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BackgroundDuring the last few years, the continuous emergence of new psychoactive substances (NPS) has become an important public health challenge. The use of NPS has been rising in two different ways: buying and consuming NPS knowingly and the presence of NPS in traditional drugs as adulterants. The rise of NPS use is increasing the number of different substances in the market to an extent impossible to study with current scientific methodologies. This has caused a remarkable absence of necessary information about newer drug effects on people who use drugs, mental health professionals, and policy makers. Current scientific methodologies have failed to provide enough data in the timeframe when critical decisions must be made, being not only too slow but also too square. Last but not least, they dramatically lack the high resolution of phenomenological details. ObjectiveThis study aims to characterize a population of e-psychonauts and the subjective effects of the NPS they used during the study period using a new, internet-based, fast, and inexpensive methodology. This will allow bridging an evidence gap between online surveys, which do not provide substance confirmation, and clinical trials, which are too slow and expensive to keep up with the new substances appearing every week. MethodsTo cover this purpose, we designed a highly personalized, observational longitudinal study methodology. Participants will be recruited from online communities of people who use NPS, and they will be followed online by means of a continuous objective and qualitative evaluation lasting for at least 1 year. In addition, participants will send samples of the substances they intend to use during that period, so they can be analyzed and matched with the effects they report on the questionnaires. ResultsThe research protocol was approved by the Institutional Review Board of the Hospital del Mar Research Institute on December 11, 2018. Data collection started in August 2019 and was still ongoing when the protocol was submitted (September 2020). The first data collection period of the study ended in October 2020. Data analysis began in November 2020, and it is still ongoing. The authors expect to submit the first results for publication by the end of 2021. A preliminary analysis was conducted when the manuscript was submitted and was reviewed after it was accepted in February 2021. ConclusionsIt is possible to conduct an institutional review board–approved study using this new methodology and collect the expected data. However, the meaning and usefulness of these data are still unknown. International Registered Report Identifier (IRRID)DERR1-10.2196/24433

Background: Despite limited data demonstrating pronounced negative effects of prenatal cannabis exposure, popular opinion and public policies still reflect the belief that cannabis is fetotoxic.Methods: This article provides a critical review of results from longitudinal studies examining the impact of prenatal cannabis exposure on multiple domains of cognitive functioning in individuals aged 0 to 22 years. A literature search was conducted through PsycINFO, PubMed, and Google Scholar. Articles were included if they examined the cognitive performance of offspring exposed to cannabis in utero.Results: An examination of the total number of statistical comparisons (n = 1,001) between groups of participants that were exposed to cannabis prenatally and non-exposed controls revealed that those exposed performed differently on a minority of cognitive outcomes (worse on

Objectives Recently, driven largely by opioid-related deaths, President Donald Trump proclaimed that the opioid problem was now a national emergency. What looks like a radical shift to a more compassionate drug policy-one that favors treatment over incarceration-has encouraged many to hope that there will be far fewer drug-related arrests and deaths than there were in previous decades. Methods and results We present evidence showing that large numbers of drug-related arrests persist and that racial discrimination is evident in opioid-related arrests. In addition, conventional strategies implemented to address opioid-related deaths have proven inadequate. Conclusions We propose solutions grounded in reason and evidence rather than moralism. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

Individuals who work nonstandard schedules, such as rotating or night shifts, are more susceptible to workplace injuries, performance decrements, and reduced productivity. This population is also almost twice as likely to use illicit drugs as individuals working a standard day shift. The purpose of this study was to examine the effects of smoked marijuana on performance, mood, and sleep during simulated shift work. Ten experienced marijuana smokers completed this 23-day, within-participant residential study. They smoked a single marijuana cigarette (0, 1.9, 3.56% Δ9-THC) one hour after waking for three consecutive days under two shift conditions: day shift and night shift. Shifts alternated three times during the study, and shift conditions were separated by an ‘off’ day. When participants smoked placebo cigarettes, psychomotor performance and subjective-effect ratings were altered during the night shift compared to the day shift: performance (e.g., vigilance) and a few subjective ratings were decreased (e.g., “Self-Confident”), whereas other ratings were increased (e.g., “Tired”). Objective and subjective measures of sleep were also disrupted, but to a lesser extent. Marijuana attenuated some performance, mood, and sleep disruptions: participants performed better on vigilance tasks, reported being less miserable and tired and sleep a greater number of minutes. Limited negative effects of marijuana were noted. These data demonstrate that abrupt shift changes produce performance, mood, and sleep decrements during night shift work and that smoked marijuana containing low to moderate Δ9-THC concentrations can offset some of these effects in frequent marijuana smokers.

Repeated drug consumption may progress to problematic use by triggering neuroplastic adaptations that attenuate sensitivity to natural rewards while increasing reactivity to craving and drug cues. Using an established laboratory model aimed at evaluating behavioral shifts in the salience of cocaine now vs. money later, we evaluated the effect on cocaine use of a single sub-anesthetic dose of the N-methyl-D-aspartate receptor antagonist ketamine, which converging evidence suggests may work to correct problematic neuroadaptations and restore motivation for non-drug rewards. We found that ketamine, as compared to the control, significantly decreased cocaine self-administration by 67% relative to baseline at greater than 24 hours post-infusion, the most robust reduction observed to date in human cocaine users and the first to involve mechanisms other than stimulant or dopamine agonist effects. These findings signal new directions in medication development for substance use disorders.

There have been mixed findings assessing the impact of regular cocaine use on cognitive functioning. This study employed a comprehensive cognitive battery to compare the performance of individuals diagnosed with a cocaine use disorder (N = 3 abusers, N = 17 dependent) against the performance of two control groups: (a) non-drug-users, and (b) marijuana users who report no cocaine use (N = 7 marijuana abusers, N = 0 dependent, N = 13 marijuana users with no Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition, DSM-IV, diagnosis).This one-session, between-participants, outpatient study was conducted at the New York State Psychiatric Institute. Sixty research volunteers completed the study. Drug users in both groups had no signs of current intoxication, but had a positive urine toxicology-which indicated use within 72 hours in the cocaine use disorder group and within the past 30 days (depending on frequency of use) for the marijuana-using control group. The National Institutes of Health (NIH) Toolbox Cognition Battery was used to assess cognitive functioning across six domains: executive function, attention, episodic memory, working memory, processing speed, and language. Each participant's score was also compared against a normative database adjusted for age.Although the mean cognitive scores for all groups fell within the normal range for all tests, marijuana-using control participants outperformed those with a cocaine use disorder on a cognitive flexibility and language measure.Cognitive functioning of individuals diagnosed with cocaine use disorder was observed to be similar to that of control group participants on the majority of tasks and fell within the normal range when compared against normative data.

The view of drug use and drug addiction as a brain disease serves to perpetuate unrealistic, costly, and discriminatory drug policies, argues Carl L. Hart.

Background Cocaine dependence involves problematic neuroadaptations that might be responsive to modulation of glutamatergic circuits. This investigation examined the effects of subanesthetic ketamine infusions on motivation for quitting cocaine and on cue-induced craving in cocaine-dependent participants, 24 hours postinfusion. Methods Eight volunteers with active DSM-IV cocaine dependence not seeking treatment or abstinence were entered into this crossover, double-blind trial. Three 52-min intravenous infusions were administered: ketamine (.41 mg/kg or .71 mg/kg) or lorazepam 2 mg, counterbalanced into three orderings in which ketamine .41 mg/kg always preceded the .71 mg/kg dose. Infusions were separated by 48 hours, and assessments occurred at baseline and at 24 hours postinfusion. Outcomes were change between postinfusion and preinfusion values for: 1) motivation to quit cocaine scores with the University of Rhode Island Change Assessment; and 2) sums of visual analogue scale craving ratings administered during cue exposure. Results Compared with the active control lorazepam, a single ketamine infusion (.41 mg/kg) led to a mean 3.9-point gain in University of Rhode Island Change Assessment ( p = .012), which corresponds to an approximately 60% increase over preceding values. There was a reduction of comparable magnitude in cue-induced craving ( p = .012). A subsequent ketamine infusion (.71 mg/kg) led to further reductions in cue-induced craving compared with the control. Infusions were well-tolerated. Conclusions Subanesthetic ketamine demonstrated promising effects on motivation to quit cocaine and on cue-induced craving, 24 hours postinfusion. Research is needed to expand on these preliminary results and to evaluate the efficacy of this intervention in clinical settings.

Sub-anesthetic ketamine infusions may benefit a variety of psychiatric disorders, including addiction. Though ketamine engenders transient alterations in consciousness, it is not known whether these alterations influence efficacy. This analysis evaluates the mystical-type effects of ketamine, which may have therapeutic potential according to prior research, and assesses whether these effects mediate improvements in dependence-related deficits, 24h postinfusion.Eight cocaine dependent individuals completed this double-blind, randomized, inpatient study. Three counter-balanced infusions separated by 48h were received: lorazepam (2mg) and two doses of ketamine (0.41mg/kg and 0.71mg/kg, with the former dose always preceding the latter). Infusions were followed within 15min by measures of dissociation (Clinician Administered Dissociative Symptoms Scale: CADSS) and mystical-type effects (adapted from Hood's Mysticism Scale: HMS). At baseline and 24h postinfusion, participants underwent assessments of motivation to stop cocaine (University of Rhode Island Change Assessment) and cue-induced craving (by visual analogue scale for cocaine craving during cue exposure).Ketamine led to significantly greater acute mystical-type effects (by HMS) relative to the active control lorazepam; ketamine 0.71mg/kg was associated with significantly higher HMS scores than was the 0.41mg/kg dose. HMS score, but not CADSS score, was found to mediate the effect of ketamine on motivation to quit cocaine 24h postinfusion.These findings suggest that psychological mechanisms may be involved in some of the anti-addiction benefits resulting from ketamine. Future research can evaluate whether the psychoactive effects of ketamine influence improvements in larger samples.

Marijuana withdrawal contributes to the high relapse rates in individuals seeking treatment for marijuana-use disorders. Quetiapine, an atypical antipsychotic, reduces characteristic symptoms of marijuana withdrawal in a variety of psychiatric conditions, including mood lability, sleep disruption and anorexia. This human laboratory study investigated the effectiveness of quetiapine to decrease marijuana withdrawal and relapse to marijuana use in non-treatment-seeking marijuana smokers. Volunteers were maintained on placebo or quetiapine (200 mg/day) in this double-blind, counter-balanced, within-subject study consisting of two 15-day medication phases, the last 8 days of which were in-patient. On the first in-patient day, active marijuana [6.2% delta (9)-tetrahydrocannabinol (THC)] was repeatedly smoked under controlled conditions. For the next 3 days, inactive marijuana (0.0% THC) was available for self-administration (withdrawal). On the subsequent 4 days, active marijuana (6.2% THC) was available for self-administration (relapse). Volunteers (n = 14) who smoked an average of 10 marijuana cigarettes/day, 7 days/week, completed the study. Under placebo, withdrawal was marked by increased subjective ratings of negative mood, decreased sleep quality, and decreased caloric intake and weight loss. Compared with placebo, quetiapine improved sleep quality, increased caloric intake and decreased weight loss. However, quetiapine increased marijuana craving and marijuana self-administration during the relapse phase. These data do not suggest that quetiapine shows promise as a potential treatment for marijuana dependence.

3,4-Methylenedioxymethamphetamine (MDMA), the main psychoactive component of the recreational drug ecstasy, is a potent serotonin (5-HT) releaser. In animals, MDMA induces 5-HT depletion and toxicity in 5-HT neurons. The aim of this study was to investigate both presynaptic (5-HT transporter, SERT) and postsynaptic (5-HT(2A) receptor) markers of 5-HT transmission in recently abstinent chronic MDMA users compared with matched healthy controls. We hypothesized that MDMA use is associated with lower SERT density and concomitant upregulation of 5-HT(2A) receptors. Positron emission tomography studies using the SERT ligand [¹¹C]DASB and the 5-HT(2A) receptor ligand [¹¹C]MDL 100907 were evaluated in 13 current and recently detoxified MDMA users and 13 matched healthy controls. MDMA users reported a mean duration of ecstasy use of 8 years, regular exposure, and at least 2 weeks of abstinence before the scans. SERT and 5-HT(2A) receptor availability (binding potential, BP(ND)) were analyzed with a two-tissue compartment model with arterial input function. Current recreational MDMA use was significantly associated with lower SERT BP(ND) and higher 5-HT(2A) receptor BP(ND) in cortical, but not subcortical regions. Decreased SERT BP(ND) was regionally associated with upregulated 5-HT(2A) receptor BP(ND). In light of the animal literature, the most parsimonious interpretation is that repeated exposure to MDMA in humans, even in moderate amounts, leads to damage in 5-HT neuron terminals innervating the cortex. Alterations in mood, cognition, and impulse control associated with these changes might contribute to sustain MDMA use. The reversibility of these changes upon abstinence remains to be firmly established.

The prevailing view is that recreational methamphetamine use causes a broad range of severe cognitive deficits, despite the fact that concerns have been raised about interpretations drawn from the published literature. This article addresses an important gap in our knowledge by providing a critical review of findings from recent research investigating the impact of recreational methamphetamine use on human cognition. Included in the discussion are findings from studies that have assessed the acute and long-term effects of methamphetamine on several domains of cognition, including visuospatial perception, attention, inhibition, working memory, long-term memory, and learning. In addition, relevant neuroimaging data are reviewed in an effort to better understand neural mechanisms underlying methamphetamine-related effects on cognitive functioning. In general, the data on acute effects show that methamphetamine improves cognitive performance in selected domains, that is, visuospatial perception, attention, and inhibition. Regarding long-term effects on cognitive performance and brain-imaging measures, statistically significant differences between methamphetamine users and control participants have been observed on a minority of measures. More importantly, however, the clinical significance of these findings may be limited because cognitive functioning overwhelmingly falls within the normal range when compared against normative data. In spite of these observations, there seems to be a propensity to interpret any cognitive and/or brain difference(s) as a clinically significant abnormality. The implications of this situation are multiple, with consequences for scientific research, substance-abuse treatment, and public policy.

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.This study examined the effects of methamphetamine and MDMA using a within-subject design.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.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.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).

Zolpidem attenuates shift-change-related sleep and performance disruptions. It is unknown whether these benefits alter the reinforcing effects of the drug during shift work. This study examined zolpidem-related reinforcing effects during simulated shift work. Eleven volunteers (3F, 8M) completed this 16-day within-participant, residential laboratory study. Each day participants were given an opportunity to self-administer oral zolpidem (10 mg) or receive a $1 voucher immediately following a 9-h work period and immediately before going to bed. Participants worked under two shift conditions: (1) during the night shift, participants completed computerized task batteries from 00:30 to 09:30 h and went to bed at 16:00 h and (2) during the day shift, participants completed task batteries from 08:30 to 17:30 h and went to bed at 24:00 h. Shift conditions alternated three times during the study. Despite the fact that sleep, psychomotor performance, and some ratings of mood were disrupted during night-shift work, there was no significant effect of shift on choice to take zolpidem. Overall, participants selected markedly fewer zolpidem doses than monetary vouchers (17% versus 83%). Thus, zolpidem did not serve as a reinforcer even when sleep was disrupted. These data are consistent with previous reports indicating that sedatives produce limited reinforcing effects in individuals without a history of drug abuse.

Rationale Previously, we reported that acute marijuana intoxication minimally affected complex cognitive performance of daily marijuana smokers. It is possible that the cognitive tests used were insensitive to marijuana-related cognitive effects. Objectives In the current study, electroencephalographic (EEG) signals were recorded as daily marijuana users performed additional tests of immediate working memory and delayed episodic memory, before and after smoking marijuana. Methods Research volunteers (N = 24), who reported smoking ∼ 24 marijuana cigarettes/week, completed this study. Participants completed baseline computerized cognitive tasks, smoked a single marijuana cigarette (0%, 1.8%, or 3.9% ∆ 9 -THC w/w), and completed additional cognitive tasks; sessions were separated by at least 72-hours. Cardiovascular and subjective effects were also assessed throughout sessions. Results Overall performance accuracy was not significantly altered by marijuana, although the drug increased response times during task performance and induced a response bias towards labeling “new” words as having been previously seen in the verbal episodic memory task. Marijuana reduced slow wave evoked potential amplitude in the episodic memory task and decreased P300 amplitude and EEG power in the alpha band in the spatial working memory task. Heart rate and “positive” subjective-effect ratings were increased in a ∆ 9 -THC concentration-dependent manner. Conclusions Relative to previous findings with infrequent marijuana users, the frequent users in the current study exhibited similar neurophysiological effects but more subtle performance effects. These data emphasize the importance of taking into account the drug-use histories of research participants and examining multiple measures when investigating marijuana-related effects on cognitive functioning.

The ability to control craving for substances that offer immediate rewards but whose long-term consumption may pose serious risks lies at the root of substance use disorders and is critical for mental and physical health. Despite its importance, the neural systems supporting this ability remain unclear. Here, we investigated this issue using functional imaging to examine neural activity in cigarette smokers, the most prevalent substance-dependent population in the United States, as they used cognitive strategies to regulate craving for cigarettes and food. We found that the cognitive down-regulation of craving was associated with ( i ) activity in regions previously associated with regulating emotion in particular and cognitive control in general, including dorsomedial, dorsolateral, and ventrolateral prefrontal cortices, and ( ii ) decreased activity in regions previously associated with craving, including the ventral striatum, subgenual cingulate, amygdala, and ventral tegmental area. Decreases in craving correlated with decreases in ventral striatum activity and increases in dorsolateral prefrontal cortex activity, with ventral striatal activity fully mediating the relationship between lateral prefrontal cortex and reported craving. These results provide insight into the mechanisms that enable cognitive strategies to effectively regulate craving, suggesting that it involves neural dynamics parallel to those involved in regulating other emotions. In so doing, this study provides a methodological tool and conceptual foundation for studying this ability across substance using populations and developing more effective treatments for substance use disorders.

Researchers have identified the association between the use of cocaine and sexual behavior as an important risk factor for HIV infection and have attempted to elucidate the nature of this association. Several lines of research have suggested that facilitation of sexual behavior during intoxication with cocaine may be because of the direct pharmacological effects of the drug (e.g., increase in sexual desire), whereas others have pointed to the importance of factors related to the context of drug use (e.g., opportunities for sexual behavior, expectations about the effects of the drug, social norms). The present study explored the perceived effects of cocaine and heroin on sexual behavior, as well as the social context of drug use as a function of drug type (cocaine vs. heroin), among 46 inner-city drug users who reported a history of regular use of both crack cocaine and heroin. Results indicated that compared to heroin, cocaine had deleterious effects on participants' perceived sexual desire and performance. Despite such deleterious effects on sexual behavior, cocaine was more frequently used with an intimate partner than heroin. Furthermore, participants did not differ in the extent to which they used the two drugs in other social contexts (e.g., with friends, family, or neighbors). These preliminary results suggest that the relationship between cocaine and sexual behavior, especially among long-term cocaine users, may be facilitated by opportunities for sex that exist in the context of cocaine use, rather than by the pharmacological effects of the drug.

The purpose of this double-blind, randomized, outpatient study was to evaluate the reinforcing and subjective effects of modafinil (200, 400, or 600 mg) in cocaine abusers. Twelve participants (2 female, 10 male) completed this study, consisting of 3 blocks of 7 sessions; each block tested a difference dose of modafinil. During the first 2 sessions of each block, participants "sampled" 1 of the doses of modafinil, and placebo. These doses of modafinil and placebo were available for the subsequent five choice sessions of the block. In each choice session, participants had an opportunity to administer active or placebo capsules. Modafinil administration did not differ from placebo administration, and subjective-effects ratings were not systematically altered as a function of modafinil dose. Results suggest that modafinil does not have abuse liability in cocaine abusers.

A post hoc analysis examined depressive symptoms in regular marijuana smokers interested in nontreatment, laboratory studies, and marijuana-dependent treatment-seekers considering clinical trial participation. Among marijuana-dependent treatment-seeking patients screened for a clinical trial, the mean Beck Depression Inventory Score (BDI) was significantly higher than for marijuana-using volunteers screened for nontreatment laboratory studies. Mean self-reported baseline marijuana use was not significantly different between groups, and BDI score was not correlated with use. Although the methods by which the two groups were selected influenced their characteristics (i.e., treatment-seekers are more likely to be experiencing some degree of clinical distress), it is notable that treatment-seeking, and not marijuana use per se, is associated with significantly higher rates of depression.

The Iowa Gambling task, which typically incorporates hypothetical monetary earnings and losses for performance, has been widely used to measure decision-making in substance abusers. We examined the effects of a cash monetary contingency on Gambling task performance in cocaine abusers and control participants.Twenty-two long-term cocaine smokers who met DSM-IV criteria for cocaine dependence and 24 non-cocaine-using control participants completed this study. Both groups were similar in terms of age, executive function, and self-reported alcohol and marijuana use. All participants performed the Gambling task under two counterbalanced conditions: under one condition, earnings and losses were hypothetical, and under the other condition, earnings and losses were in cash.Condition x group interactions on card selection and task completion time were noted (p0.05). Under the hypothetical payment condition, cocaine abusers selected a greater proportion of cards from disadvantageous decks than advantageous decks (p0.05), but took a similar amount of time to complete the task, relative to control participants. However, under the cash payment condition, no group differences were seen for card selection and cocaine abusers took more time than controls to complete the task (p0.05).The application of tangible consequences improved the decision-making and effort of cocaine abusers on the Gambling task, relative to control participants. These findings underscore the importance of considering population-specific factors (e.g., sensitivity to instructional vs. consequential control) when conducting neuropsychological research in substance abusers.

Methamphetamine attenuates disruptions that occur after changes in work shifts. The reinforcing effects of the drug during shift work have yet to be characterized. This study examined methamphetamine-related mood, performance, and reinforcing effects during simulated shift work. Ten volunteers (four women and six men) completed this 19-day study. Participants were given an opportunity to self-administer oral methamphetamine (10 mg) or receive a $1 voucher before and after an 8-h work period for four consecutive days under two shift conditions: (1) “day shift” in which they went to bed at 2400 hours and woke up at 0800 hours and (2) “night shift” when they went to bed at 1600 hours and woke up at 2400 hours. Thus, participants completed task batteries either from 0815 to 1715 hours or from 0015 to 0915 hours. Shift conditions alternated three times during the study and were separated by an “off” day. Night-shift work disrupted psychomotor task performance and some ratings of mood, especially on the first night. Consistent with this, participants chose to take methamphetamine significantly more often on the first night-shift night compared with the first day-shift day. Regardless of shift condition, however, participants selected markedly more methamphetamine doses before the work period than after it (73% versus 34%). These data show that methamphetamine self-administration occurred more often before work rather than after work, suggesting that the use of stimulants by shift workers may be one strategy employed to meet behavioral demands especially under conditions engendering poor performance, fatigue, and/or sleep disruptions.

In a limited number of studies modafinil has been shown to decrease food intake by laboratory animals and humans. The present study represents a secondary data analysis, in which the effects of modafinil on several measures of food intake were determined in humans living in a residential laboratory during simulated shift work. During this 23-day study, a wide selection of food items and beverages were freely available. During this double-blind, within-participant study, volunteers (N = 11) received oral modafinil dose (0, 200, or 400 mg) 1 h after waking for three consecutive days under two shift conditions: day shift and night shift. Shifts alternated three times during the study, and shift conditions were separated by an "off" day. Modafinil (200, 400 mg) dose-dependently decreased total caloric intake by approximately 18% and approximately 38%, respectively, regardless of shift condition, without selectively altering the proportion of total calories derived from carbohydrate, fat and protein. Ratings of "Hungry" were also significantly decreased by both active doses, but only immediately before the lunch break period. In addition, tolerance to the anorexic effects of modafinil was not apparent, as these effects remained stable across the three days of modafinil dosing. These findings show that modafinil produced clear reductions in food intake and suggest that future prospective studies should examine the drug in obese participants.

Although intranasal methamphetamine abuse has increased, there are no published data investigating the residual effects of the drug under controlled conditions. Thus, the current study examined the residual effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures. Non-treatment seeking methamphetamine abusers (n = 11) completed this two-week, in-patient, within-participant, double-blind study. The study consisted of 4 two-day blocks of sessions; each block was separated by at least 24 hrs. At approximately 1000 hrs, on the first day of each block, participants received one of four intranasal methamphetamine doses (0, 12, 25, 50 mg/70 kg). Lights were turned out at 2300 hrs that evening and sleep measures were assessed. On the morning of the second day of each block, methamphetamine plasma levels, cardiovascular measures, mood, subjective reports of the previous evening's sleep, and psychomotor performance were assessed to determine residual drug effects. The larger methamphetamine doses (25 and 50 mg) markedly disrupted subjective measures of that night's sleep and some indices of next-day mood, but only the largest dose (50 mg) dose decreased objective measures of that night's sleep and increased next-day physiological measures. Methamphetamine did not produce any negative residual effects on early next-day performance. Future studies should assess methamphetamine-related residual effects following repeated doses administered over consecutive days.

Interest in the relationship between cannabis use and psychosis has increased dramatically in recent years, in part because of concerns related to the growing availability of cannabis and potential risks to health and human functioning. There now exists a plethora of scientific articles addressing this issue, but few provide a clear verdict about the causal nature of the cannabis-psychosis association. Here, we review recent research reports on cannabis and psychosis, giving particular attention to how each report provides evidence relating to two hypotheses: (1) cannabis as a contributing cause and (2) shared vulnerability. Two primary kinds of data are brought to bear on this issue: studies done with schizophrenic patients and studies of first-episode psychosis. Evidence reviewed here suggests that cannabis does not in itself cause a psychosis disorder. Rather, the evidence leads us to conclude that both early use and heavy use of cannabis are more likely in individuals with a vulnerability to psychosis. The role of early and heavy cannabis use as a prodromal sign merits further examination, along with a variety of other problem behaviors (e.g., early or heavy use of cigarettes or alcohol and poor school performance). Future research studies that focus exclusively on the cannabis-psychosis association will therefore be of little value in our quest to better understand psychosis and how and why it occurs.

This chapter focuses on what is known about the acute effects of ±3,4-methylenedioxymethamphetamine (MDMA) based on findings from human behavioral pharmacology studies. There is a relatively large database from preclinical studies that suggests that MDMA may have long-term adverse effects including neurotoxicity and mood and cognitive disruptions. However, these studies have several limitations that make it difficult to draw conclusions about the specific risks for humans. Human behavioral pharmacology provides complementary information about both the positive effects and the negative effects of MDMA in order to better assess the drug’s risk/benefit ratio. Using this methodology, researchers have observed several effects relevant to both the safety of recreational drug users and for the potential use of the drug as a psychotherapeutic. For example, the drug produces: (1) dose-dependent increases in heart rate, blood pressure, and body temperature; (2) increases in subjective feelings of euphoria and sociability; and (3) alters social processing and behavior. Overall, human behavioral pharmacological studies of MDMA provide important information about the risk/benefit ratio of the drug, which will aid in the development of policies concerning therapeutic and recreational use.

Intranasal methamphetamine abuse has increased dramatically in the past decade, yet only one published study has investigated its acute effects under controlled laboratory conditions. Thus, the current study examined the effects of single-dose intranasal methamphetamine administration on a broad range of behavioral and physiological measures. Eleven nontreatment-seeking methamphetamine abusers (two females, nine males) completed this four-session, in-patient, within-participant, double-blind study. During each session, one of four intranasal methamphetamine doses (0, 12, 25, and 50 mg/70 kg) was administered and methamphetamine plasma concentrations, cardiovascular, subjective, and psychomotor/cognitive performance effects were assessed before drug administration and repeatedly thereafter. Following drug administration, methamphetamine plasma concentrations systematically increased for 4 h postdrug administration then declined. Methamphetamine dose dependently increased cardiovascular measures and ‘positive’ subjective effects, with peaks occurring approximately 5–15 min after drug administration, when plasma levels were still ascending. In addition, cognitive performance on less complicated tasks was improved by all active methamphetamine doses, whereas performance on more complicated tasks was improved only by the intermediate doses (12 and 25 mg). These results show that intranasal methamphetamine produced predictable effects on multiple behavioral and physiological measures before peak plasma levels were observed. Of interest is the dissociation between methamphetamine plasma concentrations with cardiovascular measures and positive subjective effects, which might have important implications for potential toxicity after repeated doses.

The impact of regular marijuana use on executive cognitive abilities, including decision making, is not well understood. While cross-sectional studies have suggested that substance abusers exhibit impaired decision making, as assessed by the Iowa Gambling Task, the direct role of marijuana use in the Gambling Task performance of marijuana smokers has not been well defined. In this report, we present data on performance on a modified Gambling Task in experienced marijuana users after they had smoked marijuana under controlled laboratory conditions. A total of 36 marijuana users, who reported smoking approximately 24 marijuana cigarettes per week, completed this 3-session outpatient study. During each session, these volunteers completed the Gambling Task once at baseline and 3 times after smoking a single marijuana cigarette (0.0, 1.8, or 3.9% Delta9-THC). Marijuana cigarettes were administered in a double-blind fashion, and the sequence of Delta9-THC concentration was balanced across volunteers. Marijuana increased the time required to complete the task. However, advantageous card selection and money earned on the task were not disrupted by marijuana. These data are consistent with previous findings that indicated that speed of performance on tests of executive function, but not accuracy, is disrupted in experienced marijuana users during marijuana intoxication.

Methamphetamine use has increased significantly and become a global health concern. Craving is known to predict methamphetamine use and relapse following abstinence. Some have suggested that cravings are automatic, generalized, and uncontrollable, but experimental work addressing these claims is lacking. In two exploratory studies we tested the boundary conditions of methamphetamine craving by asking: (1) is craving specific to users’ preferred route of administration? and (2) can craving be regulated by cognitive strategies? Two groups of methamphetamine users were recruited. In Study 1, participants were grouped by their preferred route of administration (intranasal vs. smoking), and rated their craving in response to photographs and movies depicting methamphetamine use (via the intranasal vs. smoking route). In Study 2, methamphetamine smokers implemented cognitive regulation strategies while viewing photographs depicting methamphetamine smoking. Strategies involved either focusing on the positive aspects of smoking methamphetamine or the negative consequences of doing so – the latter strategy based on treatment protocols for addiction. In Study 1, we found a significant interaction between group and route of administration, such that participants who preferred to smoke methamphetamine reported significantly stronger craving for smoking stimuli, whereas those who preferred the intranasal route reported stronger craving for intranasal stimuli. In Study 2, participants reported significantly lower craving when focusing on the negative consequences associated with methamphetamine use. Taken together, these findings suggest that strength of craving for methamphetamine is moderated by users’ route of administration and can be reduced by cognitive strategies. This has important theoretical, methodological, and clinical implications.

Non-therapeutic research with drugs of abuse in humans is important for a more comprehensive understanding of substance abuse and for the development of more effective treatments. However, the administration of substances from drug classes with abuse potential to human volunteers raises ethical questions regarding potential risk to study volunteers.The purpose of this study was to assess the psychosocial functioning and reported drug-taking behavior of volunteers before and after participating in a residential laboratory study, during which either marijuana, methamphetamine or zolpidem was administered.Twenty-two volunteers were administered Addiction Severity Index (ASI) interviews at intake and approximately six months following their study participation.No significant differences between intake and follow-up assessments were found on any ASI composite or drug/alcohol-taking variable.These preliminary data suggest that participation in residential laboratory studies involving the administration of drugs from classes with abuse potential does not alter subsequent psychosocial functioning or reported drug use.

Abstinence following daily marijuana use can produce a withdrawal syndrome characterized by negative mood (eg irritability, anxiety, misery), muscle pain, chills, and decreased food intake. Two placebo-controlled, within-subject studies investigated the effects of a cannabinoid agonist, delta-9-tetrahydrocannabinol (THC: Study 1), and a mood stabilizer, divalproex (Study 2), on symptoms of marijuana withdrawal. Participants (n=7/study), who were not seeking treatment for their marijuana use, reported smoking 6-10 marijuana cigarettes/day, 6-7 days/week. Study 1 was a 15-day in-patient, 5-day outpatient, 15-day in-patient design. During the in-patient phases, participants took oral THC capsules (0, 10 mg) five times/day, 1 h prior to smoking marijuana (0.00, 3.04% THC). Active and placebo marijuana were smoked on in-patient days 1-8, while only placebo marijuana was smoked on days 9-14, that is, marijuana abstinence. Placebo THC was administered each day, except during one of the abstinence phases (days 9-14), when active THC was given. Mood, psychomotor task performance, food intake, and sleep were measured. Oral THC administered during marijuana abstinence decreased ratings of 'anxious', 'miserable', 'trouble sleeping', 'chills', and marijuana craving, and reversed large decreases in food intake as compared to placebo, while producing no intoxication. Study 2 was a 58-day, outpatient/in-patient design. Participants were maintained on each divalproex dose (0, 1500 mg/day) for 29 days each. Each maintenance condition began with a 14-day outpatient phase for medication induction or clearance and continued with a 15-day in-patient phase. Divalproex decreased marijuana craving during abstinence, yet increased ratings of 'anxious', 'irritable', 'bad effect', and 'tired.' Divalproex worsened performance on psychomotor tasks, and increased food intake regardless of marijuana condition. Thus, oral THC decreased marijuana craving and withdrawal symptoms at a dose that was subjectively indistinguishable from placebo. Divalproex worsened mood and cognitive performance during marijuana abstinence. These data suggest that oral THC, but not divalproex, may be useful in the treatment of marijuana dependence.

Rationale. Although smoked marijuana contains at least 60 cannabinoids, Δ9-tetrahydrocannabinol (Δ9-THC) is presumed to be the cannabinoid primarily responsible for many marijuana-related effects, including increased food intake and subjective effects. Yet, there has been no systematic comparison of repeated doses of oral Δ9-THC with repeated doses of smoked marijuana in the same individuals. Objective. To compare the effects of oral Δ9-THC and smoked marijuana in humans under controlled laboratory conditions. Methods. Eleven healthy research volunteers, who reported smoking an average of six marijuana cigarettes per day, completed an 18-day residential study. Marijuana cigarettes (3.1% Δ9-THC, q.i.d.) were smoked or Δ9-THC (20 mg, q.i.d.) was taken orally using a staggered, double-blind, double-dummy procedure for three consecutive days. Four days of placebo administration separated each active drug condition. Psychomotor task performance, subjective effects, and food intake were measured throughout the day. Results. Relative to placebo baseline, oral Δ9-THC and smoked marijuana produced similar subjective-effect ratings (e.g., "high" and "mellow"), although some effects of smoked marijuana were more pronounced and less prone to the development of tolerance. Additionally, participants reported "negative" subjective effects (e.g., "irritable" and "miserable") during the days after smoking marijuana but not after oral Δ9-THC. Both drugs increased food intake for 3 days of drug administration, but had little effect on psychomotor performance. Conclusion. These results indicate that the behavioral profile of effects of smoked marijuana (3.1% Δ9-THC) is similar to the effects of oral Δ9-THC (20 mg), with some subtle differences.

Rationale. The discriminative stimulus effects of N-methyl-D-aspartate (NMDA) antagonists have been assessed in laboratory animals. To date, no published study has assessed their ability to alter methamphetamine-related discriminative stimulus effects in humans. Objective. This study investigated the discriminative stimulus, subjective (e.g. "Good Drug Effect"), psychomotor performance, and cardiovascular effects (e.g. blood pressure) of oral methamphetamine following acute oral memantine (a non-competitive NMDA antagonist) in humans. Methods. Initially, participants were trained to discriminate 10 mg methamphetamine from placebo using a standard two-response procedure (drug versus placebo). Then, the effects of memantine (0, 40 mg) on methamphetamine discrimination were examined across several methamphetamine doses (0, 5, 10, 20 mg) using a novel-response procedure (drug versus placebo versus novel). Results. Following placebo pretreatment, 10 mg methamphetamine produced 99% methamphetamine-appropriate responding and placebo produced 75% placebo-appropriate responding. Following memantine pretreatment, participants responded as if they had been given a novel compound, although memantine did not significantly alter most subjective-effects ratings following methamphetamine. Memantine alone produced "positive" subjective effects and novel drug-appropriate responding. Conclusion. These data indicate that the memantine-methamphetamine combination produced novel discriminative stimulus effects and that memantine produced some stimulant-like subjective effects.

Studies have shown that the Delta(9)-tetrahydrocannabinol (Delta(9)-THC) concentration in marijuana cigarettes is an important factor for the maintenance of marijuana self-administration. Yet, the impact of oral Delta(9)-THC treatment on marijuana self-administration is unknown. Because other agonist therapies have been demonstrated to be effective for the treatment of substance use disorders, the objective of this study was to evaluate the influence of oral Delta(9)-THC maintenance on choice to self-administer smoked marijuana. During this 18-day residential study, 12 healthy research volunteers received one of three doses of oral Delta(9)-THC capsules (0, 10, 20 mg q.i.d.) for 3 consecutive days, followed by 3 consecutive days of matching placebo. The order of active Delta(9)-THC administration was counterbalanced. Each morning, except on days 6, 12, and 18, participants smoked the 'sample' marijuana cigarette (1.8% Delta(9)-THC w/w) and received a $2 voucher (redeemable for cash at study's end). Following the sample, volunteers participated in a four-trial choice procedure during which they had the opportunity to self-administer either the dose of marijuana they sampled that morning or to receive the $2 voucher. Relative to placebo Delta(9)-THC maintenance, participants' choice to self-administer marijuana was not significantly altered by either of the two active Delta(9)-THC maintenance conditions. Some 'positive' subjective drug-effect ratings following the sample marijuana cigarette were reduced: by day 3 of active oral Delta(9)-THC maintenance, participants' rating of 'Good Drug Effect' and 'High' were significantly decreased. Smoked marijuana-related total daily caloric intake was not significantly altered under any maintenance conditions. Finally, the effects of smoked marijuana on psychomotor task performance were only minimally affected by oral Delta(9)-THC maintenance. These data indicate that participants' choice to self-administer marijuana was unaltered by the oral Delta(9)-THC dosing regimen used in the present investigation.

This talk provides a critical review of findings from recent research investigating the impact of recreational methamphetamine (MA) use on human cognition. Included in the discussion are findings from studies that have assessed the acute and long-term effects of MA on several domains of cognition. In addition, relevant neuroimaging data are reviewed in an effort to better understand neural mechanisms underlying MA-related effects on cognitive functioning. In general, the data on acute effects show that MA improves cognitive performance in selected domains. Regarding long-term effects on cognitive performance and brain-imaging measures, statistically significant differences between MA users and control participants have been observed on a minority of measures. More importantly, however, the clinical significance of these findings may be limited because cognitive functioning overwhelmingly falls within the normal range when compared against normative data. Despite this, there seems to be a propensity to int...

Although the ability to perform complex cognitive operations is assumed to be impaired following acute marijuana smoking, complex cognitive performance after acute marijuana use has not been adequately assessed under experimental conditions. In the present study, we used a within-participant double-blind design to evaluate the effects acute marijuana smoking on complex cognitive performance in experienced marijuana smokers. Eighteen healthy research volunteers (8 females, 10 males), averaging 24 marijuana cigarettes per week, completed this three-session outpatient study; sessions were separated by at least 72-hrs. During sessions, participants completed baseline computerized cognitive tasks, smoked a single marijuana cigarette (0%, 1.8%, or 3.9% Delta(9)-THC w/w), and completed additional cognitive tasks. Blood pressure, heart rate, and subjective effects were also assessed throughout sessions. Marijuana cigarettes were administered in a double-blind fashion and the sequence of Delta(9)-THC concentration order was balanced across participants. Although marijuana significantly increased the number of premature responses and the time participants required to complete several tasks, it had no effect on accuracy on measures of cognitive flexibility, mental calculation, and reasoning. Additionally, heart rate and several subjective-effect ratings (e.g., "Good Drug Effect," "High," "Mellow") were significantly increased in a Delta(9)-THC concentration-dependent manner. These data demonstrate that acute marijuana smoking produced minimal effects on complex cognitive task performance in experienced marijuana users.

Rationale: Although methamphetamine use has increased over the past several years, few studies have evaluated the effects of repeated methamphetamine administration in humans. Objectives: Because methamphetamine is often taken in a pattern of repeated use followed by a period of abstinence, the present study sought to evaluate the effects of repeated methamphetamine administration in humans. The hypothesis was that tolerance would develop to methamphetamine's effects. Methods: Seven normal, healthy volunteers participated in a 15-day residential study. Participants completed subjective-effects questionnaires and psychomotor performance tasks repeatedly throughout the experimental day. Oral methamphetamine (5, 10 mg BID) was administered on days 4–6 and 10–12; placebo was administered on all other study days. Results: Relative to placebo baseline, only two "positive" subjective ratings ("I feel a good drug effect" and "I feel high") were significantly elevated, and only on the 1st day of methamphetamine administration. In contrast, numerous "negative" ratings, including "I feel..." "a bad drug effect," "dizzy," and "flu-like symptoms" were elevated on the 3rd day of methamphetamine administration. Total caloric intake decreased and sleep was disrupted after methamphetamine administration, relative to baseline. Conclusions: The pattern of methamphetamine's positive subjective effects were altered with chronic administration such that tolerance, or a decreased effect, occurred after repeated administration. In contrast, methamphetamine's negative subjective effects increased over days. These results suggest that in this population of normal volunteers, the abuse liability of oral methamphetamine is relatively low.

Rationale: Symptoms of withdrawal after daily marijuana smoking include increased ratings of irritability and depression. Similar mood symptoms are reported by cigarette smokers during nicotine abstinence. Objective: Given the successful use of sustained-release bupropion in treating nicotine dependence, this study investigated how maintenance on bupropion influenced symptoms of marijuana withdrawal compared to maintenance on placebo. Methods: Marijuana smokers (n=10) were maintained outpatient on active (300 mg/day) or placebo (0 mg/day) bupropion for 11 days, and were then maintained inpatient on the same bupropion dose for 17 days. For the first 4 inpatient days, participants smoked active marijuana [2.8% Δ9-tetrahydrocannabinol (THC)] 5 times/day. For the remaining inpatient days, participants smoked placebo marijuana (0.0% THC) 5 times/day. Participants were then maintained outpatient on the alternate dose of bupropion for 11 days, followed by a second inpatient residential stay, paralleling the first. Medication administration was double-blind. Mood, psychomotor task performance, food intake, and sleep were measured daily during each inpatient phase. The order of active and placebo bupropion maintenance was counterbalanced between groups. Results: Bupropion had few behavioral effects when participants smoked active marijuana. During placebo marijuana smoking, i.e., active marijuana withdrawal, ratings of irritability, restlessness, depression, and trouble sleeping were increased by bupropion compared to placebo maintenance. Conclusions: These data suggest that bupropion does not show promise as a potential treatment medication for marijuana dependence.

The circadian timing system influences a vast array of behavioral responses. Substantial evidence indicates a role for the circadian system in regulating reward processing. Here we explore time of day effects on drug anticipation, locomotor activity, and voluntary methamphetamine (MA) and food intake in animals with ad libitum food access. We compared responses to drug versus a palatable treat during their normal sleep times in early day (zeitgeber time (ZT) 0400) or late day (ZT 1000). In the first study, using a between-subjects design, mice were given daily 1-h access to either peanut butter (PB-Alone) or to a low or high concentration of MA mixed in PB (MA + PB). In study 2, we repeated the experiment using a within-subjects design in which mice could choose between PB-Alone and MA + PB at either ZT 0400 or 1000. In study 3, the effects of MA-alone were investigated by evaluating anticipatory activity preceding exposure to nebulized MA at ZT 0400 vs. ZT 1000. Time of day effects were observed for both drug and palatable treat, such that in the between groups design, animals showed greater intake, anticipatory activity, and post-ingestional activity in the early day. Furthermore, there were differences among mice in the amount of MA ingested but individuals were self-consistent in their daily intake. The results for the within-subjects experiment also revealed robust individual differences in preference for MA + PB or PB-Alone. Interestingly, time of day effects on intake were observed only for the preferred substance. Anticipatory activity preceding administration of MA by nebulization was also greater at ZT 0400 than ZT 1000. Finally, pharmacokinetic response to MA administered intraperitoneally did not vary as a function of time of administration. The results indicate that time of day is an important variable mediating the voluntary intake and behavioral effects of reinforcers.

Only a small percentage of individuals seeking treatment for their marijuana use achieves sustained abstinence, suggesting more treatment options are needed. We investigated the effects of baclofen (study 1) and mirtazapine (study 2) in a human laboratory model of marijuana intoxication, withdrawal, and relapse. In study 1, daily marijuana smokers (n = 10), averaging 9.4 (±3.9) marijuana cigarettes/day, were maintained on placebo and each baclofen dose (60, 90 mg/day) for 16 days. In study 2, daily marijuana smokers (n = 11), averaging 11.9 (±5.3) marijuana cigarettes/day, were maintained on placebo and mirtazapine (30 mg/day) for 14 days each. Medication administration began outpatient prior to each 8-day inpatient phase. On the first inpatient day of each medication condition, participants smoked active marijuana (study 1: 3.3% THC; study 2: 6.2% THC). For the next 3 days, they could self-administer placebo marijuana (abstinence phase), followed by 4 days in which they could self-administer active marijuana (relapse phase); participants paid for self-administered marijuana using study earnings. In study 1, during active marijuana smoking, baclofen dose-dependently decreased craving for tobacco and marijuana, but had little effect on mood during abstinence and did not decrease relapse. Baclofen also worsened cognitive performance regardless of marijuana condition. In study 2, mirtazapine improved sleep during abstinence, and robustly increased food intake, but had no effect on withdrawal symptoms and did not decrease marijuana relapse. Overall, this human laboratory study did not find evidence to suggest that either baclofen or mirtazapine showed promise for the potential treatment of marijuana dependence.

Rationale Most reports of the effects of methamphetamine and 3,4-methylenedioxymethamphetamine (MDMA) on speech have been anecdotal. Objectives The current study used a within-participant design to assess the effects of methamphetamine and MDMA on speech. Materials and methods Eleven recreational users of amphetamines completed this inpatient, within-participant, double-blind study, during which they received placebo, methamphetamine (20, 40 mg), and MDMA (100 mg) on separate days. Following drug administration, study participants described movies viewed the previous evening and completed mood scales. Results Methamphetamine increased quantity of speech, fluency, and self-ratings of talkativeness and alertness, while it decreased the average duration of nonjuncture unfilled pauses. MDMA decreased fluency and increased self-ratings of inability to concentrate. To determine if methamphetamine- and MDMA-related effects were perceptible, undergraduates listened to the participants’ movie descriptions and rated their coherence and the speaker’s mood. Following methamphetamine, descriptions were judged to be more coherent and focused than they were following MDMA. Conclusions Methamphetamine improved verbal fluency and MDMA adversely affected fluency. This pattern of effects is consistent with the effects of these drugs on functioning in other cognitive domains. In general, methamphetamine effects on speech were inconsistent with effects popularly attributed to this drug, while MDMA-related effects were in agreement with some anecdotal reports and discordant with others.

Cigarette craving is an important contributor to cigarette smoking, and clinical approaches that focus on regulation of craving are effective in reducing rates of relapse. However, a laboratory model that targets the use of cognitive strategies to regulate craving is lacking. To develop such a model, twenty heavy cigarette smokers (>12/day), twenty-two tobacco “chippers” (

The tolerability and effects of oral Delta9-tetrahydrocannabinol (THC) have been previously investigated in adult marijuana abusers. However, no studies have included adolescent participants. This double-blind laboratory study investigated the tolerability and effects of oral THC in a group of older adolescents with marijuana use disorders.Eight participants (ages 16-21 years), smoking an average of 5.2 days/week and 2.5 "joints"/day, completed this four-session study, during which they received one of four oral THC doses (0, 2.5, 5, 10 mg) each session. Administration of oral THC doses was counterbalanced across participants. During each session, participants completed the Digit-Symbol Substitution Task (DSST) and subjective-effect ratings at baseline and 1, 2, and 3 h after oral THC administration.Oral THC (5 mg and 10 mg) increased several "positive" subjective-effect ratings (e.g., "Good Drug Effect"), while producing no significant effects on cardiovascular measures, DSST performance, or "negative" subjective-effect ratings.These results indicate that oral THC was well tolerated and suggest further study of this medication in adolescent marijuana abusers.

Seventeen non-treatment seeking cocaine-dependent individuals participated in three-week longitudinal inpatient studies of cognitive changes during drug use and abstinence. Protocols included three days drug-free baseline, three days cocaine self-administration, and two weeks complete abstinence. A repeatable cognitive battery showed attention and delayed verbal recognition memory but not working memory to be impaired in cocaine users compared to age- and sex-matched normative values. Attention was significantly poorer during the first and second week of abstinence compared to days on which cocaine was used suggesting that certain cocaine-induced impairments may be acutely normalized by cocaine use, but resurface during abstinence.

Individuals seeking treatment for their marijuana use rarely achieve sustained abstinence.The objectives of the study are to determine if THC, a cannabinoid agonist, and lofexidine, an alpha(2)-adrenergic receptor agonist, given alone and in combination, decreased symptoms of marijuana withdrawal and relapse, defined as a return to marijuana use after a period of abstinence.Nontreatment-seeking, male volunteers (n = 8), averaging 12 marijuana cigarettes/day, were maintained on each of four medication conditions for 7 days: placebo, tetrahydrocannabinol (THC) (60 mg/day), lofexidine (2.4 mg/day), and THC (60 mg/day) combined with lofexidine (2.4 mg/day); each inpatient phase was separated by an outpatient washout phase. During the first three inpatient days, placebo marijuana was available for self-administration (withdrawal). For the next 4 days, active marijuana was available for self-administration (relapse). Participants paid for self-administered marijuana using study earnings. Self-administration, mood, task performance, food intake, and sleep were measured.THC reversed the anorexia and weight loss associated with marijuana withdrawal, and decreased a subset of withdrawal symptoms, but increased sleep onset latency, and did not decrease marijuana relapse. Lofexidine was sedating, worsened abstinence-related anorexia, and did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse. The combination of lofexidine and THC produced the most robust improvements in sleep and decreased marijuana withdrawal, craving, and relapse in daily marijuana smokers relative to either medication alone.These data suggest the combination of lofexidine and THC warrant further testing as a potential treatment for marijuana dependence.