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Alcohol use disorder (AUD) treatment remains greatly underutilized. Innovative strategies are needed to improve AUD treatment access and patient engagement. The Ria Treatment Platform (RTP) is a patient-centered telemedicine AUD treatment program accessed through a smartphone application (app) that includes a package of physician visits (with AUD prescriptions as appropriate), text- and phone-based support from a recovery coach, video monitoring of medication adherence, and Bluetooth-linked breathalyzer tracking of alcohol intake.The purpose of the current study is to examine changes in alcohol use among patients utilizing the RTP.This study examines daily breathalyzer blood alcohol content (BAC) readings collected from 77 adult patients (50.7% male) over the first 90 days in treatment with the RTP. Data were analyzed using dynamic structural equation modeling.The treatment retention rate at 90 days was 55%. The best fit for the BAC data was given by a cubic curve, which showed that among patients who remained engaged for 90 days average BAC levels declined approximately 50% (from .091 to .045) from baseline to day 90.This study provides preliminary evidence of substantial alcohol use reductions among patients utilizing the RTP, an innovative telemedicine program accessed via smartphone. Although other alcohol-reduction apps have shown promise from scientific evaluations, the RTP appears to be the only app that incorporates physician-prescribed medication and a recovery coach. Research incorporating random assignment and meaningful comparison groups is needed to further evaluate this promising strategy.

Entactogens such as 3,4-Methylenedioxymethamphetamine (MDMA, "molly", "ecstasy") appear to have unusual, potentially therapeutic, emotional effects. Understanding their mechanisms can benefit from clinical experiments with related drugs. Yet the first known drug with such properties, 3,4-Methylenedioxyamphetamine (MDA), remains poorly studied and its pharmacokinetics in humans are unknown. We conducted a within-subjects, double-blind, placebo-controlled study of 1.4 mg/kg oral racemic MDA and compared results to those from our prior similar studies with 1.5 mg/kg oral racemic MDMA. MDA was well-tolerated by participants. MDA induced robust increases in heart rate and blood pressure and increased cortisol and prolactin to a similar degree as MDMA. MDA self-report effects shared features with MDMA as well as with classical psychedelics. MDA self-report effects lasted longer than those of MDMA, with MDA effects remaining elevated at 8 h while MDMA effects resolved by 6 h. Cmax and AUC0-∞ for MDA were 229 ± 39 (mean ± SD) and 3636 ± 958 µg/L for MDA and 92 ± 61 and 1544 ± 741 µg/L for the metabolite 4-hydroxy-3-methoxyamphetamine (HMA). There was considerable between-subject variation in MDA/HMA ratios. The similarity of MDA and MDMA pharmacokinetics suggests that the greater duration of MDA effects is due to pharmacodynamics rather than pharmacokinetics.

BACKGROUND: Several single-site alcohol treatment clinical trials have demonstrated efficacy for immediate-release (IR) gabapentin in reducing drinking outcomes among individuals with alcohol dependence. The purpose of this study was to conduct a large, multisite clinical trial of gabapentin enacarbil extended-release (GE-XR) (HORIZANT(®)), a gabapentin prodrug formulation, to determine its safety and efficacy in treating alcohol use disorder (AUD). METHODS: Men and women (n= 346) who met DSM–5 criteria for at least moderate AUD were recruited across 10 US clinical sites. Participants received double-blind GE-XR (600 mg twice a day [BID]) or placebo and a computerized behavioral intervention (Take Control) for 6 months. Efficacy analyses were pre-specified for the last 4 weeks of the treatment period. RESULTS: The GE-XR and placebo groups did not differ significantly on the primary outcome measure, percentage of subjects with no heavy drinking days (28.3 vs 21.5, respectively, p=0.157). Similarly, no clinical benefit was found for other drinking measures (percent subjects abstinent, percent days abstinent, percent heavy drinking days, drinks per week, drinks per drinking day), alcohol craving, alcohol-related consequences, sleep problems, smoking, and depression/anxiety symptoms. Common side-effects were fatigue, dizziness, and somnolence. A population pharmacokinetics analysis revealed that patients had lower gabapentin exposure levels compared with those in other studies using a similar dose but for other indications. CONCLUSION: Overall, GE-XR at 600 mg BID did not reduce alcohol consumption or craving in individuals with AUD. It is possible that, unlike the IR formulation of gabapentin, which showed efficacy in smaller Phase 2 trials at a higher dose, GE-XR is not effective in treating AUD, at least not at doses approved by the FDA for treating other medical conditions.

In methamphetamine (MA) users, drug-induced neurocognitive deficits may help to determine treatment, monitor adherence, and predict relapse. To measure these relationships, we developed an iPhone app (Neurophone) to compare lab and field performance of N-Back, Stop Signal, and Stroop tasks that are sensitive to MA-induced deficits.Twenty healthy controls and 16 MA-dependent participants performed the tasks in-lab using a validated computerized platform and the Neurophone before taking the latter home and performing the tasks twice daily for two weeks.N-Back task: there were no clear differences in performance between computer-based vs. phone-based in-lab tests and phone-based in-lab vs. phone-based in-field tests. Stop-Signal task: difference in parameters prevented comparison of computer-based and phone-based versions. There was significant difference in phone performance between field and lab. Stroop task: response time measured by the speech recognition engine lacked precision to yield quantifiable results. There was no learning effect over time. On an average, each participant completed 84.3% of the in-field NBack tasks and 90.4% of the in-field Stop Signal tasks (MA-dependent participants: 74.8% and 84.3%; healthy controls: 91.4% and 95.0%, respectively). Participants rated Neurophone easy to use.Cognitive tasks performed in-field using Neurophone have the potential to yield results comparable to those obtained in a laboratory setting. Tasks need to be modified for use as the app's voice recognition system is not yet adequate for timed tests.

Hyponatremia is a serious complication of 3,4-methylenedioxymethamphetamine (MDMA) use. We investigated potential mechanisms in two double-blind, placebo-controlled studies. In study 1, healthy drug-experienced volunteers received MDMA or placebo alone and in combination with the alpha-1 adrenergic inverse agonist prazosin, used as a positive control to release antidiuretic hormone (ADH). In study 2, volunteers received MDMA or placebo followed by standardized water intake. MDMA lowered serum sodium, but did not increase ADH or copeptin, although the control prazosin did increase ADH. Water loading reduced serum sodium more after MDMA than after placebo. There was a trend for women to have lower baseline serum sodium than men, but there were no significant interactions with drug condition. Combining studies, MDMA potentiated the ability of water to lower serum sodium. Thus, hyponatremia appears to be a significant risk when hypotonic fluids are consumed during MDMA use. Clinical trials and events where MDMA use is common should anticipate and mitigate this risk.

The primary objective of this study was to determine the safety of lofexidine, an α2 receptor agonist, alone and concurrent with cocaine in non-treatment seeking cocaine-dependent or cocaine-abusing participants. After screening, eligible participants received double-blind, randomized infusions of saline and 20 mg of cocaine on Day 1, and saline and 40 mg of cocaine on Day 2. Subjects were randomized and started receiving daily administration of placebo (N=4) or lofexidine on Day 3 and continued on this schedule until Day 7. Two dosing regimens for lofexedine were investigated: 0.8 QID (N=3) and 0.2 mg QID (N=11). On Days 6 and 7, subjects received double-blind infusions of saline and 20 mg of cocaine on Day 6, and saline and 40 mg of cocaine on Day 7. The data reveal a notable incidence of hemodynamic-related AEs over the course of the study. Two of the three participants at the 0.8 mg dose level discontinued, and five of 11 participants at the 0.2 mg dose level were withdrawn (or voluntarily discontinued) after hemodynamic AEs. Subjective effects and cardiovascular data were derived from all participants who were eligible to receive infusions (i.e., did not meet stopping criteria) on Days 6 and 7 (6 received lofexidine 0.2 mg, QID and 4 received placebo, QID). As expected, cocaine significantly increased heart rate and blood pressure, as well as several positive subjective effects. There was a trend for lofexidine to decrease cocaine-induced cardiovascular changes and cocaine-induced ratings for "Any Drug Effect", "Good Effects", and “Desire Cocaine”, but sample size issues limit the conclusions that can be drawn. Despite the trends to reduce cocaine-induced subjective effects, cardiovascular AEs may limit future utility of lofexidine as a treatment for this population.

The drug 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”, “molly”) is a widely used illicit drug and experimental adjunct to psychotherapy. MDMA has unusual, poorly understood socioemotional effects, including feelings of interpersonal closeness and sociability. To better understand these effects, we conducted a small ( n=12) within-subjects double-blind placebo controlled study of the effects of 1.5 mg/kg oral MDMA on social emotions and autobiographical disclosure in a controlled setting. MDMA displayed both sedative- and stimulant-like effects, including increased self-report anxiety. At the same time, MDMA positively altered evaluation of the self (i.e. increasing feelings of authenticity) while decreasing concerns about negative evaluation by others (i.e. decreasing social anxiety). Consistent with these feelings, MDMA increased how comfortable participants felt describing emotional memories. Overall, MDMA produced a prosocial syndrome that seemed to facilitate emotional disclosure and that appears consistent with the suggestion that it represents a novel pharmacological class.

Medication nonadherence is an important factor in clinical practice and research methodology. Although many methods of measuring adherence have been investigated, there is as yet no "gold standard." We compared the usefulness and accuracy of a novel measure of adherence, photographs taken by cellular telephones with 2 incumbents: capsule count and the Medication Event Monitoring System (MEMS).Twenty subjects participated in a clinical trial of the efficacy of modafinil for the treatment of methamphetamine dependence. Subjects were issued cell phones and medication in MEMS Cap equipped bottles and were instructed to take 1 capsule a day for 8 weeks, recording adherence with both systems. Pill counts were recorded at weekly inpatient visits. Subjects were paid for participation and for each capsule photograph and the returned medication bottle with MEMS Cap.Capsule count-indicated adherence (proportion of prescribed medication taken) was 94.9%. When compared with capsule count, the novel method was found to underestimate adherence, whereas MEMS overestimated adherence. By using the dosing time data collected, we determined that subjects who dosed at a consistent time daily were more likely to adhere to the prescribed regimen. We also detected discrepancies in the timestamps recorded by MEMS.Capsule photographs are a useful measure of adherence, allowing more accurate time measures and more frequent adherence assessment than MEMS or capsule count. Given the ubiquity of cellular telephone use, and the relative ease of this adherence measurement method, we believe it is a useful and cost-effective approach.

There are an estimated 11.7 million methamphetamine (MA) abusers in the United States and epidemics of MA addiction are occurring worldwide. In our human laboratory and outpatient clinical trials we use innovative methods to quantify the severity of MA addiction and test biomarkers that may predict response to therapy or risk of relapse. One potential biomarker of addiction is the quantity of abused drug intake. Qualitative urinalysis is used in clinical trials and during treatment but provides only a binary outcome measure of abuse. Using non-pharmacologic doses of deuterium labeled l-MA we have developed a continuous quantitative measure to estimate the bioavailable amount of MA addicts ingest. Brain Derived Neurotrophic Factor is a neurotrophin that encourages growth and differentiation of new neurons and synapses. Low BDNF levels are seen in many addictive disorders and BDNF is elevated in recovering MA addicts, suggesting BDNF may be a marker of MA addiction. We are investigating the effects of controlled doses of MA on BDNF levels and gene regulation and measuring BDNF in our clinical trials. We believe both patients and clinical researches will benefit from the addition of new, objective and quantifiable outcome measures that reflect disease severity and recovery from addiction.

Methamphetamine dependence has become a significant problem, but methamphetamine withdrawal symptoms have not been well studied.This prospective observational pilot study was designed to examine withdrawal symptoms, mood, anxiety, cognitive function, and subjective measures of sleep over a 4-week period in six patients entering residential treatment for methamphetamine dependence.Methamphetamine withdrawal symptoms, mood, and anxiety symptoms all resolve fairly quickly within 2 weeks of cessation of methamphetamine. Sleep was disrupted over the course of the 4-week study. No clinically significant alterations in blood pressure or heart rate were identified. This study did not demonstrate any alterations in cognitive function over the 4 weeks of the residential stay.This pilot study points toward the need for a double-blind, placebo-controlled amphetamine withdrawal paradigm in humans where changes in sleep, cognitive function, and withdrawal measures can be explored more fully.This study extends the literature by pointing toward a methamphetamine withdrawal syndrome that includes alterations in measures of sleep quality and refreshed sleep, early improvement in depression and anxiety symptoms, most striking during the first week, but persisting into the second week.

Dependence on and abuse of prescription opioid drugs is now a major health problem, with initiation of prescription opioid abuse exceeding cocaine in young people. Coincident with the emergence of abuse and dependence on prescription opioids, there has been an increased emphasis on the treatment of pain. Pain is now the "5th vital sign" and physicians face disciplinary action for failure to adequately relieve pain. Thus, physicians are whipsawed between the imperative to treat pain with opioids and the fear of producing addiction in some patients. In this article, the authors characterize the emerging epidemic of prescription opioid abuse, discuss the utility of buprenorphine in the treatment of addiction to prescription opioids, and present illustrative case histories of successful treatment with buprenorphine.

Motivational enhancement therapy (MET) is a brief therapy shown to be effective for problem drinkers. Because the response to MET for other addictive disorders is mixed, we assessed the utility of increasing the number of sessions in subjects with methamphetamine (MA) dependence. One therapist was trained in a nine-session manual of MET, which was tested over eight weeks in 30 MA-dependent outpatients. Adherence to the manual was assessed by two raters, who reviewed a random sample of 15 audiotaped therapy sessions. Interventions were rated on a seven-point Likert scale for frequency/extensiveness (1 = not at all to 7 = extensively) and skill level (1 = unacceptable to 7 = high level of mastery). Ratings of adherence were moderate for frequency/extensiveness (4.2 +/- 2.2 and 4.3 +/- 1.8; Mean +/- SD) and high for skill level (5.4 +/- 0.6 and 5.2 +/- 0.4). Subjects attended 7.0 +/- 2.5 (78%) of nine sessions. Self-reported days of methamphetamine use decreased from 841/1793 (47%) of the 60 days prior to study entry to 448/1458 (31%) during the study (p = 0.011). MA-positive urine samples decreased from 76/118 (64%) during screening to 93/210 (44%) during treatment (p = 0.015). The MET manual was readily learned, and subjects attended a high proportion of therapy sessions with marked reductions in methamphetamine use.

Nitric oxide (NO) is generated from l-arginine by NO synthases, of which three forms have been identified: endothelial, inducible and neuronal (eNOS, iNOS and nNOS, respectively). The l-arginine metabolite asymmetric dimethylarginine (ADMA) is a potent, noncompetitive inhibitor of nNOS, while its congener N(G)-monomethyl-l-arginine (l-NMMA) is a less potent, competitive inhibitor. In rat neurons large amounts of ADMA are found, suggesting its importance in modulating neuronal activity. Humans generate approximately 300mumol ( approximately 60mg) ADMA per day. It is released from myelin basic proteins that are highly expressed in neuronal tissue. ADMA is mainly degraded by the action of the enzyme dimethylarginine dimethylaminohydrolase (DDAH), which exists in two isoforms. DDAH1 is highly expressed in brain, suggesting specific function in this area. The presence of nNOS and DDAH1 in brain suggests that ADMA may have specific CNS activity and be more than an unregulated metabolite. Increased NO production-either prior to or concurrently with opioid administration-results in an enhanced rate and extent of development of tolerance to morphine in mice. NO produces an alteration in the mu-opioid receptor that increases constitutive receptor activity. It thereby reduces the ability of a selective mu-opioid agonist to activate the mu-opioid receptor; these in vitro molecular effects occur in a time course consistent with the in vivo development of antinociceptive tolerance in mice. Amongst many other synthetic NOS inhibitors of varying specificity, 7-nitroindazole (7-NI) has been shown to have a high affinity (IC(50) 0.71 microM) to nNOS. Selective blockade of nNOS by 7-NI attenuated morphine withdrawal in opiate dependent rats, suggesting nNOS as a viable target for development of pharmacotherapies. We hypothesize that, by inhibiting nNOS and reducing NO levels, ADMA may decrease mu-opiate receptor constitutive activity, resulting in alteration of the analgesic dose-response curve of morphine.

The drug 3,4-methylenedioxymethamphetamine (MDMA, ?ecstasy?, ?molly?) is a widely used illicit drug and experimental adjunct to psychotherapy. MDMA has unusual, poorly understood socioemotional effects, including feelings of interpersonal closeness and sociability. To better understand these effects, we conducted a within-subjects double-blind placebo controlled study of the effects of 1.5 mg/kg oral MDMA on social emotions and autobiographical disclosure in a controlled setting. MDMA displayed both sedative- and stimulant-like effects, including increased self-report anxiety. At the same time, MDMA positively altered evaluation of the self (i.e., increasing feelings of authenticity) while decreasing concerns about negative evaluation by others (i.e., decreasing social anxiety). Consistent with these feelings, MDMA increased how comfortable participants felt describing emotional memories. Overall, MDMA produced a prosocial syndrome that seemed to facilitate emotional disclosure and that appears consistent with the suggestion that it represents a novel pharmacological class.

Objectives: Methamphetamine (MA) addiction has no known effective pharmacotherapy. Small trials showed beneficial effects for oral naltrexone in amphetamine users. Trials in alcohol-dependent subjects showed better response in persons with the A118G single nucleotide polymorphism of the μ-opioid receptor. We conducted a pharmacogenetic trial of sustained release intramuscular naltrexone to examine the role of the A118G single nucleotide polymorphism in MA dependence. Method: All eligible A118G subjects screened were enrolled; an equal number of wild type (A118A) subjects were selected using modified urn randomization, balanced on sex and frequency of recent MA use. Enrolled subjects received a single 380 mg naltrexone injection and weekly psychotherapy for 4 weeks. Self-report of MA use and urine toxicology for MA was assessed twice weekly. Urine samples with less than 1000 ng/mL of MA were considered negative. Results: Eleven A118G and 11 A118A subjects were enrolled. There were no significant differences between the groups in days of abstinence from MA use (11.5 vs 14.8, respectively, P = 0.51), the number of MA-negative urine samples (1.7 vs 1.8, respectively, P = 0.97), consecutive MA-negative urine samples (1.0 vs 1.5, respectively, P = 0.91), or the number of MA-negative urine samples before first relapse (0.9 vs 1.5, respectively, P = 0.86). Conclusions: Although A118G polymorphism has been shown to be associated with improved treatment response to naltrexone among alcoholics, whether this polymorphism impacts naltrexone treatment response among MA users is unclear at this time.

Objective To help predict the consequences of precursor regulation, we compared the pharmacokinetics and pharmacodynamics of the methamphetamine (INN, metamfetamine) stereoisomers. Methods In this study 12 methamphetamine abusers received intravenous d-methamphetamine (0.25 and 0.5 mg/kg), l-methamphetamine (0.25 and 0.5 mg/kg), racemic methamphetamine (0.5 mg/kg), or placebo with the use of a 6-session, double-blind, placebo-controlled, balanced crossover design. Pharmacokinetic measures (including area under the plasma concentration-time curve [AUC], elimination half-life, systemic clearance, apparent volume of distribution during the elimination phase, and apparent bioavailability) and pharmacodynamic measures (including heart rate, blood pressure, respiratory rate, and visual analog scale ratings for “intoxication,” “good drug effect,” and “drug liking”) were obtained. Results Pharmacokinetic parameters for the individual enantiomers given separately were similar, with dose-proportional increases in AUC and maximum plasma concentration. After racemate administration, the AUC for d-methamphetamine was 30% smaller than that for l-methamphetamine (P = .0085). The elimination half-lives were longer for l-methamphetamine (13.3–15.0 hours) than for d-methamphetamine (10.2–10.7 hours) (P < .0001). Compared with placebo, d-methamphetamine (0.25 mg/kg, 0.5 mg/kg, and racemic) increased the heart rate (P < .0001), blood pressure (P < .0001), and respiratory rate (P < .05), and this increase lasted for 6 hours. The peak heart rate changes after racemic methamphetamine and 0.5 mg/kg d- and l-methamphetamine were similar (18.7 ± 23.4 beats/min, 13.5 ± 18.5 beats/min, and 10.7 ± 10.2 beats/min, respectively), but racemic methamphetamine and 0.5 mg/kg d-methamphetamine increased systolic blood pressure more than 0.5 mg/kg l-methamphetamine (33.4 ± 17.8 beats/min and 34.5 ± 18.9 beats/min, respectively, versus 19.5 ± 11.3 beats/min; P < .01). l-Methamphetamine, 0.5 mg/kg, was psychoactive, producing peak intoxication (46.0 ± 35.3 versus 30.3 ± 24.9) and drug liking (47.7 ± 35.1 versus 28.6 ± 24.8) ratings similar to 0.5 mg/kg d-methamphetamine, but the effects of l-methamphetamine dissipated more quickly (approximately 3 hours versus 6 hours). The effects of 0.25 mg/kg l-methamphetamine were similar to those of placebo. Racemic methamphetamine was similar to d-methamphetamine with regard to most pharmacodynamic measures. Conclusion The pharmacokinetics of the methamphetamine enantiomers are similar, but there are substantial pharmacodynamic differences between the isomers. At high doses, l-methamphetamine intoxication is similar to that of d-methamphetamine, but the psychodynamic effects are shorter-lived and less desired by abusers. Racemic and d-methamphetamine have similar effects and would be expected to have comparable abuse liabilities. Clinical Pharmacology & Therapeutics (2006) 80, 403–420; doi: 10.1016/j.clpt.2006.06.013

Decreasing response to stress has been one goal of interventions aimed at reducing relapse to substances of abuse. A laboratory stress test that can be repeated would be helpful in testing the efficacy of interventions in decreasing the response to stress before more extensive trials are begun. The effects of two types of psychological stress tests, the Trier Social Stress Test (TSST) and a stress imagery test, on psychological, physiological, and hormonal responses (salivary cortisol and DHEA) were examined when each test was given twice to cocaine- or methamphetamine-dependent human subjects, 24 of whom completed at least one session. The stress imagery test produced significant changes in several of the subjective response measures in both first and second sessions, including several measures of negative affect and a craving measure. The TSST produced significant changes only in the second session. The stress imagery protocol showed better replicability across two sessions. Cocaine users and methamphetamine users did not respond similarly in their craving responses. Reported craving for methamphetamine after stress testing showed decreases or much smaller increases compared to that for cocaine. Neither stress test significantly increased salivary cortisol or DHEA, and changes in hormone concentrations were not related to subjective responses. These results suggest that stress imagery testing procedures may be useful as provocative tests of stress-induced affect and stimulant drug craving. Although less convincing because of the heterogeneity of the subjects, they also suggest that HPA axis responsivity is not clearly linked to acute stress-induced stimulant craving or affective response.

Background Patients in harm-reduction treatment programs are switching from intravenous to other routes of methamphetamine (INN, metamfetamine) administration to avoid risks associated with needle use. Relatively little has been reported about the bioavailability of methamphetamine when smoked or used intranasally. Methods Eight experienced methamphetamine users were administered smoked or intranasal methamphetamine concurrently with an intravenous dose of deuterium-labeled methamphetamine. Plasma and urine concentrations were measured for calculation of bioavailability and other pharmacokinetic parameters by noncompartmental methods. Results Methamphetamine was well absorbed after smoking or intranasal administration, with bioavailabilities of 79% after intranasal administration and 67% of the estimated delivered dose or 37.4% of the absolute (pipe) dose after smoking. Maximum methamphetamine concentrations occurred at 2.7 and 2.5 hours after intranasal and smoked doses. The elimination half-life was similar for intravenous (11.4 hours), intranasal (10.7 hours), and smoked (10.7 hours) methamphetamine. Clearance (272 mL x h(-1) x kg(-1)), steady-state volume of distribution (4.2 L/kg), and mean residence time (16 hours) of the intravenous dose were similar to previously reported values. Dextroamphetamine (INN, dexamfetamine) half-life (all routes) was 16.2 hours. Methamphetamine and dextroamphetamine renal clearances (all routes) were about 100 and 1100 mL x h(-1) x kg(-1), respectively. Conclusions Intranasal and smoked methamphetamine are well absorbed. Although intranasal or smoked routes may decrease the risk of transmission of blood-borne diseases, exposure to methamphetamine and the possibility of drug-related complications remain substantial.

[Abstract [ The aim of this study was to determine whether or not the skin acts as a reservoir for cocaine. Cocaine-ds (1 mg/kg) was administered to five nondependent, cocaine-experienced volunteers. Skin tissue, interstitial fluid, sebum, stratum corneum, and plasma were collected for 72 h after drug administration. Cocaine and benzoylecgonine (BE) levels were determined using GC-MS. Cocaine concentrations peaked in plasma at 1 h after administration, with pharmacokinetic parameters (tl/2, CL, Vd) also in the expected ranges. In skin, cocaine levels peaked around 1.5 h after administration and became undetectable by 6 h. A correlation was found between the plasma and skin AUC for cocaine (R = 0.99, p = 0.006, N = 4). BE was not detected in skin. In interstitial fluid (N = 4), cocaine concentrations peaked around 5 h after drug administration and were undetectable by 24 h. BE peaks varied between 2 and 24 h and were not detectable at 48 h. In sebum, cocaine levels peaked between 3 and 24 h. BE was found in three samples between 12 and 24 h. In stratum corneum, cocaine was measurable in only one sample from one subject. These findings suggest that skin does not act as a reservoir for cocaine. Rather, cocaine appears to be distributed rapidly to the skin and eliminated, following a time course similar to that of plasma.

A major metabolite of norepinephrine (NE) in brain is 4-hydroxy-3-methoxyphenylethylene glycol (MHPG). In many species, a large fraction of MHPG formed in brain is converted to the sulfate conjugate. Consequently, MHPG sulfate has been proposed as a biomarker for NE metabolism in the central nervous system. As part of the clinical trials of the monoamine oxidase inhibitor selegiline for treating cocaine addiction, we required a method for measuring urine concentrations of MHPG sulfate. Using a deuterium-labeled analogue as an internal standard, we developed a liquid chromatography-electrospray ionization tandem mass spectrometry (LC-MS/ MS) method for determination of MHPG sulfate in human urine. Sample preparation involves simply diluting 50 microL of urine with 1 mL of ammonium formate buffer and adding the internal standard. The sample is centrifuged, the supernate is transferred to an autosampler vial, and 10 microL is injected into the LC-MS/MS system. Standard curves from 50 to 10,000 ng/mL are generated. Only one sample of 277 clinical samples analyzed had a concentration outside of this range. Precision (coefficient of variation) ranged from 1.9 to 9.7%, and accuracy ranged from 97 to 103% of expected values for controls prepared by spiking sulfatase-treated urine with MHPG sulfate.

3,4-Methylenedioxymethamphetamine (MDMA) is a widely used phenethylamine. Reports have described the effects of MDMA in a controlled laboratory setting, but the full range of effects of MDMA in humans is still not completely characterized.To describe the physiological, subjective, and hormonal changes after single doses of MDMA in a laboratory setting and examine relationships between these effects.Eight MDMA-experienced volunteers each received placebo, 0.5 mg/kg, and 1.5 mg/kg oral doses of MDMA in a double-blind crossover study.The 1.5 mg/kg dose (comparable to that typically used by most participants) produced significant subjective effects, peaking at about 2 h after dosing, including some effects commonly associated with stimulant drugs, hallucinogens, and entactogens. MDMA significantly increased plasma cortisol, prolactin, and dehydroepiandrosterone (DHEA) levels. Increase in plasma cortisol after the 1.5 mg/kg dose correlated with increased heart rate, rate-pressure product, and drug liking. Rise in DHEA correlated with euphoria.A typically used dose of MDMA produced effects commonly associated with stimulants and hallucinogens. Subjects liked MDMA. Correlations between cortisol and DHEA levels and some physiological and psychological effects are consistent with animal data suggesting that hormones modulate some responses to drugs of abuse.

RATIONALE: Several laboratories have conducted placebo controlled drug challenge studies with 34 methylenedioxymethamphetamine (MDMA) providing a unique source of data to examine the reliability of the acute effects of the drug across subject samples and settings. We examined the subjective and physiological responses to the drug across three different laboratories and investigated the influence of prior MDMA use. METHODS: Overall 220 healthy volunteers with varying levels of previous MDMA experience participated in laboratory based studies in which they received placebo or MDMA orally (1.5 mg/kg or 125 mg fixed dose) under double blind conditions. Cardiovascular and subjective effects were assessed before and repeatedly after drug administration. The studies were conducted independently by investigators in Basel San Francisco and Chicago. RESULTS: Despite methodological differences between the studies and differences in the subjects' drug use histories MDMA produced very similar cardiovascular and subjective effects across the sites. The participants' prior use of MDMA was inversely related to feeling "Any Drug Effect" only at sites testing more experienced users. CONCLUSIONS: These data indicate that the pharmacological effects of MDMA are robust and highly reproducible across settings. There was also modest evidence for tolerance to the effects of MDMA in regular users.

Hallucinogens are drugs that alter consciousness by distorting primarily auditory and visual perception but can affect any sensory system. Hallucinogens also affect judgment, orientation, memory, and emotions. Despite profound alterations in perception, adverse effects are minimal and hallucinogens are not addictive. Hallucinogen use has its roots in shamanic practices of indigenous cultures and is even incorporated in today's religions like the Native American church. By putting a person in an altered state of consciousness, many religions believed that the user was able to see beyond the boundaries of reality and reach out to mythical beings. Hallucinogen use in scientific research was not popular until the 1950s when Albert Hoffman discovered lysergic acid diethylamide (LSD). The discovery of the drug encouraged further research into understanding its mechanisms and its relationship with mental diseases like schizophrenia. Unfortunately, the Comprehensive Drug Abuse Prevention and Control Act of 1970 significantly limited hallucinogenic research and human research for 42 years before 2012. However, animal research between 1990 and 2010 has determined the importance of serotonergic mechanisms and more specifically the 5-HT2A receptors in mediating LSD's hallucinogenic effects. Researchers continue to identify mechanisms of LSD action through additional receptors such as dopaminergic and metabotropic glutamate receptors. Positron emission tomography scans and functional magnetic resonance imaging have also revealed the importance of the prefrontal cortical region and its interaction with other areas during a hallucinogenic state. Although human clinical research is limited, recent research sees a much deeper relationship by linking LSD brain activity and neurotransmitter levels to psychotic behaviors. The relationship between LSD and acute psychosis is being explored via animal models. Further understanding of hallucinogens on a physiological and psychological level has led to possible psychotherapeutic areas of research in anxiety and substance abuse. This chapter describes a brief history of hallucinogenic research, the pharmacology and neuroanatomy of serotonergic hallucinogens, the acute and chronic adverse effects of serotonergic hallucinogens, the possible treatments for complications with hallucinogenic use, the epidemiology, the relationship between hallucinogens and schizophrenia, and possible therapeutic uses of serotonergic hallucinogens.

We describe the syntheses of benzoylecgonine (1,1,1- 2 H 3 )methyl ester [( 2 H 3 ) cocaine], ( 2 H 5 )benzoylecgonine, ( 2 H 5 )benzoylecgonine methyl ester [( 2 H 5 )cocaine], benzoylecgonine (2,2,2- 2 H 3 )ethyl ester [( 2 H 3 )cocaethylene], ( 2 H 5 )benzoylecgonine ethyl ester [( 2 H 5 )cocaethylene], ( 2 H 5 )benzoylecgonine (2,2,2- 2 H 3 )ethyl ester [( 2 H 8 )cocaethylene], ecgonine (1,1,1- 2 H 3 )methyl ester, ecgonine (2,2,2- 2 H 3 )ethyl ester, ecgonine (1,1,2,2,2- 2 H 5 )ethyl ester and anhydroecgonine (1,1,1- 2 H 3 )methyl ester. ( 2 H 5 )Cocaine and ( 2 H 3 )cocaethylene have been administered to human subjects to study the interactions of cocaine and ethanol. The other eight compounds were utilized as analytical standards or internal standards for GC-MS quantitation of cocaine and its metabolites in biological fluids.

Buprenorphine is an effective new treatment for opiate dependence. This study compared the bioavailability of buprenorphine from a tablet to that from a reference solution. Six men experienced with, but not dependent on, opiates (DSM-III-R) were each administered 7.7 mg of buprenorphine in liquid form and 8 mg in tablet form 1 week apart in a balanced crossover design. Plasma levels were measured by electron capture capillary gas chromatography (GC), and concentration-time curves were constructed. Pharmacokinetic data were analyzed by analysis of variance. The bioavailability from the tablet was approximately 50% that from the liquid and was not affected by saliva pH. Lower bioavailability from the tablet may be due to slow dissolution.

Sublingual buprenorphine is a promising new treatment for opiate dependence, but its opioid agonist effects pose a risk for parenteral abuse. A formulation combining buprenorphine with the opiate antagonist naloxone could discourage such abuse. The effects of three intravenous (IV) buprenorphine and naloxone combinations on agonist effects and withdrawal signs and symptoms were examined in 12 opiate-dependent subjects. Following stabilization on a daily dose of 60 mg morphine intramuscularly, subjects were challenged with IV doses of buprenorphine alone (2 mg) or in combination with naloxone in ratios of 2:1, 4:1, and 8:1 (1, 0.5, or 0.25 mg naloxone), morphine alone (15 mg) or placebo. Buprenorphine alone did not precipitate withdrawal and had agonist effects similar to morphine. A naloxone dose-dependent increase in opiate withdrawal signs and symptoms and a decrease in opioid agonist effects occurred after all drug combinations. Buprenorphine with naloxone in ratios of 2:1 and 4:1 produced moderate to high increases in global opiate withdrawal, bad drug effect, and sickness. These dose ratios also decreased the pleasurable effects and estimated street value of buprenorphine, thereby suggesting a low abuse liability. The dose ratio of 8:1 produced only mild withdrawal symptoms. Dose combinations at 2:1 and 4:1 ratios may be useful in treating opiate dependence.

Objective Sublingual buprenorphine appears useful in the treatment of opiate dependence. A combination sublingual dose of buprenorphine and naloxone could have less potential for parenteral use by opiate-dependent individuals. To estimate the abuse potential of a combination formulation, we assessed the parenteral effects of a buprenorphine and naloxone combination in untreated heroin addicts. Methods Eight healthy, opiate-dependent daily users of heroin were given, under double-blind conditions on four separate occasions, either (1) 2 mg buprenorphine, (2) 2 mg naloxone, (3) 2 mg buprenorphine and 2 mg naloxone combined, or (4) placebo as a single intravenous infusion during a 30-second interval. Opiate agonist and antagonist physiologic and subjective effects were measured. Data were analyzed by analysis of variance. Results Buprenorphine increased opiate intoxication and relieved withdrawal. The buprenorphine and naloxone combination precipitated opiate withdrawal and was unpleasant and dysphoric in all subjects. Fifty percent of the subjects were unable to distinguish between naloxone alone and the combined medications during the first hour of testing. Conclusions The buprenorphine and naloxone combination has a low abuse potential in opiate-dependent daily heroin users. Clinical Pharmacology & Therapeutics (1996) 60, 105–114; doi

Study objectives and design Arterial vasoconstriction is thought to play a role in the etiology of cocaine-induced cardiovascular complications, but little is known about the immediate effects of cocaine on the thoracic aorta and coronary arteries. To examine these effects, we used transesophageal echocardiography to examine the thoracic aorta and coronary arteries before and immediately after intravenous (IV) cocaine (1.2 mg/kg) in 15 subjects. Measurements and results Immediately after cocaine infusion, average heart rate, systolic BP, and double product were increased compared with baseline (22%, 15%, 35%, respectively). There was no significant change in the diameters of the ascending aorta (27.5 vs 27.1 mm; p=0.85), the descending aorta (19.8 vs 20.4 mm; p=0.62), or the left main coronary artery (4.3 vs 4.7 mm; p=0.15). However, there was a trend for an increase in coronary blood flow immediately after cocaine (226 vs 309 mL/min; p=0.10). Conclusions We conclude that in the 15 subjects studied, there was no evidence of thoracic aorta or coronary artery vasoconstriction immediately after IV cocaine. Instead, we found that the diameters of the thoracic aorta and the left main coronary artery were unchanged, and that there was a trend for augmentation of coronary artery blood flow.

A gas chromatographic method for the simultaneous determination of methamphetamine and its metabolite amphetamine in human plasma and urine is described. The method utilizes reductive alkylation with propionaldehyde and sodium borohydride to produce N-propyl derivatives, which have excellent chromatographic properties. Structural analogs of the analytes, p-methylmethamphetamine and p-methylamphetamine, are used as internal standards. The method has good precision and accuracy for concentrations ranging from less than 10 ng/ml to 5000 ng/ml and has been used to measure plasma concentrations as part of a pharmacokinetic/pharmacodynamic study of methamphetamine in humans.

Background Case reports and series indicate that ketamine, an anesthetic agent, causes lower urinary tract symptoms (LUTS). This study explored whether ketamine users were more likely to report LUTS compared to other substance users. Methods Participants were recruited through an online survey on erowid.org, a drug information website. A notice posted on the website invited substance users to participate in a web-based survey on “drug use and health”. The notice did not mention ketamine, or other aspects of the research questions, to avoid participation bias. The anonymous survey collected demographics, drug use history, and history of LUTS (urinary frequency, urgency, incontinence, hematuria, and dysuria). Results Of 18,802 participants, 18.7% and 5.8% reported ever (lifetime) and recent (past-6-month) use of ketamine, respectively. Prevalence of LUTS among ever, recent, and never users of ketamine were 28%, 30%, and 24% respectively. Multivariate analysis showed significant associations between recent ketamine use and urinary symptoms. For each additional day of ketamine use in the last 180 days, the odds of developing urinary frequency, urgency, dysuria, and hematuria increased by 1.6%, 1.4%, 1.7%, and 1.9% respectively. One excess case of urinary frequency was reported per 17 recent users of ketamine. Conclusion Compared to non-users, recent ketamine users had increased odds of LUTS. This is the first large-scale community-based study assessing the association of non-medical ketamine use with LUTS. Associations between ketamine and urological symptoms should be confirmed through longitudinal studies.

Antipsychotic medications, which comprise one of the most widely prescribed medication classes, have proven effective in many psychiatric conditions. However, these agents can also be associated with obesity and other metabolic abnormalities, the mechanisms of which have been partially elucidated. We review here the current state of knowledge of the effects of these medications on weight and appetite, as well as genetic markers that may help predict weight gain and prevent the undesirable cardiometabolic effects of these agents. Clinical Pharmacology & Therapeutics (2011) 90 1, 179–183. doi:10.1038/clpt.2011.97

Ethanol alters the hepatic biotransformation of cocaine, resulting in transesterification to a novel active metabolite, cocaethylene. Because of first pass metabolism, oral drug administration might be expected to produce relatively larger concentrations of cocaethylene than would intravenous or smoked administration. We, therefore, compared the effects of route of cocaine administration on the formation and elimination of cocaethylene. Six experienced cocaine users were tested in 6 sessions, approximately 1 week apart. Deuterium-labeled cocaine (d₅) was administered in all conditions. Oral cocaine-d₅ 2.0 mg/kg, intravenous cocaine-d₅ 1.0 mg/kg, and smoked cocaine-d₅ (200 mg) were administered after oral ethanol 1.0 g/kg or placebo. A small, intravenous dose of deuterated cocaethylene (d₃) also was administered with all conditions for determination of cocaethylene formation. Physiologic and subjective effects were recorded and plasma cocaine-d₅, cocaethylene-d₅, cocaethylene-d₃, and benzoylecgonine-d₅ were measured by gas chromatography-mass spectrometry. About 24% (± 11) of intravenous cocaine was converted to cocaethylene. The oral route (34% ± 20) was significantly greater than from the smoked route (18% ± 11) and showed a trend toward significance for greater formation of cocaethylene compared to the intravenous route. Within each route, the cocaine-ethanol combination produced greater increases in heart rate and rate-pressure product than cocaine alone. Global intoxication effects across time after smoking or intravenous administration were significantly greater when cocaine and ethanol were both given. Administration of cocaine by different routes alters the amount of cocaethylene formed through hepatic first-pass effects. Increased cardiovascular and subjective effects might explain the toxicity and popularity of the combined drugs.

Qualitative urinalysis can verify abstinence of drug misuse but cannot detect changes in drug intake. For drugs with slow elimination, such as methamphetamine (MA), a single episode of abuse can result in up to 5 days of positive urine drug screens. Thus, interventions that produce substantial decreases in drug use but do not achieve almost complete abstinence are classified as ineffective. Using nonpharmacologic doses of deuterium-labeled l-methamphetamine (l-MA-d(3)) we have developed a simple, robust method that reliably estimates changes in MA intake. Twelve subjects were dosed with 5 mg of l-MA-d(3) daily and challenged with 15, 30, and 45 mg of nonlabeled d-MA (d-MA-d(0)) after reaching plasma steady status of l-MA-d(3). Urinary concentration ratios of d-MA-d(0) to l-MA-d(3) provided clear separation of the administered doses with as little as 15-mg dose increments. Administered doses could not be resolved using d-MA-d(0) concentrations alone. In conclusion, the urinary [d-MA-d(0)]:[l-MA-d(3)] provides a quantitative, continuous measure of illicit MA exposure. The method reliably detects small, clinically relevant changes in illicit MA intake from random urine specimens, is amenable to deployment in clinical trials, and can be used to quantify patterns of MA abuse.

Potential complications of prescription opioid use include abuse and constipation. 6β-Naltrexol (6βNTX), a neutral opioid antagonist, may alleviate these complications when co-formulated with μ-opioid analgesics. In a double-blind ascending dose study, four subjects on methadone maintenance received 6βNTX (0.05, 0.15, 0.50 and 1.0 mg). 6βNTX was generally well tolerated; three of four subjects reported willingness to take higher doses. Increased gastrointestinal activity was evidenced by decreased oral-cecal transit time and prompt laxation at higher doses.

Sixty treatment-seeking individuals with methamphetamine (MA) dependence entered a randomized, placebo-controlled, double-blind clinical trial of oral dextroamphetamine (d-AMP) as a replacement therapy for MA dependence. The subjects took 60 mg sustained-release d-AMP for 8 weeks, during which time they received eight 50-min sessions of individual psychotherapy. Adverse events and urine toxicology for MA were assessed two times a week. There were no serious adverse events. Urine samples containing 0.05). However, withdrawal and craving scores were significantly lower in the d-AMP group (P < 0.05 for both). Although subjects taking d-AMP did not reduce their use of MA, the significant reductions observed in withdrawal and craving scores in this group support the need for further exploration of d-AMP as a pharmacologic intervention for MA dependence, possibly at higher doses.

Background The mechanisms of drug-induced visions are poorly understood. Very few serotonergic hallucinogens have been studied in humans in decades, despite widespread use of these drugs and potential relevance of their mechanisms to hallucinations occurring in psychiatric and neurological disorders. Methodology/Principal Findings We investigated the mechanisms of hallucinogen-induced visions by measuring the visual and perceptual effects of the hallucinogenic serotonin 5-HT2AR receptor agonist and monoamine releaser, 3,4-methylenedioxyamphetamine (MDA), in a double-blind placebo-controlled study. We found that MDA increased self-report measures of mystical-type experience and other hallucinogen-like effects, including reported visual alterations. MDA produced a significant increase in closed-eye visions (CEVs), with considerable individual variation. Magnitude of CEVs after MDA was associated with lower performance on measures of contour integration and object recognition. Conclusions/Significance Drug-induced visions may have greater intensity in people with poor sensory or perceptual processing, suggesting common mechanisms with other hallucinatory syndromes. MDA is a potential tool to investigate mystical experiences and visual perception. Trial Registration Clinicaltrials.gov NCT00823407

Rationale Salvinorin A (SA) is a highly selective kappa opioid receptor agonist and the putative psychoactive compound in Salvia divinorum (SD), an increasingly abused hallucinogenic plant. Objectives The objectives of this study were to characterize the physiological and subjective effects of SA versus placebo and measure drug and metabolite levels. Methods Sublingual SA doses up to 4 mg were administered in dimethyl sulfoxide/polyethylene glycol 400 solution to eight SD-experienced subjects using a placebo-controlled ascending-dose design. Results No dose of SA produced significantly greater physiological or subjective effects than placebo. Furthermore, effects did not resemble reported “typical” effects of smoked SD. SA was detectable in plasma and urine, but was, in most cases, below the reliable limit of quantification (0.5 ng/mL). Conclusions Our results suggest that the sublingual bioavailability of SA is low. Higher doses, alternate formulations, or alternate routes of administration will be necessary to study the effects of SA in humans.

All addictive drugs produce tolerance and addicts compensate by increasing drug exposure. Thus, the quantity of illicit drug ingested is related to the severity of addiction. Unfortunately, there are no objective methods to estimate intake for most addictive drugs. Using experimenter-administered doses of deuterium-labeled R-methamphetamine (R-[-]-MA-d3), we have developed a method to estimate the amount of abused methamphetamine intake in addicts enrolled in clinical trials. This study assessed the pharmacokinetics, pharmacodynamics, and tolerability of single oral doses of R-MA in healthy adults to select a dose of R-MA-d3 to be used as a biomarker for estimation the amount of methamphetamine abuse. This was a five-session randomized, double-blind, placebo-controlled, balanced crossover study in eight subjects. Oral R-(-)-MA was dosed at 0 mg, 1 mg, 2.5 mg, 5 mg, or 10 mg; bioavailability was estimated by slow intravenous dosing (30 minutes) of 2.5 mg R-(-)-MA-d3 given with the 2.5 mg R-(-)-MA oral dose condition. Pharmacokinetic and pharmacodynamic measures were obtained. No serious adverse events occurred during the study and all doses of R-MA were well tolerated. Linear pharmacokinetics was observed within our oral dose range of 1 to 10 mg. Complete bioavailability and pharmacologic inactivity were found for all oral doses. These characteristics indicate the advantage of using a small oral R-(-)-MA-d3 dose as a biomarker to estimate exposure to abused methamphetamine. Based on these results, 5 mg R-(-)-MA-d3 has been selected as the biomarker dose in future studies. Preliminary findings from our study indicate that experimenter-administered oral R-(-)-MA-d3 may allow estimation of abused methamphetamine intake and exposure. Knowledge of the quantity of methamphetamine intake may allow better estimation of disease severity and treatment efficacy. Experience gained from this study also can be applied to the management of other drug dependence problems such as cocaine, cannabinoid, and opiate addiction.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Methamphetamine (MA) is a chiral compound. • The S-(+) enantiomer is more commonly abused and is more potent in producing central nervous system and cardiovascular effects than the R-(−) enantiomer. • Studies describing the metabolism of MA have mainly been done with the S-(+)-isomer; pharmacokinetic data for R-(−)-MA or racemic MA are very limited. WHAT THIS STUDY ADDS • Stereoselectivity exists in the metabolism of MA. • Urinary excretion of para hydroxymethamphetamine (pOH-MA) was found to be least affected by stereoselectivity. • It is suggested that pOH-MA may be a more stable biomarker of MA abuse. AIM To characterize the formation and urinary elimination of metabolites of S-(+) and R-(−) methamphetamine (MA) in humans. METHODS In this 12-subject, six-session, double-blind, placebo-controlled, balanced, crossover design study, the formation of the MA metabolites para hydroxymethamphetamine (pOH-MA) and amphetamine (AMP) were determined in urine after intravenous doses of S-(+)-MA 0.25 and 0.5 mg kg−1, R-(−)-MA 0.25 and 0.5 mg kg−1, racemic MA 0.5 mg kg−1, or placebo. Parent drug and metabolite levels in urine and plasma were measured by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by noncompartmental models using WinNonlin. RESULTS An approximately threefold enantioselectivity difference in elimination was observed for AMP, with 7% of the dose converted to S-(+)-AMP vs. 2% to R-(−)-AMP (P < 0.001). Furthermore, less R-(−)-pOH-MA was excreted in the urine compared with S-(+)-pOH-MA (8% vs. 11%, P= 0.02). Correspondingly, S-(+)-MA excretion was less than R-(−)-MA (42% vs. 52%; P= 0.005). CONCLUSIONS The metabolism of MA is enantioselective, with formation of AMP having the highest isomer selectivity. A greater percentage of MA is converted to pOH-MA (8–11%) than AMP (2–7%). The formation of pOH-MA was less affected by the MA enantiomer administered, suggesting that urine pOH-MA may be a more stable biomarker of MA metabolism.

Background There is growing use of Salvia divinorum (SD), a psychoactive plant that produces hallucinogen-like effects through a kappa opioid receptor (KOR) mechanism. Little is known about KOR agonist effects in humans and about users of SD. Objectives To characterize the reasons, methods, and reported consequences of SD use. Methods Individuals reading SD-related pages of a drug-information website were invited to anonymously complete an online questionnaire if they had used SD. Results Participants (N = 500) were 92.6% male and 23.4 ± 8.7 (mean ± s.d.) years old. They had used a median of six times (range 1–250). 80.6% probably or definitely would use SD again. Most participants (92.6%) typically smoked or vaporized SD product. When smoked, the drug's main effects were estimated to last 14.1 ± 12.8 (range 0.5–120) minutes. When asked to compare SD effects to other methods of altering consciousness, the most common answer was that SD was unique (38.4%). 25.8% reported persisting (≥24 h) positive effects (often described as increased sense of well-being) on at least one occasion. 4.4% reported persisting negative effects (most often anxiety). Conclusions SD is typically smoked, acute effects are brief, and persistent adverse effects are uncommon. In addition to acute hallucinogenic effects, SD may produce subacute increases in subjective well-being. Such a subacute effect would be unusual for a drug that is used non-medically, as withdrawal from other drugs typically either does not affect mood or causes dysphoria. Findings from this convenience sample should be confirmed and extended using surveys of random samples and controlled clinical studies.

Dependence on and abuse of prescription opiate drugs is now a major health problem with initiation of prescription opiate abuse exceeding cocaine in young people. Coincident with the emergence of abuse and dependence on prescription opiates there has been an increased emphasis on the treatment of pain. Pain is now the “5th vital sign” and physicians face disciplinary action for failure to adequately relieve pain. Thus, physicians are whipsawed between the imperative to treat pain with opiates and the consequences of producing addiction in some patients. Novel approaches are needed to allow appropriate prescribing yet diminish the risk of iatrogenic addiction. In this chapter, we propose a method to develop opioid medications that are resistant to drug abuse and show reduced adverse effects. Among the various strategies to reduce addiction liability, the addition of small doses of an opioid antagonist has received recent attention. This is done with the expectation that the antagonist does not affect the analgesic actions if the combination is given for therapeutic purposes, but will accumulate and then block the opioid effects when the drug is abused — either in high oral doses or by intravenous administration. However, opioid antagonist engender strong adverse effects in opioid-dependent and tolerant subjects. Our method emerges from recent advances in our understanding of the molecular pharmacology of opioid receptors, whereby antagonist can be classified into inverse agonists (e.g., naltrexone) that block basal receptor activity, and neutral antagonists (e.g., 6β-naltrexol) that block only the agonist-stimulated effects — thereby causing less withdrawal effects. Preclinical results indicate that 6β-naltrexol (a main metabolite of naltrexone) has all the desired pharmacokinetic and pharmacodynamic attributes as an ideal candidate for such a combination therapeutic, potentially yielding a significant advance in pain therapy with opiates. In this chapter, we review the evidence for the unfolding prescription opiate epidemic and describe the potential of 6β-naltrexol, a neutral opiate antagonist, in limiting maximal μ-agonist effects of oral opiate analgesics.

BackgroundWe studied the pharmacology of l-methamphetamine, the less abused isomer, when used as a nasal decongestant.Methods12 subjects self-administered l-methamphetamine from a nonprescription inhaler at the recommended dose (16 inhalations over 6 hours) then at 2 and 4 (32 and 64 inhalations) times this dose. In a separate session intravenous phenylephrine (200 microg) and l-methamphetamine (5 mg) were given to define alpha agonist pharmacology and bioavailability. Physiological, cardiovascular, pharmacokinetic, and subjective effects were measured.ResultsPlasma l-methamphetamine levels were often below the level of quantification so bioavailability was estimated by comparing urinary excretion of the intravenous and inhaled doses, yielding delivered dose estimates of 74.0 +/- 56.1, 124.7 +/- 106.6, and 268.1 +/- 220.5 microg for ascending exposures (mean 4.2 +/- 3.3 microg/inhalation). Physiological changes were minimal and not dose-dependent. Small decreases in stroke volume and cardiac output suggesting mild cardiodepression were seen.ConclusionInhaled l-methamphetamine delivered from a non-prescription product produced minimal effects but may be a cardiodepressant.

Introduction: Corticosteroids may modulate addiction. We previously described subjective, physiological, and endocrine effects of 0.5 mg/kg of intravenous methamphetamine after augmenting cortisol level with hydrocortisone or blocking cortisol response with the corticosteroid synthesis inhibitor metyrapone in a double-blind, balanced crossover study. Although the pharmacologic manipulations produced the expected hormonal changes, pleasurable subjective effects of methamphetamine were unchanged. Metyrapone was followed by frequent premature ventricular complexes (PVCs) in two subjects during methamphetamine administration. In order to better understand these results, we examined changes in two plasma catecholamine metabolites, homovanillic acid (HVA) and 3-methoxy-4-hydroxyphenylglycol (MHPG), and their relationship to the previously reported hormonal changes and physiological and subjective responses. Methods: Plasma from 10 methamphetamine subjects from the earlier study was assayed for HVA and MHPG by high performance liquid chromatography. Results: HVA levels were greater after hydrocortisone or metyrapone pretreatment compared to placebo, and MHPG levels were greater after metyrapone pretreatment. Hydrocortisone pretreatment diminished HVA and MHPG increases after methamphetamine (perhaps explaining the lack of expected increase in pleasurable effects), but metyrapone did not. HVA and MHPG concentrations were not correlated with pleasurable drug effects but were inversely related to reports of "Bad Drug Effect." Increases in MHPG and DHEA concentrations were positively correlated. Metyrapone pre-treated subjects with PVCs had lower HVA and MHPG concentrations. Conclusion: Raising cortisol concentration and blocking cortisol synthesis did not produce opposite effects, perhaps because of metyrapone's effect on the hypothalamic-pituitary-adrenal axis, its stress-like effects, and its effects on neurosteroids.