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Synthetic cannabinoids (SC), originally developed as research tools, are now highly abused novel psychoactive substances. We present a comprehensive systematic review covering in vivo and in vitro animal and human pharmacokinetics and analytical methods for identifying SC and their metabolites in biological matrices. Of two main phases of SC research, the first investigated therapeutic applications, and the second abuse-related issues. Administration studies showed high lipophilicity and distribution into brain and fat tissue. Metabolite profiling studies, mostly with human liver microsomes and human hepatocytes, structurally elucidated metabolites and identified suitable SC markers. In general, SC underwent hydroxylation at various molecular sites, defluorination of fluorinated analogs and phase II metabolites were almost exclusively glucuronides. Analytical methods are critical for documenting intake, with different strategies applied to adequately address the continuous emergence of new compounds. Immunoassays have different cross-reactivities for different SC classes, but cannot keep pace with changing analyte targets. Gas chromatography and liquid chromatography mass spectrometry assays - first for a few, then numerous analytes - are available but constrained by reference standard availability, and must be continuously updated and revalidated. In blood and oral fluid, parent compounds are frequently present, albeit in low concentrations; for urinary detection, metabolites must be identified and interpretation is complex due to shared metabolic pathways. A new approach is non-targeted HRMS screening that is more flexible and permits retrospective data analysis. We suggest that streamlined assessment of new SC's pharmacokinetics and advanced HRMS screening provide a promising strategy to maintain relevant assays.

Background: Craving is a major issue in drug addiction, and a target for drug treatment. The Marijuana Craving Questionnaire-Short Form (MCQ-SF) is a useful tool for assessing cannabis craving in clinical and research settings., Objective: To validate the French version of the MCQ-SF (FMCQ-SF)., Methods: Young adult cannabis users not seeking treatment (n = 679) completed the FMCQ-SF and questionnaires assessing their frequency of cannabis use and craving, cannabis use disorder criteria, and alcohol use., Results: Confirmatory factor analysis of the four-factor FMCQ-SF model did not fit the data well. Exploratory factor analysis suggested a two-factor solution ("pleasure", characterized by planning and expectation of positive effects, and "release of tension", characterized by relief from anxiety, nervousness, or tension) with good psychometric properties. This two-factor model showed good internal and convergent validity and correlated with cannabis abuse and dependence and with frequency of cannabis use and craving., Conclusion: Validation of the FMCQ-SF generated a two-factor model, different from the four-factor solution generated in English language studies. Considering that craving plays an important role in withdrawal and relapse, this questionnaire should be useful for French-language addiction professionals.

Background: The management of withdrawal absorbs substantial clinical efforts in opioid dependence (OD). The real challenge lies in improving current pharmacotherapies. Although widely used, clonidine causes problematic adverse effects and does not alleviate important symptoms of opioid withdrawal, alone or in combination with the opioid antagonist naltrexone. Very low-dose naltrexone (VLNTX) has been shown to attenuate withdrawal intensity and noradrenaline release following opioid agonist taper, suggesting a combination with clonidine may result in improved safety and efficacy., Objectives: We investigated the effects of a VLNTX-clonidine combination in a secondary analysis of data from a double-blind, randomized opioid detoxification trial., Methods: Withdrawal symptoms and treatment completion were compared following VLNTX (.125 or .25 mg/day) and clonidine (.1-.2 mg q6h) in 127 individuals with OD undergoing 6-day methadone inpatient taper at a community program., Results: VLNTX was more effective than placebo or clonidine in reducing symptoms and signs of withdrawal. The use of VLNTX in combination with clonidine was associated with attenuated subjective withdrawal compared with each medication alone, favoring detoxification completion in comparison with clonidine or naltrexone placebo. VLNTX/clonidine was effective in reducing symptoms that are both undertreated and well controlled with clonidine treatment and was not associated with significant adverse events compared with other treatments., Conclusions and Scientific Significance: Preliminary results elucidate neurobiological mechanisms of OD and support the utility of controlled studies on a novel VLNTX + low-dose clonidine combination for the management of opioid withdrawal.

Background: The endocannabinoid system modulates the hypothalamic-pituitary-adrenal (HPA) axis, but the effect of cannabinoid type 1 (CB1) receptor antagonism following chronic CB1 receptor stimulation in humans is unknown., Objectives: To evaluate effects of the CB1 receptor antagonist rimonabant on the HPA axis in cannabis-dependent individuals., Methods: Fourteen daily cannabis smokers received increasingly frequent 20 mg oral Δ9-tetrahydrocannabinol (THC) doses (60-120 mg/day) over 8 days to standardize cannabis tolerance. Concurrent with the last THC dose, double-blind placebo or rimonabant (20 or 40 mg) was administered. Cannabinoid, rimonabant, and cortisol plasma concentrations were measured 1.5 hours prior to rimonabant administration and 2.0, 5.5, and 12.5 hours post-dose., Results: Ten participants completed before premature study termination due to rimonabant's withdrawal from development. Five participants received 20 mg, three received 40 mg, and two placebo. There was a significant positive association between rimonabant concentration and change in cortisol concentration from baseline (r = .53, p < .01). There also was a borderline significant association between rimonabant dose and cortisol concentrations when the dose-by-time interaction was included. Four of eight participants receiving rimonabant (none of two receiving placebo) had greater cortisol concentrations 2 hours after dosing (at 11:30) than at 08:00, while normal diurnal variation should have peak concentrations at 08:00., Conclusion: Rimonabant 20 or 40 mg did not significantly increase plasma cortisol concentrations, consistent with an absence of antagonist-elicited cannabis withdrawal., Scientific Significance: Rimonabant doses >40 mg might elicit cortisol changes, confirming a role for CB1 receptors in modulating the HPA axis in humans.

Background: Cannabis withdrawal can be a negative reinforcer for relapse, but little is known about its association with demographic characteristics., Objectives: Evaluate the association of demographic characteristics with the experience of cannabis withdrawal., Methods: Retrospective self-report of a "serious" cannabis quit attempt without formal treatment in a convenience sample of 104 non-treatment-seeking, adult cannabis smokers (mean age 35 years, 52% white, 78% male) with no other current substance use disorder (except tobacco) or chronic health problems. Reasons for quitting, coping strategies to help quit, and 18 specific withdrawal symptoms were assessed by questionnaire., Results: Among withdrawal symptoms, only anxiety, increased sex drive, and craving showed significant associations with age, race, or sex. Women were more likely than men to report a physical withdrawal symptom (OR = 3.2, 95% CI = .99-10.4, p = .05), especially upset stomach. There were few significant demographic associations with coping strategies or reasons for quitting., Conclusions and Scientific Significance: This small study suggests that there are few robust associations between demographic characteristics and cannabis withdrawal. Future studies with larger samples are needed. Attention to physical withdrawal symptoms in women may help promote abstinence.

Background: Several behaviors, besides psychoactive substance ingestion, produce short-term reward that may engender persistent behavior, despite knowledge of adverse consequences, i.e., diminished control over the behavior. These disorders have historically been conceptualized in several ways. One view posits these disorders as lying along an impulsive-compulsive spectrum, with some classified as impulse control disorders. An alternate, but not mutually exclusive, conceptualization considers the disorders as non-substance or "behavioral" addictions., Objectives: Inform the discussion on the relationship between psychoactive substance and behavioral addictions., Methods: We review data illustrating similarities and differences between impulse control disorders or behavioral addictions and substance addictions. This topic is particularly relevant to the optimal classification of these disorders in the forthcoming fifth edition of the American Psychiatric Association Diagnostic and Statistical Manual of Mental Disorders (DSM-V)., Results: Growing evidence suggests that behavioral addictions resemble substance addictions in many domains, including natural history, phenomenology, tolerance, comorbidity, overlapping genetic contribution, neurobiological mechanisms, and response to treatment, supporting the DSM-V Task Force proposed new category of Addiction and Related Disorders encompassing both substance use disorders and non-substance addictions. Current data suggest that this combined category may be appropriate for pathological gambling and a few other better studied behavioral addictions, e.g., Internet addiction. There is currently insufficient data to justify any classification of other proposed behavioral addictions., Conclusions and Scientific Significance: Proper categorization of behavioral addictions or impulse control disorders has substantial implications for the development of improved prevention and treatment strategies.

We compared treadmill exercise stress testing (EST) in 28 medically screened, chronic cocaine users with the cardiovascular effects of an IV cocaine challenge (25 mg or 50 mg). All subjects had a clinically normal EST and echocardiography (except 2 subjects had septal wall hypokinesis). The EST produced significantly greater increases in heart rate and rate-pressure product than did the cocaine challenges. These findings suggest that EST may not provide additional diagnostic information in medically screened cocaine users. EST may cause more cardiac work (indicated by heart rate and blood pressure) than intravenous cocaine (at the doses in this study).

Objectives: 3,4-Methylenedioxymethamphetamine (MDMA, ecstasy) use has been associated with cardiac arrhythmias. Markers of ventricular late potentials (VLP), which may be a precursor to malignant ventricular arrhythmias, can be detected by signal-averaged electrocardiography (SA-ECG), but not by standard ECG., Methods: We evaluated SA-ECG parameters in 21 physically healthy, recently abstinent MDMA users who also used cannabis (11 males, mean [SD] age 23.3 [4.6] years, 2.8 [2.0] years of use), 18 physically healthy cannabis users (8 males, mean [SD] age 26.6 [7.1] years, 11.2 [5.4] years of use) and 54 non-drug-using controls (21 males, mean [SD] age 28.4 [7.8] years). We analyzed three SA-ECG parameters considered markers of VLPs: duration of filtered QRS complex (fQRS), duration of low amplitude potentials during terminal 40 ms of QRS complex (LAS40), and root mean square voltage during terminal 40 ms of QRS complex (RMS40)., Results: MDMA users, cannabis users, and non-drug-using controls did not differ significantly from each other in fQRS, LAS40, or RMS40 values or in the proportion of subjects with abnormal SA-ECG parameters. There were significant gender differences among controls, but not among MDMA users., Conclusion: These findings suggest that chronic MDMA use is neither quantitatively nor qualitatively associated with a high prevalence of abnormal SA-ECG parameters indicative of VLP markers.

Substance use is significantly associated with physical injury, yet relatively little is known about the prevalence of specific substance use disorders among trauma patients, or their associated sociodemographic characteristics. We evaluated these issues in an unselected sample of 1,118 adult inpatients at the University of Maryland Shock Trauma Center, Baltimore, MD, who were interviewed with the psychoactive substance use disorder section of the Structured Clinical Interview for DSM-III-R. Among trauma inpatients, lifetime alcohol users (71.8% of subjects) were more likely male; users of illegal drugs (45.3%) were also more likely to be younger, unmarried, and poor. Patients with current drug abuse/dependence (18.8%) were more likely to be non-white, less educated, and poor; those with current alcohol abuse/dependence (32.1%) were also more likely male, unmarried, and older. These findings highlight the need for screening for substance use disorders in trauma settings and referral of patients to substance abuse treatment programs.

One measure of a substance's addictive risk is the proportion of users who become dependent. This study evaluates the lifetime and current risk of substance dependence among lifetime substance users' among trauma inpatients and provides a relative ranking of addictive risk among the substances. Data on use of 8 substance groups (alcohol, opiates, marijuana, cocaine, other stimulants, sedative-hypnotics, hallucinogens, other drugs) were obtained by interview (Structured Clinical Interview for the DSM-III-R) from 1,118 adult trauma inpatients. Prevalence of lifetime dependence among lifetime users ranged from 80.7% for opiates and 70.9% for cocaine to 33.3% for hallucinogens and 26.6% for sedative-hypnotics. The rank order of addictive risk was similar to that found in the general population. Trauma inpatients had a higher absolute addictive risk than the general population, comparable to the risk found in patients in treatment for substance use disorders, suggesting the importance of screening trauma inpatients for substance dependence.

Background: This study examines remuneration spending by drug-using participants in residential drug abuse research., Methods: Ninety-four adult males who participated in residential, non-treatment drug abuse research studies earned remuneration based on length of stay and specific research procedures. Remuneration could be in cash after discharge or for in-kind purchases and bill payments. Spending of remuneration was extracted from charts and evaluated with multivariate analyses., Results: Participants received average remuneration of 1,454 dollars, taking 59% in cash. Other categories included cigarettes (60.6% of subjects), toiletries (60.6%), clothing (54.3%), and housing (52.1%). Primary drug of abuse, total remuneration, monthly income, length of stay on the residential research unit, age, and education were significantly associated with in-kind remuneration choices. Less total remuneration, intoxication in the month prior to study, higher IQ, and non-white race were associated with taking more in cash., Conclusion: Residential drug abuse research participants prefer cash to in-kind research remuneration, and their choices reflected drug use and economic status.

Combinations of medications are often used in neuropsychiatry to enhance treatment efficacy. This 8-week, open-label study tested the combination of bupropion (< or =300 mg) and bromocriptine (< or =7.5 mg) daily in 34 cocaine-dependent (DSM-IIIR) outpatients also receiving weekly individual counseling. The first 18 subjects spent one week at maximum dose; the next 16 spent three weeks. Both groups showed significant reductions in self-reported cocaine use, with no significant change in proportion of urine toxicology tests positive for cocaine. There were no significant differences in outcome between groups. These results suggest that the combination of bupropion and bromocriptine is safe in cocaine addicts, but provide ambiguous evidence of its efficacy.

Almost all data on pathophysiological abnormalities associated with human cocaine use comes from clinical observation and testing of cocaine abusers seeking treatment. Such data are subject to several confounding factors which preclude drawing definitive conclusions about the pathophysiological mechanism for the observed abnormality, its prevalence and prognosis, and individual differences in susceptibility. Confounding factors include the unknown purity of cocaine used, uncertainty as to quantity and duration of cocaine exposure, effects of other substances frequently used by cocaine users, abnormalities associated with drug route of administration and the drug abuse lifestyle, and selection bias. Future studies can address these issues by employing more sophisticated research designs, such as prospective, longitudinal follow-up of large, representative samples of cocaine users, case-control comparisons of well characterized cocaine users with appropriately matched groups, and experimental administration of cocaine under safe, controlled conditions.

We studied the self-reported temporal sequence of cocaine-related problems in 45 male predominantly Black (85%), lower SES cocaine addicts undergoing inpatient treatment at a large urban VA psychiatric hospital. Subjects reported recent average use of 2.5 g of cocaine per day for 14 days each month and experiencing a mean of 14 cocaine-related problems. The temporal sequence of cocaine-related problems was roughly consistent with the sequence of alcohol-related problems reported for alcoholics, with the earliest problems being interpersonal (e.g., arguments with others) and the most recent problems the severest (e.g., job loss, marital separation). The cocaine addicts showed a faster progression from first cocaine use to first cocaine-related problems (mean of 3.75 years) than that reported for alcoholics from first drink to first heavy drinking (8-10 years). Cocaine smokers had a faster course (3.4 years) than intranasal users (5.3 years).

Screening of 155 consecutive admissions to a voluntary, 4-6 week substance abuse inpatient rehabilitation program revealed a 13% prevalence of PCP abuse (defined by DSM-III criteria) and a 23% prevalence of nonabusive PCP use. The 20 PCP abusers were significantly younger (31.6 vs 40.2 years) and had more prior arrests (2.0 vs 0.8) than the 36 nonabusive users, but did not differ in other sociodemographic characteristics. The age range of patients was older than previously reported in the literature, with three PCP abusers (15%) and 15 users (42%) 40 years of age or older. A majority of both abusers (80%) and users (97%) also abused other drugs, including alcohol (57%), opiates (29%), marijuana (29%), and stimulants (18%). The mean length of stay for PCP abusers was 27 days, with 11 completing inpatient treatment. Urine samples were collected upon admission from all patients and assayed for PCP by gas chromatography with N-P detection (sensitivity = 0.1 ng/mL). Patients with initial positive PCP results had follow-up urines collected at least weekly until the PCP assay was negative or they left the treatment program. Twenty-seven percent of patients had PCP detected in admission urine samples, one-third of whom initially denied PCP use. Six patients still had PCP detected after 4 weeks of hospitalization, without evidence of PCP reuse. These findings suggest that PCP abuse and use are common among unselected patients seeking substance abuse inpatient treatment and that they are not confined to the adolescent/young adult age group.

Despite the persistence of phencyclidine (PCP) abuse as a public health problem in many urban areas of the United States, there are no published data on outpatient treatment outcome. We studied 37 unselected male PCP abusers (mean age 32 years, 73% Black, 19% married, 68% unemployed) who attended at least one outpatient treatment session at the Brentwood Division, West Los Angeles VA Medical Center. Subjects had smoked PCP for an average of 7 years, with 84% using it at least weekly (38% daily) and 76% using other drugs (alcohol, marijuana, or cocaine). All subjects reported psychological dependence on PCP (i.e., liking PCP use and difficulty stopping despite adverse consequences), while none reported a physiological withdrawal syndrome when stopping PCP use. Subjects stayed in treatment an average of 21 weeks (range 1-155 weeks), attending an average of 68% of the group meetings. PCP was detected in weekly urine samples 78% of the time, with verbal self-report of recent PCP use occurring before 29% of the group meetings. Four subjects (11%) achieved at least 1 year of abstinence, 10 (30%) transferred to residential treatment or a community recovery home, 16 (48%) dropped out of treatment, and two (6%) were jailed. Treatment outcome was not significantly associated with subject characteristics. Age was the only subject characteristic that significantly predicted length of stay (r = .40).