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Rationale Despite their chemical similarities, methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) produce differing neurochemical and behavioral responses in animals. In humans, individual studies of methamphetamine and MDMA indicate that the drugs engender overlapping and divergent effects; there are only limited data comparing the two drugs in the same individuals. Objectives This study examined the effects of methamphetamine and MDMA using a within-subject design. Methods Eleven adult volunteers completed this 13-day residential laboratory study, which consisted of four 3-day blocks of sessions. On the first day of each block, participants received oral methamphetamine (20, 40 mg), MDMA (100 mg), or placebo. Drug plasma concentrations, cardiovascular, subjective, and cognitive/psychomotor performance effects were assessed before drug administration and after. Food intake and sleep were also assessed. On subsequent days of each block, placebo was administered and residual effects were assessed. Results Acutely, both drugs increased cardiovascular measures and “positive” subjective effects and decreased food intake. In addition, when asked to identify each drug, participants had difficulty distinguishing between the amphetamines. The drugs also produced divergent effects: methamphetamine improved performance and disrupted sleep, while MDMA increased “negative” subjective-effect ratings. Few residual drug effects were noted for either drug. Conclusions It is possible that the differences observed could explain the differential public perception and abuse potential associated with these amphetamines. Alternatively, the route of administration by which the drugs are used recreationally might account for the many of the effects attributed to these drugs (i.e., MDMA is primarily used orally, whereas methamphetamine is used by routes associated with higher abuse potential).

Adult hippocampal neurogenesis is critically implicated in rodent models of stress and anxiety as well as behavioral effects of antidepressants. Whereas similar factors such as psychiatric disorder and antidepressant administration are correlated with hippocampal volume in humans, the relationship between these factors and adult neurogenesis is less well understood. To better bridge the gap between rodent and human physiology, we examined the numbers of proliferating neural precursors and immature cells in the hippocampal dentate gyrus (DG) as well as in vivo magnetic resonance imaging (MRI)-estimated whole hippocampal volume in eight socially dominant- or subordinate-like (SL) baboons administered the antidepressant fluoxetine or vehicle. SL baboons had lower numbers of proliferating cells and immature neurons than socially dominant-like baboons. Fluoxetine treatment was associated with a larger whole hippocampal volume but surprisingly resulted in lower numbers of immature neurons. These findings are the first to indicate that adult neurogenesis in the baboon hippocampal DG may be functionally relevant in the context of social stress and mechanisms of antidepressant action.

Few individuals seeking treatment for marijuana use achieve sustained abstinence. The cannabinoid receptor agonist, Δ(9)-tetrahydrocannabinol (THC; dronabinol), decreases marijuana withdrawal symptoms, yet does not decrease marijuana use in the laboratory or clinic. Dronabinol has poor bioavailability, which may contribute to its poor efficacy. The FDA-approved synthetic analog of THC, nabilone, has higher bioavailability and clearer dose-linearity than dronabinol. This study tested whether nabilone administration would decrease marijuana withdrawal symptoms and a laboratory measure of marijuana relapse relative to placebo. Daily, nontreatment-seeking marijuana smokers (8 men and 3 women), who reported smoking 8.3±3.1 marijuana cigarettes/day completed this within-subject study comprising three, 8-day inpatient phases; each phase tested a different nabilone dose (0, 6, 8 mg/day, administered in counter-balanced order on days 2-8). On the first inpatient day, participants took placebo capsules and smoked active marijuana (5.6% THC) at six timepoints. For the next 3 days, they had the opportunity to self-administer placebo marijuana (0.0% THC; withdrawal), followed by 4 days in which active marijuana was available for self-administration (5.6% THC; relapse). Both nabilone dose conditions decreased marijuana relapse and reversed withdrawal-related irritability and disruptions in sleep and food intake (p<0.05). Nabilone (8 mg/day) modestly worsened psychomotor task performance. Neither dose condition increased ratings of capsule 'liking' or desire to take the capsules relative to placebo. Thus, nabilone maintenance produced a robust attenuation of marijuana withdrawal symptoms and a laboratory measure of relapse even with once per day dosing. These data support testing of nabilone for patients seeking marijuana treatment.

Rationale Partial dopamine receptor agonists have been proposed as candidate pharmacotherapies for cocaine dependence. Objective This 42-day, within-subject, human laboratory study assessed how maintenance on aripiprazole, a partial D 2 receptor agonist, influenced smoked cocaine self-administration, cardiovascular measures, subjective effects, and cocaine craving in nontreatment-seeking, cocaine-dependent volunteers. Methods In order to achieve steady-state concentrations, participants ( n  = 8 men) were administered placebo and aripiprazole (15 mg/day) capsules in counter-balanced order for 21 days. A smoked cocaine dose–response curve (0, 12, 25, 50 mg) was determined twice under placebo and aripiprazole maintenance. Sessions comprised a “sample” trial, when participants smoked the cocaine dose available that session, and five choice trials, when they responded on a progressive-ratio schedule of reinforcement to receive the cocaine dose or receive $5.00. Results Cocaine’s reinforcing, subjective, and cardiovascular effects were dose-dependent. Aripiprazole significantly increased cocaine (12, 25 mg) self-administration. Following a single administration of cocaine (25 mg), aripiprazole decreased ratings of how much participants would pay for that dose. Following repeated cocaine (50 mg) self-administration, aripiprazole decreased ratings of cocaine quality, craving, and good drug effect as compared to placebo. Conclusions These data suggest that aripiprazole may have increased self-administration to compensate for a blunted subjective cocaine effect. Overall, the findings do not suggest aripiprazole would be useful for treating cocaine dependence.

Cannabis use disorder (CUD) is widespread, and there is no pharmacotherapy to facilitate its treatment. AEF0117, the first of a new pharmacological class, is a signaling-specific inhibitor of the cannabinoid receptor 1 (CB 1 -SSi). AEF0117 selectively inhibits a subset of intracellular effects resulting from Δ 9 -tetrahydrocannabinol (THC) binding without modifying behavior per se. In mice and non-human primates, AEF0117 decreased cannabinoid self-administration and THC-related behavioral impairment without producing significant adverse effects. In single-ascending-dose (0.2 mg, 0.6 mg, 2 mg and 6 mg; n  = 40) and multiple-ascending-dose (0.6 mg, 2 mg and 6 mg; n  = 24) phase 1 trials, healthy volunteers were randomized to ascending-dose cohorts ( n  = 8 per cohort; 6:2 AEF0117 to placebo randomization). In both studies, AEF0117 was safe and well tolerated (primary outcome measurements). In a double-blind, placebo-controlled, crossover phase 2a trial, volunteers with CUD were randomized to two ascending-dose cohorts (0.06 mg, n  = 14; 1 mg, n  = 15). AEF0117 significantly reduced cannabis’ positive subjective effects (primary outcome measurement, assessed by visual analog scales) by 19% (0.06 mg) and 38% (1 mg) compared to placebo ( P  < 0.04). AEF0117 (1 mg) also reduced cannabis self-administration ( P  < 0.05). In volunteers with CUD, AEF0117 was well tolerated and did not precipitate cannabis withdrawal. These data suggest that AEF0117 is a safe and potentially efficacious treatment for CUD. ClinicalTrials.gov identifiers: NCT03325595 , NCT03443895 and NCT03717272 . The signaling-specific inhibitor AEF0117 selectively inhibits CB 1 activation by THC and reduces self-administration and subjective effects of cannabis in clinical trials, making it a potential treatment for cannabis use disorder.

Symptoms of dependence and withdrawal after the frequent administration of high doses (210 mg/day) of oral delta9-tetrahydrocannabinol (THC) have been reported, yet little is known about dependence on lower oral THC doses, more relevant to levels attained by smoking marijuana. In a 20-day residential study, male (n = 6) and female (n = 6) marijuana smokers worked on five psychomotor tasks during the day (0915-1700 hours), and in the evening engaged in private or social recreational activities (1700-2330 hours); subjective-effects measures were completed 10 times/day, and a sleep questionnaire was completed each morning. Food and beverages were available ad libitum from 0830 to 2330 hours. Capsules were administered at 1000, 1400, 1800, and 2200 hours. Placebo THC was administered on days 1-3, 8-11, and 16-19. Active THC was administered on days 4-7 (20 mg qid) and on days 12-15 (30 mg qid). Both active doses of THC increased ratings of \"High,\" \"Good Drug Effect,\" and \"Willingness to Take Dose Again\" compared to baseline (days 1-3). THC also increased food intake by 35-45%, and decreased verbal interaction among participants compared to placebo baseline. Tolerance developed to the subjective effects of THC but not to its effects on food intake or social behavior. Abstinence from THC increased ratings of \"Anxious,\" \"Depressed,\" and \"Irritable,\" decreased the reported quantity and quality of sleep, and decreased food intake by 20-30% compared to baseline. These behavioral changes indicate that dependence develops following exposure to lower daily doses of THC than have been previously studied, suggesting that the alleviation of abstinence symptoms may contribute to the maintenance of daily marijuana use.

In a previous study, we showed that the positive subjective effects of cocaine were higher during the follicular phase compared to the luteal phase of the menstrual cycle. The purpose of the present study was to determine if exogenously administered progesterone during the follicular phase in females would attenuate the response to cocaine compared to the normal follicular phase, thus making the response to cocaine similar to the luteal phase. To address the role of sex differences, males were also administered exogenous progesterone during one inpatient stay. In all, 11 female and 10 male non-treatment-seeking cocaine smokers participated. Females had three inpatient stays: one during a normal follicular phase, one during a normal luteal phase, and one during a follicular phase when exogenous progesterone was administered. Males had two inpatient stays: one when exogenous progesterone was administered and the other when placebo was administered. During each inpatient admission, there were four smoked cocaine administration sessions: participants were administered six doses of cocaine (0, 6, 12, or 25 mg cocaine base) at 14 min intervals. Smoked cocaine increased heart rate, blood pressure and several subjective effects such as 'good drug effect' and 'drug quality' cluster scores. Administration of progesterone during the follicular phase in women attenuated the positive subjective effects of cocaine, whereas only minimal changes were observed in men. These results indicate that progesterone modulates the response to cocaine in women and suggests that fluctuations in endogenous progesterone levels account for some of the sex differences observed in humans.

Rationale Each year, over 300,000 individuals in the USA enter treatment for cannabis use disorder (CUD). The development of effective pharmacotherapy for CUD is a priority. Objective This placebo-controlled study examined the effects of zolpidem alone and in combination with nabilone on cannabis withdrawal and a laboratory measure of relapse. Methods Eleven daily, non-treatment-seeking cannabis users completed three, 8-day inpatient phases; each phase tested a different medication condition in counter-balanced order. On the first day of each phase, participants were administered placebo capsules t.i.d. and smoked experimenter-administered active cannabis (5.6 % Δ 9 -tetrahydrocannabinol (THC)). On days 2–8, the participants were administered capsules containing either placebo (0 mg at 0900, 1800, and 2300 hours), zolpidem (0 mg at 0900 and 1800, and 12.5 mg at 2300), or zolpidem (12.5 mg at 2300) and nabilone (3 mg at 0900 and 1800). Cannabis withdrawal, subjective capsule effects, and cognitive performance were examined on days 3–4, when only inactive cannabis (0.0 % THC) was available for self-administration. “Relapse” was measured on days 5–8, when participants could self-administer active cannabis. Results Both medication conditions decreased withdrawal-related disruptions in sleep, but only zolpidem in combination with nabilone decreased withdrawal-related disruptions in mood and food intake relative to placebo. Zolpidem in combination with nabilone, but not zolpidem alone, decreased self-administration of active cannabis. Zolpidem in combination with nabilone also produced small increases in certain abuse-related subjective capsule ratings, while zolpidem alone did not. Neither medication condition altered cognitive performance. Conclusions Clinical testing of nabilone, either alone, or in combination with zolpidem is warranted.

Identifying the processes by which environmental stimuli can come to influence drug use is important for developing more efficacious interventions. This study investigated derived relational responding and the transfer of differential conditioned effects of environmental stimuli paired with “smoked” cocaine in accordance with the relations of symmetry, transitivity, and equivalence using Heart Rate as the measure of conditioning among 12 adults with significant histories of cocaine use. Match-to-sample (MTS) procedures were used to test for emergent relations among two four-member stimulus groupings. One member of a group was then paired with 25 -mg of smoked cocaine and one member of the other group was paired with 0 -mg of smoked cocaine. Ten participants completed the MTS protocol: four participants demonstrated two four-member equivalence classes, three participants demonstrated two three-member equivalence classes, and two participants demonstrated symmetry only. One participant demonstrated no derived relations. Differential respondent elicited changes in HR was demonstrated in the presence of stimuli paired with smoked cocaine among four of the six participants completing the conditioning phase; all four of the participants demonstrated a bidirectional transfer of these functions in accordance with symmetry. Transfer was not reliably demonstrated in accordance with transitive or equivalence relations. The results suggest that respondent elicitation in the context of drug use may be a function of both direct conditioning and derived relational processes. These findings have implications for studying and understanding the processes by which stimuli in the natural ecology can set the occasion for cocaine use and developing cocaine use disorder.

Modafinil has been reported to reduce cocaine use in a clinical sample of infrequent users (2 days/week), but the effects of modafinil on cocaine self-administration in the laboratory have not been studied. The present study investigated the effects of modafinil maintenance on cocaine self-administration by frequent users (4 days/week) under controlled laboratory conditions. During this 48-day double-blind, crossover design study, the effects of modafinil maintenance (0, 200, and 400 mg/day) on response to smoked cocaine (0, 12, 25, and 50 mg) were examined in nontreatment-seeking cocaine-dependent individuals ( n =8). Cocaine significantly increased self-administration, subjective-effect ratings, and cardiovascular measures; modafinil at both doses (200 and 400 mg/day) markedly attenuated these effects. These findings agree with data from previous human laboratory and clinical investigations of modafinil as a potential cocaine abuse treatment medication. Thus, our data support the potential of modafinil as a pharmacotherapy for cocaine dependence.