3.1 Included Assessments

Following the inclusion criteria, 42 studies were included, consisting of four units of analysis, namely self-reports, paradigms, molecules (biochemical components such as neurotransmitters and receptors), and circuits (neural circuitry) (Tables 2 and 3).

Table 2 The effects of LSD on positive valence systems (human studies)Table 3 The effects of LSD on positive valence systems (animal studies)

Twenty of the included studies measured LSD-elicited effects with the “self-reports” units of analysis (47.62 %), 17 with the “paradigms” units of analysis (40.48 %), ten with the “molecules” units of analysis (23.81 %) and five with the “circuits” units of analysis (11.90 %).

Thirteen unique self-reports were extracted. The positive affect subscale of the Positive and Negative Affect Scale (PANAS) was the only extracted outcome measure that was directly proposed by the RDoC task force [21]. This questionnaire evaluates the extent to which an individual experiences a positive mood such as joy, interest, or enthusiasm and is sensitive to signals of reward [22]. The positive affect (PA) subscale can reflect reward reactivity and was hence categorized in the reward responsiveness construct in the RDoC matrix [22, 23]. Five studies included PANAS as a self-report measure [24,25,26,27,28]. Encouraged by the flexible approach taken by the RDoC task force aimed at using the principles of the framework to integrate and define elements of the RDoC matrix, we have identified an additional 12 types of proxy measures that could similarly gauge altered mood consequent to a perceived reward [29]. Taking these newly identified proxy measures into consideration, 45 self-report measures were extracted from the included studies that investigated the effect of LSD on the PVS.

The most widely used proxy self-report was the Altered States of Consciousness questionnaire (ASC) and its variations [30, 31]. The ASC evaluates the subjective effects of psychedelic drugs in a retrospective manner and constitutes 19 (42.22 %) of the extracted outcome measures. The subscale “blissful state” assesses the positive mood induced by rewarding experiences during the peak drug effect [31]. We also included subjects’ and investigators’ rating of mood expressed on different scales such as the visual analogue scale (VAS) (eight outcome measures, 17.78%). Other commonly used proxy measures obtained from self-reports were the “vigor” subscale of the Profile of Mood State (POMS) questionnaire (four outcome measures, 8.89 %), the “emotional excitation” and “well-being” items of the Adjective Mood Rating Scale (AMRS) (four outcome measures, 8.89%), subscales “deeply felt positive mood” and “positive mood” from variations of the Mystical Type Experience Questionnaire (MEQ) (five outcome measures, 11.11%), subscales “ positive mood changes”, “positive attitude toward life and self”, “positive behavior changes” and “well-being and life satisfaction” from the Persisting Effect Questionnaire (PEQ) (one outcome measure, 2.22%), item “want more of you received” from drug effect questionnaire (DEQ) (one outcome measures, 2.22%), and subscale “optimism” from the revised life orientation test (one outcome measures, 2.22%) [32,33,34,35,36,37].

Paradigm units of analysis provided insights for all three constructs of the PVS, namely, reward responsiveness, reward learning, reward valuation. Included under the reward learning construct in the RDoC framework, conditioning paradigms evaluate learning behavior as modified by a present or prospective rewarding stimuli [23, 38]. Moreover, we have included nine paradigms as proxy measures. Two paradigms suggested as proxy measures for reward responsiveness are the electrophysiological monetary incentive delay task derived from human studies, and sucrose preference test from the animal studies. Two of the proxy paradigms, eyeblink conditioning task and probabilistic reward learning task, could potentially help determine whether LSD impacts the reward learning construct. Five proxy measures included under the reward valuation construct were the forced swim test, the reinstatement of self-administration of alcohol, the intracranial self-stimulation (ICSS) test, animal model of the Iowa gambling test, derived from preclinical studies, and the Cambridge gambling task, derived from clinical studies. The distribution of the included human and animal studies based on the PVS constructs (reward responsiveness, learning and valuation) across units of analysis (self-report, paradigm, circuit, and molecule) is summarized in Fig. 2.

Fig. 2

Distribution of outcome measures extracted from human and animal studies by Research Domain Criteria (RDoC) units of analysis (self-report, paradigm, circuit, and molecule) and constructs of the positive valence system (PVS)

The isolated involvement of the remaining units of analysis, molecules, and circuits, in the PVS is not feasible, given their potential relevance to multiple domains and constructs. For instance, the serotonergic system is involved in all six of the RDoC domains [39]. Consequently, reporting their involvement with a certain domain and construct is context-dependent and relies on supplementary higher-level analyses. For example, examining the impact of the serotonergic system on the positive affect subscale of the PANAS narrows the focus to its role within the context of the PVS. Accordingly, we have discussed circuits and molecules in their pertinent contexts.

3.2 Human Data

Twenty-eight unique clinical studies involving 477 participants were identified. As for the reported units of analysis, 23 studies assessed LSD-induced alterations of the PVS using self-reports, while five studies employed the molecules units of analysis, four examined circuits, and three utilized paradigms (Fig. 2). Twenty-seven studies were conducted with healthy participants primarily in biomedically oriented lab settings encompassing a wide range of psychometric, neurobehavioral, and brain imaging assessments. Only one study consisted of results from a clinical trial, which investigated the effects of LSD on patients suffering from anxiety disorders [40]. It is important to highlight that in all the included studies, the dosage range for LSD administration varied from 5 to 200 mcg, which was administered via and different routes, including oral, sublingual, and intravenous.

Besides self-reports, five of the studies reported molecular units of analysis, examining the effects of a 5-HT2A receptor antagonist, ketanserin, on the subjective effects of LSD. Additionally, we extracted results from three paradigms. These paradigms assessed the reward processing systems and included the Cambridge gambling task, probabilistic reversal learning task, and electrophysiological monetary incentive task. We will explore their potential relevance to distinct constructs within the PVS in the corresponding sections.

All the included studies utilized self-report questionnaires (psychometric) to assess participants' hedonic responses to the LSD-induced experience. Our results have indicated a dose-response relationship, particularly when comparing very low (“micro-doses”) to high doses of LSD, as reported in self-reports, which constituted the majority of our findings from the human studies. In light of this observed dose-response relationship and to streamline the organization of our findings, we have classified the human data into two distinct categories based on dosage: full-dose and micro-dose. In the literature, a micro-dose is typically defined as 1/10th or 1/20th of recreational dosing, which, according to the studies included in this review, amounts to ≤ 26 mcg. Furthermore, data for each of these categories, whether full-dose or micro-dose, were grouped by their measurement class (units of analysis), including self-report, paradigm, molecule, or circuits, where applicable.

3.2.1 Full-Dose Studies3.2.1.1 Self Reports

Forty-five self-reports were extracted from the included studies that investigated the effects of full-dose LSD on the reward responsiveness. This construct involves an individual's hedonic response to rewarding stimuli, which is reflected in various measures, including subjective reports [5].

The self-reports from the full-dose studies indicated that LSD improved mood in both the short (15 studies) and the long term (three studies). Considering the plasma half-life of LSD, which typically falls within the 3- to 4-hour range and utilizing the standard calculation for drug clearance based on five half-lives, we have classified outcomes into two categories based on timeframes. Evaluations conducted within 24 hours of drug administration were classified as short-term outcomes, while those conducted thereafter were categorized as long-term outcomes (Table 2) [41, 42]; it is crucial to note that the long-term assessments included in this review extend well beyond this initial 24-hour timeframe. Specifically, these long-term assessments span a period ranging from two weeks to 12 months post-administration.

Six studies evaluated the dose-dependent effect of LSD. Among these studies, two were conducted in biomedical laboratory settings and involved the same group of participants. These two studies specifically examined the effects of two LSD doses, namely 100 and 200 mcg, on various factors, including “well-being” as measured by the Altered States of Consciousness Rating Scale (AMRS) “deeply felt positive mood” assessed through the MEQ (Mystical Experience Questionnaire) scale, and subjective ratings of the item “happy” [43, 44]. Their findings suggested a significant (p < 0.05) difference only between the higher dose of LSD and placebo for related items of AMRS and MEQ scales. The scores of the latter scale also showed that 200 mcg of LSD was associated with higher scores of “deeply felt positive mood” when compared to the effects of a 75 mg single dose of 3,4-methylenedioxymethamphetamine (MDMA). Conversely, the effects of both doses of LSD were similar but significantly higher than placebo (p < 0.05) for the item “happy” in the subjective ratings. In another study, Schmid et al. pooled the dose-effect findings of various doses of LSD, specifically 100 and 200 mcg, on the different mood assessments in healthy and patient populations [40]. Intriguingly, in the patient population, the effects of various doses of LSD on items “blissful state” on 5D-ASC and “deeply felt positive mood” and “positive mood” on different variations of the MEQ scale were not significantly different from one another but were nevertheless greater than placebo. The effects of LSD on healthy participants, however, were dose dependent with the 200 mcg eliciting higher scores than the 100 mcg on the related items of 5D-ASC and MEQ scales. Moreover, the effects of both doses on the aforementioned mood-related scales were significantly higher than placebo (p < 0.05). In another double-blind placebo-controlled study, Holze et al. studied the acute effects of two doses of LSD (100 and 200 mcg) as well as two doses of psilocybin (15 and 30 mg) on measures of mood [45]. In contrast to previous studies, they found no significant differences between the effects of the two LSD doses (100 and 200 mcg) on the relevant items of AMRS (“emotional excitation”), 5D-ASC (“blissful state”) and MEQ scales (“deeply felt positive mood” and “positive mood”). Furthermore, there were no significant differences between either the dose of LSD and the psilocybin doses (15 and 30 mg). However, the aforementioned items for acute changes in mood were significantly higher than placebo (p < 0.05).

3.2.1.2 Molecules

The five studies that reported LSD effect at the molecular level used ketanserin, a 5-HT2A receptor antagonist, to investigate whether the 5-HT2A receptor subtype is involved in the subjective and neural effects of LSD [24, 25, 27, 46,47,48]. All five studies showed that a pretreatment of 40 mg ketanserin can reverse LSD-elicited increases in subjective mood as assessed by items “blissful state” in 5D-ASC and “positive mood” in PANAS. Preller et al. further studied how ketanserin can affect the changes in connectivity associated with LSD [48]. Their main goal was to identify LSD-induced effects on neural and behavioral measures. Preller et al. showed that LSD concurrently increased somatosensory and thalamic connectivity while reducing associative network connectivity, and that ketanserin prevented these LSD-induced changes in neural connectivity.

3.2.1.3 Paradigms

Two studies investigated the effects of full-dose LSD with paradigms [47, 49]. Pokorny et al. conducted the only study that assessed reward valuation using the Cambridge Gambling Task (CGT) paradigm [47]. This task mainly evaluates risk-taking behavior and reward-based decision making outside of a learning context [50]. The CGT shares similarities with the probabilistic selection task, an RDoC-recommended task for the reward valuation construct. Both tasks involve decision making under conditions of uncertainty and requiring participants to learn through trial and error as to which trial is associated with positive versus negative outcomes. Accordingly, we suggest CGT as a proxy measure within the reward valuation construct [7]. The authors found no effect of LSD on the task parameters, namely the quality of decision making or risk taking [47].

Kanen et al. lead another study that used paradigms to evaluate the effects of LSD on reward processing [49]. The authors investigated the effects of 75 mcg intravenous LSD (same study as Carhart-Harris et al. 2016 [51]) in a probabilistic reversal learning task (PRL) [52]. In a PRL task, participants are asked to identify, through trial and error, the stimulus most frequently associated with reward during the acquisition phase. During the reversal phase, the contingencies change, necessitating participants to adapt their choices based on the new conditions. We propose that this paradigm aligns with the reward learning construct. Reward learning is a form of reinforcement learning that involves organisms gathering information about stimuli, actions, and situations that forecast favorable results. It also encompasses the adjustment of behavior when a new reward arises or when outcomes surpass initial expectations [6]. The PRL task effectively aligns with the construct of reward learning as it replicates key elements of this process. In the acquisition phase, participants must identify stimuli associated with rewards, mirroring how organisms gather information about positive outcomes. The subsequent reversal phase, where stimulus-reward contingencies change, necessitates participants to adapt their choices, reflecting the behavior modification component of reward learning when outcomes deviate from expectations or novel rewards emerge.

In their analysis, the authors explored the effects of LSD on different reinforcement learning parameters based on either raw data measures of behavior or the parameters obtained by fitting reinforcement learning computational models to the behavioral data. The results on the raw data measures showed that LSD did not affect the sensitivity to the immediate feedback but increased perseveration, which quantified the number of preservative errors involving stimuli that were formerly correct but are incorrect in the reversal trial. In terms of computational model parameters related to reinforcement learning, LSD increased both reward learning and punishment learning parameters, demonstrating its influence on learning from positive and negative outcomes. Additionally, LSD reduced “stimulus stickiness,” indicating a decreased propensity for choice repetition, irrespective of the outcome. The impact on reinforcement sensitivity, which measures the influence of past rewards and punishments on decision making, was different in acquisition and reversal trials. LSD did not significantly affect reinforcement sensitivity during acquisition trials but increased it during reversal trials, suggesting varying sensitivity to past reinforcement in different decision-making contexts.

3.2.1.4 Circuits

In two studies that also performed circuit-level analysis, notable associations were observed between self-reported positive mood states and functional connectivity as assessed by functional magnetic resonance imaging (fMRI) [53, 54]. Luppi et al. found that LSD-induced increases in “blissful state” are associated with increased “small-world” neural network organization, which is a pattern of brain activity that typically decreases in states of impaired or lowered consciousness [54]. In another study, Preller et al. found that LSD-induced increases in “blissful states” is correlated with elevated somatosensory connectivity [48].

3.2.2 Micro-dosing3.2.2.1 Self Reports

Five of the included studies sought to determine the effects of micro-doses of LSD on mood, among other assessments [26, 28, 53, 55, 56]. The results of self-reports from all five studies shown non-significant effects with doses ≤ 20 mcg, suggesting that the subjective mood-enhancing properties of LSD are dose dependent.

Bershad et al. investigated the acute effects of single, low doses of 6.5, 13, and 26 mcg [26]. Following the administration of 13 and 26 mcg of LSD, the item “vigor” on POMS scored significantly higher than placebo (p < 0.05) only at the highest dose, and the item “blissful state” on 5D-ASC scored significantly higher than placebo (p < 0.05) after the administration of 13 and 26 mcg of LSD. None of the doses affected item “elation” on the POMS. The effects of the 13-mcg dose on measures of mood were not replicated in their later study as there was no significant difference between LSD and placebo on items “positive mood” on PANAS and “blissful state” on 5D-ASC scales [53]. In another study, Hutten et al. examined the acute effects of 5, 10, and 20 mcg of LSD on mood in a double-blind, within-subject, placebo-controlled study. They observed an enhancement of mood following the administration of 20 mcg, but not with the lower dosage of LSD, as measured by items “positive mood” on POMS and “happy” on subjective rating scales. None of the administered doses had an impact on the item “blissful state” on 5D-ASC [57].

In a study conducted by de Wit et al., the effects of four repeated doses of LSD, either 13- or 26 mcg, or placebo, were investigated on different subjective assessment of mood, namely, POMS, PANAS, DEQ, and 5D-ASC [28]. Their results suggest that only 26 mcg of LSD increased the scores on items “vigor” on the POMS and “blissful state” on the 5D-ASC. No doses affected the relevant subscales of mood of PANAS or DEQ. Moreover, they found no residual effect on the drug-free follow-up session.

Murray et al. investigated the effects of 13- and 26-mcg doses compared to a placebo on subjective measures of mood indexed by POMS, DEQ, and 5D-ASC in healthy volunteers [56]. Murray et al. found that only 26 mcg of LSD produced perceptible subjective changes in mood, namely by increasing the score of items “vigor” and “elated” on the POMS questionnaire, “want more of what you received” on the DEQ, and “blissful state” on the 5D-ASC questionnaires [56].

3.2.2.2 Paradigms and Circuits

Two studies that investigated the effects of micro-doses of LSD also reported results from concurrent assessments using paradigms alongside neuroimaging (circuits).

In a complementary study to that of Murray et al., elaborated above, Glazer et al included neural measures of reward processing as assessed by task-based EEG [58]. While the results of Murray et al. indicated no subjective effects for doses lower than 26 mcg, Glazer et al. showed that 13 mcg of LSD led to neural changes in a reward-processing paradigm called the electrophysiological monetary incentive delay (eMID) task [58]. During this task, the event-related potentials (ERPs) of the EEG signals were recorded while processing positive and negative feedback under both reward and non-reward conditions. We interpreted the MID task as a proxy for measuring reward responsiveness because this task directly aligns with the RDoC guidelines, which emphasize assessing “neural activity in response to the receipt of rewards and reward cues [5]. The results of Glazer et al. suggested that at 13 mcg, LSD increased both the affective values of reward feedback (vs neutral feedback) as measured by late positive potential (LPP) amplitudes and hedonic impact of the positive feedback in reward conditions, as indexed by Reward Positivity (ReWP). They also showed that both doses of LSD, 13 and 26 mcg, increased the motivational salience of the stimuli by elevating the feedback P3 (FB-P3) amplitudes. Intriguingly, none of these neural measurements were associated with the subjective measures of mood in their respective studies. In a similar vein, in another study involving the “micro-dose” group, led by Bershad et al, no subjective effects were reported with the 13-mcg dose of LSD, but there was an observed increase in the correlation between amygdala-prefrontal connectivity and measures of positive mood [53].

3.3 Animal Data

All 14 included animal studies reported LSD effects using paradigm units of analysis. Five studies additionally included molecular outcomes, while one included outcome at the circuit level to assess the effects of LSD on the PVS. The studies encompass both short-term assessments (conducted on the administration day) and long-term assessments (conducted two days or more after administration). In these studies, all three RDoC-defined PVS constructs were addressed, although not all subconstructs were tested. Three of the identified studies employed measures of reward responsiveness [59,60,61], and the rest of the studies focused on the constructs of reward valuation [62,63,64,65,66,