Human thalamic low-frequency oscillations correlate with expected value and outcomes during reinforcement learning.

Reinforcement-based adaptive decision-making is believed to recruit fronto-striatal circuits. A critical node of the fronto-striatal circuit is the thalamus. However, direct evidence of its involvement in human reinforcement learning is lacking. We address this gap by analyzing intra-thalamic electrophysiological recordings from eight participants while they performed a reinforcement learning task. We found that in both the anterior thalamus (ATN) and dorsomedial thalamus (DMTN), low frequency oscillations (LFO, 4-12 Hz) correlated positively with expected value estimated from computational modeling during reward-based learning (after outcome delivery) or punishment-based learning (during the choice process). Furthermore, LFO recorded from ATN/DMTN were also negatively correlated with outcomes so that both components of reward prediction errors were signaled in the human thalamus. The observed differences in the prediction signals between rewarding and punishing conditions shed light on the neural mechanisms underlying action inhibition in punishment avoidance learning. Our results provide insight into the role of thalamus in reinforcement-based decision-making in humans.

Culturally tailored digital therapeutic for substance use disorders with urban Indigenous people in the United States: A randomized controlled study.

INTRODUCTION: Indigenous people experience health disparities, including higher rates of substance use disorders (SUDs). Digital therapeutics are a growing platform for treatment services and have the potential to expand access to culturally responsive interventions for Indigenous people. As one of the first randomized controlled trials for SUDs for American Indian and Alaska Native (AI/AN) adults, the aim of this study was to pilot test the efficacy of a culturally tailored intervention among urban Indigenous adults. METHODS: The study used a randomized controlled parallel design of 12 weeks of treatment-as-usual (TAU) (n = 26) versus TAU + Therapeutic Education System-Native Version (TES-NAV) (n = 27) with follow-up assessments at end of treatment and week 24 in an urban outpatient addiction treatment program for Native American adults. TAU consisted of individual/group counseling and cultural activities. The TES-NAV arm comprised TAU + 26 self-directed culturally tailored digital skills-based modules grounded in the community reinforcement approach with contingency management for abstinence and module completion. Primary outcome was longest consecutive weeks of abstinence from drugs and heavy drinking measured using self-report (Timeline Followback) and urine alcohol and drug toxicology screen during 12 weeks of treatment. Secondary outcomes were percent days abstinence during and posttreatment, coping strategies, social connectedness, and substance use and sexual risk behaviors. RESULTS: The study enrolled fifty-three (52.8 % male) AI/AN adults seeking treatment for a SUD. Although the study did not detect a benefit of TAU+TES-NAV over TAU on the primary outcome (Median = 2 consecutive weeks of abstinence for both arms) at end of treatment (treatment effect: Z = -0.78, p = 0.437), TAU+TES-NAV participants did demonstrate significantly greater percent days of abstinence at the week 24 follow-up (69.3 % versus 49.0 % for TAU; t = 2.08, p = 0.045) and significantly greater change in social connectedness mean score, baseline to week 12 (Z = -2.66, p = 0.011), compared to TAU. The study detected no differences between treatment arms for coping strategies or risk behaviors. CONCLUSION: The addition of TES-NAV to TAU did not significantly improve consecutive weeks of abstinence from drugs or heavy drinking; however, several secondary findings suggest promise for a culturally tailored digital therapeutic SUD intervention among urban Indigenous people. CLINICAL TRIALS: GOV REGISTRATION: #NCT03363256.

Focused-attention mindfulness increases sensitivity to current schedules of reinforcement.

Four experiments explored the impact of focused-attention mindfulness training on human performance on free-operant schedules of reinforcement. In each experiment, human participants responded on a multiple random ratio (RR), random interval (RI) schedule. In all experiments, responding was higher on RR than RI schedules, despite equated rates of reinforcement. A 10-min focused-attention mindfulness intervention (focused attention) produced greater differentiation between schedules than relaxation training (Experiments 1, 2, and 4), or no intervention (Experiment 3). Focused-attention mindfulness improved learning when the schedules associated with components of the multiple schedule were reversed. This occurred irrespective of whether the focused-attention mindfulness was before (Experiment 2) or after (Experiments 3 and 4) initial training, or whether compared to relaxation (Experiments 2 and 4) or no intervention (Experiment 3). In Experiment 4, following multiple RR, RI training, focused-attention mindfulness increased sensitivity to contingency reversal and did not interfere with previous training in a group that did not receive a contingency reversal. In contrast, relaxation training did not facilitate reversal learning and interfered with previous learning. The results suggest that focused-attention mindfulness improves awareness of operative contingencies by focusing participants on the present, rather than reducing interference from previous learning. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

The effect of brief mindfulness training on the micro-structure of human free-operant responding: Mindfulness affects stimulus-driven responding.

BACKGROUND AND OBJECTIVES: The current study examines the extent to which mindfulness impacts on operant conditioning processes, and explores the suggestion that mindfulness training serves to make humans more sensitive to the current reinforcement contingencies with which they are presented. In particular, the effect of mindfulness on the micro-structure of human schedule performance was explored. It was expected that mindfulness might impact bout-initiation responding to a greater degree than within-bout responding, premised on the assumption that bout-initiation responses are habitual and not under conscious control, but within-bout responses are goal-directed and conscious. METHODS: Nonclinical participants experienced one of three brief (15min) interventions: focused attention breathing exercise (mindfulness), an unfocused attention breathing exercises, or no intervention. They then responded on a multiple random ratio (RR) random interval (RI) schedule. RESULTS: In the no intervention and unfocused attention groups, overall and within-bout response rates were higher on the RR than the RI schedule, but bout-initiation rates were the same on the two schedules. However, for the mindfulness groups all forms of responding were higher for the RR than the RI schedule. Previous work has noted that habitual, and/or unconscious or fringe-conscious events, are impacted by mindfulness training. LIMITATIONS: A nonclinical sample may limit generality. CONCLUSIONS: The current pattern of results suggests that this is also true in schedule-controlled performance, and offers an insight into the manner in which mindfulness alongside conditioning-based interventions, to bring all responses under conscious control.

The voluntary operant and the operant nature of volition: Three views.

Many philosophers, psychologists, and lay folk associate volition with autonomy (actions are independent of an individual's environment) and free will (individuals originate their actions). Most behaviorists hold these views to be incompatible with behavior analyses. The present paper describes volition as interpreted by B. F. Skinner, Howard Rachlin, and Allen Neuringer. Skinner relates volition to positively reinforced operant behavior. That works because, like operants, voluntary actions are free, in the sense of not physically constrained; they affect their environments, often resulting in positive outcomes, and are sometimes unpredictable. Rachlin, while incorporating Skinnerian methods, interprets volition within his own Teleological Behaviorism framework. For Rachlin, reinforcement of an individual response is often incompatible with voluntary control, thereby disagreeing with Skinner. Responses are voluntary only when they are members of extended response patterns. Neuringer also begins with Skinner's operants, but argues that, under the control of reinforcing consequences, both voluntary actions and operant responses are sometimes predictable and other times "truly" unpredictable. Neuringer does not assume that environments determine voluntary actions, thereby disagreeing with Skinner and Rachlin. Taken together, the agreements and disagreements among these three behaviorists may help to shed light on the relationship between operants and volition.

The catecholamine precursor Tyrosine reduces autonomic arousal and decreases decision thresholds in reinforcement learning and temporal discounting.

Supplementation with the catecholamine precursor L-Tyrosine might enhance cognitive performance, but overall findings are mixed. Here, we investigate the effect of a single dose of tyrosine (2g) vs. placebo on two catecholamine-dependent trans-diagnostic traits: model-based control during reinforcement learning (2-step task) and temporal discounting, using a double-blind, placebo-controlled, within-subject design (n = 28 healthy male participants). We leveraged drift diffusion models in a hierarchical Bayesian framework to jointly model participants' choices and response times (RTS) in both tasks. Furthermore, comprehensive autonomic monitoring (heart rate, heart rate variability, pupillometry, spontaneous eye blink rate) was performed both pre- and post-supplementation, to explore potential physiological effects of supplementation. Across tasks, tyrosine consistently reduced participants' RTs without deteriorating task-performance. Diffusion modeling linked this effect to attenuated decision-thresholds in both tasks and further revealed increased model-based control (2-step task) and (if anything) attenuated temporal discounting. On the physiological level, participants' pupil dilation was predictive of the individual degree of temporal discounting. Tyrosine supplementation reduced physiological arousal as revealed by increases in pupil dilation variability and reductions in heart rate. Supplementation-related changes in physiological arousal predicted individual changes in temporal discounting. Our findings provide first evidence that tyrosine supplementation might impact psychophysiological parameters, and suggest that modeling approaches based on sequential sampling models can yield novel insights into latent cognitive processes modulated by amino-acid supplementation.

Prospective and retrospective values integrated in frontal cortex drive predictive choice.

To make a deliberate action in a volatile environment, the brain must frequently reassess the value of each action (action-value). Choice can be initially made from the experience of trial-and-errors, but once the dynamics of the environment is learned, the choice can be made from the knowledge of the environment. The action-values constructed from the experience (retrospective value) and the ones from the knowledge (prospective value) were identified in various regions of the brain. However, how and which neural circuit integrates these values and executes the chosen action remains unknown. Combining reinforcement learning and two-photon calcium imaging, we found that the preparatory activity of neurons in a part of the frontal cortex, the anterior-lateral motor (ALM) area, initially encodes retrospective value, but after extensive training, they jointly encode the retrospective and prospective value. Optogenetic inhibition of ALM preparatory activity specifically abolished the expert mice's predictive choice behavior and returned them to the novice-like state. Thus, the integrated action-value encoded in the preparatory activity of ALM plays an important role to bias the action toward the knowledge-dependent, predictive choice behavior.

Choice-selective sequences dominate in cortical relative to thalamic inputs to NAc to support reinforcement learning.

How are actions linked with subsequent outcomes to guide choices? The nucleus accumbens, which is implicated in this process, receives glutamatergic inputs from the prelimbic cortex and midline regions of the thalamus. However, little is known about whether and how representations differ across these input pathways. By comparing these inputs during a reinforcement learning task in mice, we discovered that prelimbic cortical inputs preferentially represent actions and choices, whereas midline thalamic inputs preferentially represent cues. Choice-selective activity in the prelimbic cortical inputs is organized in sequences that persist beyond the outcome. Through computational modeling, we demonstrate that these sequences can support the neural implementation of reinforcement-learning algorithms, in both a circuit model based on synaptic plasticity and one based on neural dynamics. Finally, we test and confirm a prediction of our circuit models by direct manipulation of nucleus accumbens input neurons.

Reinforcement Learning Methods in Public Health.

PURPOSE: Reinforcement learning (RL) is the subfield of machine learning focused on optimal sequential decision making under uncertainty. An optimal RL strategy maximizes cumulative utility by experimenting only if and when the information generated by experimentation is likely to outweigh associated short-term costs. RL represents a holistic approach to decision making that evaluates the impact of every action (ie, data collection, allocation of resources, and treatment assignment) in terms of short-term and long-term utility to stakeholders. Thus, RL is an ideal model for a number of complex decision problems that arise in public health, including resource allocation in a pandemic, monitoring or testing, and adaptive sampling for hidden populations. Nevertheless, although RL has been applied successfully in a wide range of domains, including precision medicine, it has not been widely adopted in public health. The purposes of this review are to introduce key ideas in RL and to identify challenges and opportunities associated with the application of RL in public health. METHODS: We provide a nontechnical review of the theoretical and methodologic underpinnings of RL. A running example of RL for the management of an infectious disease is used to illustrate ideas. FINDINGS: RL has the potential to make a transformative impact in a range of sequential decision problems in public health. By allocating resources if, when, and where they are most impactful, RL can improve health outcomes while reducing resource consumption. IMPLICATIONS: Public health researchers and stakeholders should consider RL as a means of efficiently using data to inform optimal evidence-based decision making.

Engagement patterns with a digital therapeutic for substance use disorders: Correlations with abstinence outcomes.

INTRODUCTION: Patient engagement may play a key role in the success or failure of treatments for substance use disorder (SUD). This exploratory analysis of data from a large, multisite effectiveness trial (NCT01104805) sought to determine how patient engagement with a digital therapeutic for SUD delivered at clinics was associated with abstinence outcomes. METHODS: The study evaluated engagement for 206 participants enrolled in a treatment program for SUDs related to cocaine, alcohol, cannabis, or other stimulants who were randomized to receive treatment as usual (TAU) or reduced TAU plus the digital Therapeutic Education System (TES) for 12 weeks. Participants were eligible for contingency management incentives for module completion (modules cover Community Reinforcement Approach topic areas) and negative urine drug screens. Analyses examined the association of module completion with end-of-treatment abstinence. RESULTS: Participants completed a mean of 38.8 (range 0-72) TES modules over 12 weeks of treatment. Study completers (n = 157) completed a mean of 45.5 (range 9-72) TES modules, whereas study noncompleters (n = 49) completed a mean of 17.4 (range 0-45) TES modules. The study observed a strong positive correlation between TES engagement (i.e., total number of modules completed) and the probability of abstinence during weeks 9-12 of treatment among 157 study completers (OR = 1.11; 95% CI 1.08-1.14). Each module completed increased the odds of abstinence during weeks 9-12 by approximately 11% for study completers and 9% for the full sample. The study observed a similar, but weaker, association between engagement and abstinence among 49 patients who did not complete the study (OR = 1.02; 95% CI 0.98-1.07). CONCLUSIONS: Greater engagement with a digital therapeutic for patients with SUD (i.e., number of modules completed over time) was strongly associated with the probability of abstinence in the last four weeks of treatment among those who completed the recommended 12-week treatment. TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT01104805.

Contrasting Mind-Wandering, (Dark) Flow, and Affect During Multiline and Single-Line Slot Machine Play.

Slot machines are a very popular form of gambling in which a small proportion of gamblers experience gambling-related problems. These players refer to a trance-like state that researchers have labelled 'dark flow'-a pleasurable, but maladaptive state where players become completely occupied by the game. We assessed 110 gamblers for mindfulness (using the Mindful Attention Awareness Scale), gambling problems (using the Problem Gambling Severity Index), depressive symptoms (using the Depression, Anxiety, and Stress Scale), and boredom proneness (using the Boredom Proneness Scale). Participants played both a multiline and single-line slot machine simulator and were occasionally interrupted with thought probes to assess whether they were thinking about the game or something else. After playing each game, we retrospectively assessed dark flow and affect during play. Our key results were that the number of "on-game" reports during the multiline game were significantly higher than the single-line game, and that we found significantly greater flow during the multiline game than the single-line game. We also found significantly lower negative affect during the multiline game than the single-line game. Using hierarchical multiple regression, we found that dark flow accounted for unique variance when predicting problem gambling severity (over and above depression, mindfulness, and boredom proneness). These assessments help bolster our previous assertions about escape gambling-if some players are prone to having their mind-wander to negative places, the frequent but unpredictable reinforcement of multiline slot machines may help rein in the wandering mind and prevent minds from unintentionally wandering to negative thoughts.

Alpha activity neuromodulation induced by individual alpha-based neurofeedback learning in ecological context: a double-blind randomized study.

The neuromodulation induced by neurofeedback training (NFT) remains a matter of debate. Investigating the modulation of brain activity specifically associated with NF requires controlling for multiple factors, such as reward, performance, congruency between task and targeted brain activity. This can be achieved using sham feedback (FB) control condition, equating all aspects of the experiment but the link between brain activity and FB. We aimed at investigating the modulation of individual alpha EEG activity induced by NFT in a double-blind, randomized, sham-controlled study. Forty-eight healthy participants were assigned to either NF (n = 25) or control (n = 23) group and performed alpha upregulation training (over 12 weeks) with a wearable EEG device. Participants of the NF group received FB based on their individual alpha activity. The control group received the auditory FB of participants of the NF group. An increase of alpha activity across training sessions was observed in the NF group only (p < 0.001). This neuromodulation was selective in that there was no evidence for similar effects in the theta (4-8 Hz) and low beta (13-18 Hz) bands. While alpha upregulation was found in the NF group only, psychological outcome variables showed overall increased feeling of control, decreased anxiety level and increased relaxation feeling, without any significant difference between the NF and the control groups. This is interpreted in terms of learning context and placebo effects. Our results pave the way to self-learnt, NF-based neuromodulation with light-weighted, wearable EEG systems.

Defensive freezing and its relation to approach-avoidance decision-making under threat.

Successful responding to acutely threatening situations requires adequate approach-avoidance decisions. However, it is unclear how threat-induced states-like freezing-related bradycardia-impact the weighing of the potential outcomes of such value-based decisions. Insight into the underlying computations is essential, not only to improve our models of decision-making but also to improve interventions for maladaptive decisions, for instance in anxiety patients and first-responders who frequently have to make decisions under acute threat. Forty-two participants made passive and active approach-avoidance decisions under threat-of-shock when confronted with mixed outcome-prospects (i.e., varying money and shock amounts). Choice behavior was best predicted by a model including individual action-tendencies and bradycardia, beyond the subjective value of the outcome. Moreover, threat-related bradycardia (high-vs-low threat) interacted with subjective value, depending on the action-context (passive-vs-active). Specifically, in action-contexts incongruent with participants' intrinsic action-tendencies, stronger bradycardia related to diminished effects of subjective value on choice across participants. These findings illustrate the relevance of testing approach-avoidance decisions in relatively ecologically valid conditions of acute and primarily reinforced threat. These mechanistic insights into approach-avoidance conflict-resolution may inspire biofeedback-related techniques to optimize decision-making under threat. Critically, the findings demonstrate the relevance of incorporating internal psychophysiological states and external action-contexts into models of approach-avoidance decision-making.

Reinforcement of Self-Regulated Brain Activity in Schizophrenia Patients Undergoing Rehabilitation.

The experiment was aimed to compare the effects of different forms of rehabilitation applied in patients with schizophrenia. Verification of the obtained results was based on the analysis of the level of cognitive and social functioning of the subjects. For this purpose, the following clinical tools were used: Positive and Negative Syndrome Scale (PANSS), Beck Cognitive Insight Scale (BCIS), Color Trial Test (CTT-1, CTT-2), d2 psychological tests, Acceptance of Illness Scale (AIS), Self-efficacy Scale (GSES), Quantitative Electroencephalogram Biofeedback (QEEG-BF), auditory event-related potentials (ERPs), and serum levels of brain-derived neurotrophic factor (BDNF). The subjects were mentally stable male schizophrenia patients who had been in remission. They were divided into two groups which received different types of rehabilitation for three months. Group 1 patients followed a standard rehabilitation and Group 2 patients received GSR Biofeedback (galvanic skin response Biofeedback, GSR-BF) training. Pretherapy and posttherapy measurements were made for each group. Experimental rehabilitation based on GSR-BF training resulted in regulatory control of neurophysiological mechanisms, and the parameters obtained demonstrated improvement in the subjects' cognitive and social function. The following therapy outcomes were observed: (1) reduce psychopathological symptoms (2) improving cognitive (concentration, attention) and social functions (3) increase in the neurotrophic factor BDNF. GSR-BF can be used as an alternative to conventional rehabilitation in schizophrenia patients.

Daidzein modulates cocaine-reinforcing effects and cue-induced cocaine reinstatement in CD-1 male mice.

RATIONALE: Cocaine addiction is a chronic relapsing disorder that lacks of an effective treatment. Isoflavones are a family of compounds present in different plants and vegetables like soybeans that share a common chemical structure. Previous studies have described that synthetic derivatives from the natural isoflavone daidzin can modulate cocaine addiction, by a mechanism suggested to involve aldehyde-dehydrogenase (ALDH) activities. OBJECTIVES: Based on these previous studies, we investigated the effects of three natural isoflavones, daidzin, daidzein, and genistein, on the modulation of the cocaine reinforcing effects and on cue-induced reinstatement in an operant mouse model of cocaine self-administration. RESULTS: Chronic treatment with daidzein or genistein decreased operant responding to obtain cocaine intravenous infusions. On the other hand, daidzein and daidzin, but not genistein, were effective in decreasing cue-induced cocaine reinstatement. Complementary studies revealed that daidzein effects on cocaine reinforcement were mediated through a mechanism that involved dopamine type-2/3 receptors (DA-D2/3) activities. CONCLUSIONS: Our results suggest that these natural compounds alone or in combination can be a potential therapeutic approach for cocaine addiction. Further clinical studies are required in order to ascertain their potential therapeutic use.

An amygdala-to-hypothalamus circuit for social reward.

Social interactions and relationships are often rewarding, but the neural mechanisms through which social interaction drives positive experience remain poorly understood. In this study, we developed an automated operant conditioning system to measure social reward in mice and found that adult mice of both sexes display robust reinforcement of social interaction. Through cell-type-specific manipulations, we identified a crucial role for GABAergic neurons in the medial amygdala (MeA) in promoting the positive reinforcement of social interaction. Moreover, MeA GABAergic neurons mediate social reinforcement behavior through their projections to the medial preoptic area (MPOA) and promote dopamine release in the nucleus accumbens. Finally, activation of this MeA-to-MPOA circuit can robustly overcome avoidance behavior. Together, these findings establish the MeA as a key node for regulating social reward in both sexes, providing new insights into the regulation of social reward beyond the classic mesolimbic reward system.

Role of the central amygdala in acupuncture inhibition of methamphetamine-induced behaviors in rats.

Methamphetamine (METH) enhances dopamine (DA) transmission in the mesolimbic system implicated in its reinforcing effects. Our previous studies have shown that acupuncture attenuates drug-seeking behaviors by modulating GABAergic transmission in the ventral tegmental area and DA release in the nucleus accumbens (NAc) of the striatum. The effects of acupuncture on METH-induced behaviors and its mediation by neural pathways remain a relatively understudied area of research. The central amygdala (CeA) plays a critical role in physiological and behavioral responses to somatosensory and drug stimuli and has been implicated in negative reinforcement. Thus, we evaluated the role of the CeA in acupuncture effects on locomotor activity, positive affective states, and DA release in the NAc following acute administration of METH. Acupuncture at acupoint HT7 reduced locomotor activity, 50-kHz ultrasonic vocalizations (USVs), and NAc DA release following systemic injection of METH, which was prevented by electrolytic lesions or optogenetic inhibition of the CeA. Acupuncture alone excited CeA neurons and reversed the suppression of CeA neurons induced by METH. These results suggest that acupuncture can relieve psychomotor responses and positive affective states following METH by inhibiting NAc DA release and this effect is mediated by activation of CeA neurons.

The credit assignment problem in cortico-basal ganglia-thalamic networks: A review, a problem and a possible solution.

The question of how cortico-basal ganglia-thalamic (CBGT) pathways use dopaminergic feedback signals to modify future decisions has challenged computational neuroscientists for decades. Reviewing the literature on computational representations of dopaminergic corticostriatal plasticity, we show how the field is converging on a normative, synaptic-level learning algorithm that elegantly captures both neurophysiological properties of CBGT circuits and behavioral dynamics during reinforcement learning. Unfortunately, the computational studies that have led to this normative algorithmic model have all relied on simplified circuits that use abstracted action-selection rules. As a result, the application of this corticostriatal plasticity algorithm to a full model of the CBGT pathways immediately fails because the spatiotemporal distance between integration (corticostriatal circuits), action selection (thalamocortical loops) and learning (nigrostriatal circuits) means that the network does not know which synapses should be reinforced to favor previously rewarding actions. We show how observations from neurophysiology, in particular the sustained activation of selected action representations, can provide a simple means of resolving this credit assignment problem in models of CBGT learning. Using a biologically realistic spiking model of the full CBGT circuit, we demonstrate how this solution can allow a network to learn to select optimal targets and to relearn action-outcome contingencies when the environment changes. This simple illustration highlights how the normative framework for corticostriatal plasticity can be expanded to capture macroscopic network dynamics during learning and decision-making.

Δ9-tetrahydrocannabinol: Drug discrimination abuse liability testing in female Lister Hooded rats: Trials, tribulations and triumphs.

INTRODUCTION: The assessment of the abuse potential of CNS-active drugs is a regulatory requirement. Drug discrimination is one of the nonclinical tests that contribute to this assessment by providing information on a drug's potential to induce a discriminative stimulus comparable to that of a known drug of abuse. AIM: The objective was to validate drug discrimination in the rat for the purpose of supporting regulatory submissions for novel drugs with potential cannabinoid-like activity. METHODS: Ten female Lister hooded rats were trained to discriminate no-drug from Δ9-THC (1.5 mg/kg, IP) under a FR10 schedule of reinforcement. Once trained, a Δ9-THC dose-response curve was obtained using doses of 0.25, 0.75, 1.5, and 3 mg/kg, IP. This was followed by evaluation of amphetamine (0.3 mg/kg, SC); morphine (3 mg/kg, IP); midazolam (2.5 mg/kg, PO); and the synthetic cannabinoids WIN55,212-2 (0.75 to 2 mg/kg, IP), CP-47,497 (0.5 to 2 mg/kg, IP), and JWH-018 (1 mg/kg, IP) for their discriminative stimulus similarity to Δ9-THC. RESULTS: Pharmacological specificity was demonstrated by achieving the anticipated dose-response curve for Δ9-THC, and a vehicle-like response for the non-cannabinoid drugs. Although full generalisation was obtained for JWH-018, in contrast to published literature, WIN55,212-2 and CP-47,497 failed to generalise to Δ9-THC. DISCUSSION: Based on the literature review performed in light of the results obtained, contrasting and unpredictable behavioural responses produced by cannabinoids in animals and humans raises the question of the reliability and relevance of including drug discrimination and self-administration studies within an abuse potential assessment for novel cannabinoid-like drugs.