，表现出剂量依赖性的情绪改善（20 项短期和 3 项长期研究）。LSD 的主观和神经效应与 5-HT 受体（分子）有关。动物研究（14 项研究）表明，LSD 可能轻度增强条件性位置偏好而无厌恶，减少对其他奖励的反应性。奖励学习方面的发现不一致，但暗示可能增强了联想学习能力。奖励估值测量表明，对其他强化物的努力支出可能减少。
我们的研究结果与我们之前的工作一致，表明经典迷幻药物主要是 5-羟色胺 2A 受体激动剂，增强了健康个体和患者群体的奖励反应性。麦角酰二乙胺在奖励学习和估值结构中表现出独特的特征。使用基于 RDoC 的框架，我们确定了未来研究的领域，增强了我们对 LSD 对奖励处理影响的理解。然而，由于最初并非以 RDoC 为导向的各种研究设计，将 RDoC 应用于迷幻药物研究存在局限性。局限性包括与 RDoC 结构对齐的主观结果测量选择和综合各种研究的潜在偏差。此外，一些人类研究是开放性的，与随机、双盲研究相比，可能存在潜在偏差。
