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Despite the availability of numerous pain medications, the current array of Food and Drug Administration-approved options falls short in adequately addressing pain states for numerous patients and consequently worsens the opioid crisis. Thus, it is imperative for basic research to develop novel and nonaddictive pain medications. Toward addressing this clinical goal, nalfurafine (NLF) was chosen as a lead and its structure–activity relationship (SAR) systematically studied through design, syntheses, and in vivocharacterization of 24 analogues. Two analogues, 21and 23, showed longer durations of action than NLF in a warm-water tail immersion assay, produced in vivoeffects primarily mediated by KOR and DOR, penetrated the blood–brain barrier, and did not function as reinforcers. Additionally, 21produced fewer sedative effects than NLF. Taken together, these results aid the understanding of NLF SAR and provide insights for future endeavors in developing novel nonaddictive therapeutics to treat pain.

Substance use disorders are defined by persistent drug consumption despite adverse consequences. Accordingly, we developed two fentanyl-vs-shock avoidance/escape choice procedures in which male and female rats responded under a fixed-ratio (FR)1:FR1 concurrent schedule of shock avoidance/escape and IV fentanyl under either mutually exclusive or non-exclusive choice conditions. Initial experiments using a discrete-trial procedure determined behavioral allocation between mutually exclusive shock avoidance/escape and different fentanyl doses (0.32–18 μg/kg/infusion; Experiment 1). Shock intensity (0.1–0.7 mA) and shock avoidance/escape response requirement (FR1-16) were also manipulated (Experiment 2). Next, we used a free-operant procedure in which shock avoidance/escape and fentanyl were continuously available under non-exclusive conditions, and response-shock (R-S) interval (30–1000 s) was manipulated (Experiment 3). Finally, we tested the hypothesis that extended-access fentanyl self-administration would produce fentanyl dependence, establish fentanyl withdrawal as an endogenous negative reinforcer, and increase fentanyl choice in both procedures (Experiments 4 and 5). The shock avoidance/escape contingency decreased fentanyl self-administration, and rats consistently chose shock avoidance/escape over fentanyl in both choice conditions. Decreasing shock intensity or increasing shock avoidance/escape response requirement failed to increase fentanyl choice, suggesting that fentanyl and shock avoidance/escape are independent economic commodities. Increasing the R-S interval increased fentanyl choice but failed to increase shock delivery. Extended fentanyl access engendered high fentanyl intake and opioid withdrawal signs but failed to increase fentanyl choice under either choice condition. These results suggest that neither positive fentanyl reinforcement nor negative reinforcement by fentanyl withdrawal is sufficient to reduce shock avoidance/escape-maintained responding and increase foot shock as an adverse consequence.

Recent studies suggest that dopamine D3 receptors (D3R) may be a therapeutic target for opioid use disorders (OUD). This study examined the effects of the D3R partial agonist (±)VK4-40 and the D3R-selective antagonist (±)VK4-116, compared to the mu-opioid receptor antagonist naltrexone (NTX), in nonhuman primate models of OUD and antinociception. Adult male and female (N= 4/sex) cynomolgus monkeys were trained to self-administer oxycodone (0.003–0.1 mg/kg/injection) first under a fixed-ratio (FR) and then a progressive-ratio (PR) schedule of reinforcement during daily 1- and 4-hr sessions, respectively. Under the FR schedule, intravenous NTX (0.01–0.1 mg/kg), (±)VK4-116 (1.0–10 mg/kg), and (±)VK4-40 (1.0–10 mg/kg) were studied in combination with the peak oxycodone dose and a dose on the descending limb of the dose-effect curve; NTX and (±)VK4-40 were also studied at the peak of the PR dose-response curve (N= 4). Following saline extinction, each compound was examined on oxycodone-induced reinstatement. Finally, these compounds were assessed in adult male rhesus monkeys (N= 3) in a warm-water (38 °C, 50 °C, 54 °C) tail withdrawal assay. NTX decreased responding on the peak of the FR oxycodone dose-response curve, but increased responding on the descending limb. (±)VK4-40, but not (±)VK4-116, significantly decreased peak oxycodone self-administration; (±)VK4-40 did not increase responding on the descending limb. NTX and (±)VK4-40, but not (±)VK4-116, attenuated oxycodone-induced reinstatement. Under PR responding, NTX and (±)VK4-40 decreased breakpoints. Oxycodone-induced antinociception was attenuated by NTX, but not by (±)VK4-40 or (±)VK4-116. Together, these results suggest that further research evaluating the effects of (±)VK4-40 as a novel pharmacotherapy for OUD is warranted.

The high efficacy mu-opioid receptor (MOR) agonist methadone is an effective opioid use disorder (OUD) medication used exclusively in opioid-dependent patients. However, methadone has undesirable effects that limit its clinical efficacy. Intermediate efficacy MOR agonists may treat OUD with fewer undesirable effects. We compared the effects of methadone with the intermediate efficacy MOR agonist TRV130 (oliceridine) on fentanyl-vs.-food choice and somatic withdrawal signs in opioid-dependent and post-opioid-dependent rats. Male rats (n= 20) were trained under a fentanyl-vs.-food choice procedure. Rats were then provided extended fentanyl (3.2 µg/kg/infusion) access (6 p.m.–6 a.m.) for 10 days to produce opioid dependence/withdrawal. Rats were treated with vehicle (n= 7), TRV130 (3.2 mg/kg; n= 8), or methadone (3.2 mg/kg; n= 5) three times per day after each extended-access session (8:30 a.m., 11 a.m., 1:30 p.m.). Withdrawal sign scoring (1:55 p.m.) and choice tests (2–4 p.m.) were conducted daily. Vehicle, TRV130, and methadone effects on fentanyl choice were redetermined in post-opioid-dependent rats. Vehicle-, TRV130-, and methadone-treated rats had similar fentanyl intakes during extended access. Vehicle-treated rats exhibited increased withdrawal signs and decreased bodyweights. Both methadone and TRV130 decreased these withdrawal signs. TRV130 was less effective than methadone to decrease fentanyl choice and increase food choice in opioid-dependent rats. Neither methadone nor TRV130 decreased fentanyl choice in post-opioid-dependent rats. Results suggest that higher MOR activation is required to reduce fentanyl choice than withdrawal signs in fentanyl-dependent rats. Additionally, given that TRV130 did not precipitate withdrawal in opioid-dependent rats, intermediate efficacy MOR agonists like TRV130 may facilitate the transition of patients with OUD from methadone to lower efficacy treatments like buprenorphine.

Substance use disorders (SUDs) are heterogeneous and complex, making the development of translationally predictive rodent and nonhuman primate models to uncover their neurobehavioral underpinnings difficult. Neuroscience‐focused outcomes have become highly prevalent, and with this, the notion that SUDs are disorders of the brain embraced as a dominant theoretical orientation to understand SUD etiology and treatment. These efforts, however, have led to few efficacious pharmacotherapies, and in some cases (as with cocaine or methamphetamine), no pharmacotherapies have translated from preclinical models for clinical use. In this theoretical commentary, we first describe the development of animal models of substance use behaviors from a historical perspective. We then define and discuss three logical fallacies including 1) circular explanation, 2) affirming the consequent, and 3) reification that can apply to developed models. We then provide three case examples in which conceptual or logical issues exist in common methods (i.e., behavioral economic demand, escalation, and reinstatement). Alternative strategies to refocus behavioral models are suggested for the field to better bridge the translational divide between animal models, the clinical condition of SUDs, and current and future regulatory pathways for intervention development.

Relapse within the context of a substance use disorder can be triggered by cues that function as discriminative stimuli to signal contingencies of drug availability and promote drug‐taking behavior. Extinction procedures can weaken this association between drug‐associated cues and drug‐taking behavior and may reduce the probability of relapse. This study evaluated a regimen of extinction training on cocaine and heroin self‐administration in rhesus monkeys under a drug‐vs‐food choice procedure. Behavior was initially maintained under a concurrent schedule of food (1‐g food pellets; fixed‐ratio 100 schedule) and cocaine injections (0–0.1 mg/kg/injection; fixed‐ratio 10) (n = 4 males) or heroin injections (0–0.01 mg/kg/injection; fixed‐ratio 10) (n = 3 females and 1 male) during daily 2‐hr choice sessions. Subsequently, choice sessions were supplemented by daily 20‐hr saline self‐administration sessions for 14 consecutive days. During saline self‐administration sessions, only drug‐associated discriminative stimuli were presented and responding produced saline injections. Drug continued to be available during choice sessions. Prior to extinction training, both cocaine and heroin maintained dose‐dependent increases in drug‐vs‐food choice. Exposure to 14 saline self‐administration sessions failed to significantly decrease drug choice and increase food choice. These preclinical results do not support the effectiveness of extinguishing drug‐associated discriminative stimuli as a nonpharmacological treatment strategy for reducing drug choice.

Opioid withdrawal is a key driver of opioid addiction and an obstacle to recovery. However, withdrawal effects on opioid reinforcement and mesolimbic neuroadaptation are understudied, and the role of sex is largely unknown.

Critical features of human addiction are increasingly being incorporated into complementary animal models, including escalation of drug intake, punished drug seeking and taking, intermittent drug access, choice between drug and non-drug rewards, and assessment of individual differences based on criteria in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders(DSM-IV). Combined with new technologies, these models advanced our understanding of brain mechanisms of drug self-administration and relapse, but these mechanistic gains have not led to improvements in addiction treatment. This problem is not unique to addiction neuroscience, but it is an increasing source of disappointment and calls to regroup. Here we first summarize behavioural and neurobiological results from the animal models mentioned above. We then propose a reverse translational approach, whose goal is to develop models that mimic successful treatments: opioid agonist maintenance, contingency management and the community-reinforcement approach. These reverse-translated ‘treatments’ may provide an ecologically relevant platform from which to discover new circuits, test new medications and improve translation.

Clinical evidence suggest that men are more sensitive than women to the abuse-related effects of mu-opioid agonists. In contrast, preclinical studies suggest the opposite sex difference. The aim of the present study was to clarify this discrepancy using a fentanyl vs. diluted Ensure®choice procedure to assess sex differences in opioid reinforcement. Sex differences in intravenous (IV) fentanyl self-administration were examined under a fixed-ratio (FR5) schedule, a multi-day progressive-ratio (PR) schedule for behavioral economic analysis, and a concurrent (choice) schedule of fentanyl and diluted Ensure®reinforcement in Sprague–Dawley male and female rats. The fentanyl dose-effect function under the FR5 schedule was significantly shifted upward in females compared to males. Similarly, the reinforcing effectiveness of both fentanyl (3.2 and 10 µg/kg per injection, IV) and diluted Ensure®(18 and 56%) were greater in females than in males as assessed using behavioral economic analysis, irrespective of dose or concentration. However, under a fentanyl vs. foodchoice procedure, males chose 3.2 µg/kg per injection fentanyl injections over 18%, but not 56%, diluted Ensure®at a higher percentage compared to females. Overall, these results suggest that the expression of sex differences in opioid reinforcement depends upon the schedule of reinforcement and that preclinical opioid vs. food choice procedures provide a translationally relevant measure (i.e., behavioral allocation) consistent with the direction of sex differences reported in the clinical literature.

Sex differences in μ-opioid receptor (MOR) agonist-induced antinociception have been reported in nonhuman primates. The degree to which μ-opioid receptor agonist sex differences in nonhuman primates extend to other behavioral endpoints remains unknown. The present study compared the behavioral effects of three MOR ligands (fentanyl, buprenorphine, and naltrexone) that varied in efficacy to stimulate [35S]-GTPγS binding (from highest to lowest: fentanyl, buprenorphine, and naltrexone) in male and female rhesus monkeys. Male (n=3) and female (n=3) monkeys were trained to respond under a fixed-ratio 10 schedule of food presentation during daily sessions consisting of multiple components. Once rates of responding were stable, cumulative dose–effect functions were determined for intramuscular fentanyl (0.00032–0.032 mg/kg), buprenorphine (0.001–1 mg/kg), and naltrexone (0.01–0.1 mg/kg). Fentanyl dose-dependently decreased rates of responding in both sexes and the corresponding ED50values were not significantly different. Buprenorphine dose-dependently decreased rates of responding in females, but not males. Naltrexone did not significantly alter behavior in either females or males. Overall, these results suggest that the expression of sex differences in MOR pharmacology depends upon both the efficacy of the MOR ligand and the behavioral endpoint.

μ-Opioid agonists are clinically effective analgesics, but also produce undesirable effects such as sedation and abuse potential that limit their clinical utility. Glutamatergic systems also modulate nociception and N-methyl d-aspartate (NMDA) receptor antagonists have been proposed as one useful adjunct to enhance the therapeutic effects and/or attenuate the undesirable effects of μ-opioid agonists. Whether NMDA antagonists enhance the antiallodynic effects of μ-agonists in preclinical models of thermal hypersensitivity (i.e. capsaicin-induced thermal allodynia) are unknown. The present study determined the behavioral effects of racemic ketamine, (+)-MK-801, (−)-nalbuphine, and (−)-oxycodone alone and in fixed proportion mixtures in assays of capsaicin-induced thermal allodynia and schedule-controlled responding in rhesus monkeys. Ketamine, nalbuphine, and oxycodone produced dose-dependent antiallodynia. MK-801 was inactive up to doses that produced undesirable effects. Ketamine, but not MK-801, enhanced the potency of μ-agonists to decrease rates of operant responding. Ketamine and nalbuphine interactions were additive in both procedures. Ketamine and oxycodone interactions were additive or subadditive depending on the mixture. Furthermore, oxycodone and MK-801 interactions were subadditive on antiallodynia and additive on rate suppression. These results do not support the broad clinical utility of NMDA receptor antagonists as adjuncts to μ-opioid agonists for thermal allodynic pain states.

Substance use disorders (i.e., drug addiction) constitute a global and insidious public health issue. Preclinical biomedical research has been invaluable in elucidating the environmental, biological, and pharmacological determinants of drug abuse and in the process of developing innovative pharmacological and behavioral treatment strategies. For more than 70 years, nonhuman primates have been utilized as research subjects in biomedical research related to drug addiction. There are already several excellent published reviews highlighting species differences in both pharmacodynamics and pharmacokinetics between rodents and nonhuman primates in preclinical substance abuse research. Therefore, the aim of this review is to highlight three advantages of nonhuman primates as preclinical substance abuse research subjects. First, nonhuman primates offer technical advantages in experimental design compared to other laboratory animals that afford unique opportunities to promote preclinical-to-clinical translational research. Second, these technical advantages, coupled with the relatively long lifespan of nonhuman primates, allows for pairing longitudinal drug self-administration studies and noninvasive imaging technologies to elucidate the biological consequences of chronic drug exposure. Lastly, nonhuman primates offer advantages in the patterns of intravenous drug self-administration that have potential theoretical implications for both the neurobiological mechanisms of substance use disorder etiology and in the drug development process of pharmacotherapies for substance use disorders. We conclude with potential future research directions in which nonhuman primates would provide unique and valuable insights into the abuse of and addiction to novel psychoactive substances.

Cocaine use disorder is a global public health problem for which there are no Food and Drug Administration-approved pharmacotherapies. Emerging preclinical evidence has implicated both serotonin (5-HT) 2C and 2A receptors as potential mechanisms for mediating serotonergic attenuation of cocaine abuse-related neurochemical and behavioral effects. Therefore, the present study aim was to determine whether repeated 7-day treatment with the 5-HT2Cagonist lorcaserin (0.1–1.0 mg/kg per day, intramuscular; 0.032–0.1 mg/kg/h, intravenous) or the 5-HT2Ainverse agonist/antagonist pimavanserin (0.32–10 mg/kg per day, intramuscular) attenuated cocaine reinforcement under a concurrent ‘choice’ schedule of cocaine and food availability in rhesus monkeys. During saline treatment, cocaine maintained a dose-dependent increase in cocaine vs food choice. Repeated pimavanserin (3.2 mg/kg per day) treatments significantly increased small unit cocaine dose choice. Larger lorcaserin (1.0 mg/kg per day and 0.1 mg/kg/h) and pimavanserin (10 mg/kg per day) doses primarily decreased rates of operant behavior. Coadministration of ineffective lorcaserin (0.1 mg/kg per day) and pimavanserin (0.32 mg/kg per day) doses also failed to significantly alter cocaine choice. These results suggest that neither 5-HT2Creceptor activation nor 5-HT2Areceptor blockade are sufficient to produce a therapeutic-like decrease in cocaine choice and a complementary increase in food choice. Overall, these results do not support the clinical utility of 5-HT2Cagonists and 5-HT2Ainverse agonists/antagonists alone or in combination as candidate anti-cocaine use disorder pharmacotherapies.

The dopamine transporter (DAT) inhibitor and nicotinic acetylcholine (nACh) receptor antagonist bupropion is being investigated as a candidate ‘agonist’ medication for methamphetamine addiction. In addition to its complex pharmacology, bupropion also has two distinct pharmacologically active metabolites. However, the mechanism by which bupropion produces methamphetamine-like ‘agonist’ effects remains unknown. The aim of the present study was to determine the role of DAT inhibition, nACh receptor antagonism, and the hydroxybupropion metabolites in the methamphetamine-like discriminative stimulus effects of bupropion in rhesus monkeys. In addition, varenicline, a partial agonist at the nACh receptor, and risperidone, a dopamine antagonist, were tested as controls. Monkeys (n=4) were trained to discriminate 0.18?mg/kg intramuscular methamphetamine from saline in a two-key food-reinforced discrimination procedure. The potency and time course of methamphetamine-like discriminative stimulus effects were determined for all compounds. Bupropion, methylphenidate, and 2S,3S-hydroxybupropion produced full, at least 90%, methamphetamine-like effects. 2R,3R-Hydroxybupropion, mecamylamine, and nicotine also produced full methamphetamine-like effects, but drug potency was more variable between monkeys. Varenicline produced partial methamphetamine-like effects, whereas risperidone did not. Overall, these results suggest DAT inhibition as the major mechanism of the methamphetamine-like ‘agonist’ effects of bupropion, although nACh receptor antagonism appeared, at least partially, to contribute. Furthermore, the contribution of the 2S,3S-hydroxybupropion metabolite could not be completely ruled out.

Phendimetrazine is a clinically available anorectic and candidate medication for the treatment of cocaine addiction. Phendimetrazine can be metabolized to the amphetamine-like monoamine releaser phenmetrazine, but it is unclear if phendimetrazine functions as an inactive prodrug or might have activity on its own. As one method to address this issue, the present study compared the potency and time course of phendimetrazine and phenmetrazine to produce cocaine-like discriminative stimulus effects in adult, male rats (N=5) trained to discriminate cocaine (5.6?mg/kg, intraperitoneally) from saline in a two-key food-reinforced discrimination procedure. We hypothesized that, if metabolism to phenmetrazine was required for phendimetrazine effects, then phendimetrazine would be less potent and have a slower onset and offset of effects than phenmetrazine. Both phendimetrazine and phenmetrazine produced dose-dependent cocaine-like discriminative stimulus effects, and phendimetrazine was 7.8-fold less potent than phenmetrazine. However, the time courses of discriminative stimulus effects produced by phendimetrazine and phenmetrazine were similar, with peak effects at 10?min and offset by 100?min. These results show the effectiveness of phendimetrazine to rapidly produce cocaine-like behavioral effects in rats and support other nonhuman primate evidence to suggest that metabolism to phenmetrazine may not be required for phendimetrazine effects.

Ethanol (EtOH) and nicotine abuse are 2 leading causes of preventable mortality in the world, but little is known about the pharmacological mechanisms mediating co‐abuse. Few studies have examined the interaction of the acute effects of EtOH and nicotine. Here, we examine the effects of nicotine administration on the duration of EtOH‐induced loss of righting reflex (LORR) and characterize the nature of their pharmacological interactions in C57BL/6J mice. We assessed the effects of EtOH and nicotine and the nature of their interaction in the LORR test using isobolographic analysis after acute injection in C57BL/6J male mice. Next, we examined the importance of receptor efficacy using nicotinic partial agonists varenicline and sazetidine. We evaluated the involvement of major nicotinic acetylcholine receptor (nAChR) subtypes using nicotinic antagonist mecamylamine and nicotinic α4‐ and α7‐knockout mice. The selectivity of nicotine's actions on EtOH‐induced LORR was examined by testing nicotine's effects on the hypnotic properties of ketamine and pentobarbital. We also assessed the development of tolerance after repeated nicotine exposure. Last, we assessed whether the effects of nicotine on EtOH‐induced LORR extend to hypothermia and EtOH intake in the drinking in the dark (DID) paradigm. We found that acute nicotine injection enhances EtOH's hypnotic effects in a synergistic manner and that receptor efficacy plays an important role in this interaction. Furthermore, tolerance developed to the enhancement of EtOH's hypnotic effects by nicotine after repeated exposure of the drug. α4* and α7 nAChRs seem to play an important role in nicotine–EtOH interaction in the LORR test. In addition, the magnitude of EtOH‐induced LORR enhancement by nicotine was more pronounced in C57BL/6J than DBA/2J mice. Furthermore, acute nicotine enhanced ketamine and pentobarbital hypnotic effects in the mouse. Finally, nicotine enhanced EtOH‐induced hypothermia but decreased EtOH intake in the DID test. Our results demonstrate that nicotine synergistically enhances EtOH‐induced LORR in the mouse.

‘Rate dependency’ in the discipline of behavioral pharmacology describes a phenomenon wherein the effect of a drug on the rate of a behavior varies systematically as a function of the baseline, predrug rate of that behavior. Historically, rate-dependency studies have compared drug effects on different baseline rates of behavior maintained either by different schedules of reinforcement or during sequential segments of a fixed-interval schedule. The current experiment generated different baseline rates of behavior by altering frequency of electrical stimulation in an intracranial self-stimulation assay. Amphetamine and 10 other monoamine releasers were analyzed for their ability to produce rate-dependent effects in this assay. There were three main findings. First, all compounds produced rate-dependent effects at some dose. Second, one parameter of rate-dependency plots (peak Y-intercept of the regression line) correlated with in-vitro neurochemical data on selectivity of these compounds to release dopamine versus serotonin (P<0.025, R2=0.50). Lastly, a correlation between peak Y-intercept and breakpoints under a progressive-ratio procedure in nonhuman primates was also significant (P<0.05, R2=0.64). Overall, these results extend the rate-dependent effects of monoamine releasers to behavior maintained under intracranial self-stimulation and suggest that, at least for monoamine releasers, the Y-intercept parameter of rate-dependency plots might be a useful metric of drug reward and predictor of drug self-administration measures of drug reinforcement.

Mu-opioid agonists are effective analgesics but have undesirable effects such as sedation and abuse liability that limit their clinical effectiveness. Serotonergic systems also modulate nociception, and serotonin uptake inhibitors may be useful as adjuncts to enhance analgesic effects and/or attenuate undesirable effects of mu agonists. This study examined the effects of the serotonin uptake inhibitor clomipramine on behavioral effects produced in rhesus monkeys by mu agonists with varying efficacy at mu receptors (nalbuphine < morphine < methadone). Clomipramine and each mu agonist were studied alone and in fixed-proportion mixtures in assays of schedule-controlled responding, thermal nociception, and capsaicin-induced thermal allodynia. In the assay of schedule-controlled responding, all mu agonists dose-dependently decreased response rates. Clomipramine was inactive alone and did not alter the effects of mu agonists. In the assay of thermal nociception, all mu agonists produced dose-dependent antinociception. Clomipramine was inactive alone but produced a proportion-dependent enhancement of the antinociceptive effects of nalbuphine > morphine > methadone. In the assay of capsaicin-induced allodynia, nalbuphine produced dose-dependent antiallodynia. Clomipramine alone was inactive, but as in the assay of thermal nociception, it produced a proportion-dependent enhancement in the effects of nalbuphine. These findings suggest that serotonin uptake inhibitors can selectively enhance the antinociceptive effects of mu agonists in nonhuman primates. These effects of serotonin uptake inhibitors may depend on the proportion of the serotonin uptake inhibitor and the efficacy of the mu agonist. The greatest enhancement was observed with intermediate proportions of clomipramine in combination with the low-efficacy mu agonist nalbuphine.

Changes in ambient temperature are known to alter both the hyperthermic and the serotonergic consequences of 3,4-methylenedioxymethamphetamine (MDMA). Metabolism of MDMA has been suggested to be a requisite for these neurotoxic effects, whereas the hyperthermic response is an important contributing variable. The aim of the present study was to investigate the interaction between ambient temperature, MDMA-induced thermodysregulation, and its metabolic disposition in monkeys. MDMA (1.5 mg/kg i.v.) was administered noncontingently at cool (18°C; n = 5), room (24°C; n = 7), and warm (31°C; n = 7) ambient temperatures. For 240 min following MDMA administration, core temperature was recorded and blood samples were collected for analysis of MDMA and its metabolites 3,4-dihydroxymethamphetamine (HHMA), 3,4-dihydroxyamphetamine, and 3,4-methylenedioxyamphetamine (MDA). A dose of 1.5 mg/kg MDMA induced a hypothermic response at 18°C, a hyperthermic response at 31°C, and did not significantly change core temperature at 24°C. Regardless of ambient temperature, plasma MDMA concentrations reached maximum within 5 min, and HHMA was a major metabolite. Curiously, the approximate elimination half-life (t½) of MDMA at 18°C (136 min) and 31°C (144 min) was increased compared with 24°C (90 min) and is most likely because of volume of distribution changes induced by core temperature alterations. At 18°C, there was a significantly higher MDA area under the concentration-time curve (AUC) and a trend for a lower HHMA AUC compared with 24°C and 31°C, suggesting that MDMA disposition was altered. Overall, induction of hypothermia in a cool environment by MDMA may alter its disposition. These results could have implications for MDMA-induced serotonergic consequences.