Matthew J. Baggott

Buprenorphine and naloxone interactions in opiate-dependent volunteers

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.

Cardiovascular Effects of 3,4-Methylenedioxymethamphetamine: A Double-Blind, Placebo-Controlled Trial

3,4-Methylenedioxymethamphetamine (MDMA),also known as ecstasy, is a psychostimulant with structural similarities to both amphetamine and the hallucinogenic phenethylamine mescaline. 3,4-Methylenedioxymethamphetamine (and its analogues) seems to produce a spectrum of pharmacologic effects distinct from such structurally similar compounds, suggesting that MDMA may represent a new class of psychotropic agents (1-4). Use of MDMA may be increasing. Emergency department visits related to MDMA increased from 637 in 1997 to 1143 in 1998. In 1998, the estimated lifetime prevalence and annual prevalence of MDMA use, respectively, were 2.7% and 1.8% in 8th graders, 5.8% and 3.6% in 12th graders, and 7.2% and 2.9% in young adults (5). Use of MDMA has been associated with sudden death and cardiovascular collapse (6). Acute cardiovascular effects of MDMA (and its analogues) include tachycardia and hypertension (7, 8). Understanding the cardiovascular effects of MDMA may improve prediction of and intervention in cases of MDMA cardiotoxicity. The purpose of this study was to measure the acute cardiovascular effects of oral MDMA and to compare these effects with those of a well-characterized cardiostimulant, the -agonist dobutamine. The cardiovascular response to MDMA and dobutamine were measured by using quantitative two-dimensional echocardiography. Methods The study was approved by the University of California, San Francisco, Committee on Human Research and was performed under an investigational new drug (IND) protocol approved by the U.S. Food and Drug Administration (IND 53,648). All participants provided informed consent. The eight healthy paid volunteers had used MDMA at least four times in the past 3 years. At least 1 week after dobutamine echocardiography, participants were tested in 3 weekly sessions with an ascending-dose, double-blind, placebo-controlled design using orally administered MDMA hydrochloride, 0.5 mg/kg of body weight or 1.5 mg/kg, or placebo. Participants underwent a medical examination and laboratory screening tests to confirm good general health. Exclusion criteria were significant medical or psychiatric illness; dependence on drugs (except caffeine or nicotine), according to criteria defined by the Diagnostic and Statistical Manual of Mental Disorder, 4th edition; history of adverse reactions to study drugs or recent use of psychoactive drugs; cardiovascular risk factors (total cholesterol level>6.48 mmol/L [250 mg/dL] or smoking>2 packs of tobacco cigarettes per day); deficient cytochrome P450 2D6 activity (assessed by using dextromethorphan phenotyping); or inability to give informed consent. Women were required to have negative results on a serum pregnancy test (Unilab, San Jose, California) on admission to the study and negative results on a urine pregnancy test (TestPack Plus, Abbott Laboratories, Abbott Park, Illinois) before each MDMA session. Participants were asked to refrain from use of illicit psychoactive drugs for at least 7 days and ethanol for at least 48 hours before testing. Nicotine and caffeine were restricted during MDMA sessions until 8 hours after drug administration and were otherwise not allowed within 30 minutes of any measure. To rule out recent psychoactive drug use, qualitative urinalysis (Unilab, San Jose, California) was performed the day before MDMA sessions and on each day that data were collected. Dobutamine hydrochloride (Dobutrex, Lilly, Indianapolis, Indiana) was administered in ascending doses of 5, 20, and 40 g/kg per minute. Doses were delivered intravenously and increased every 5 minutes until the dose of 40 g/kg per minute was completed. Heart rate, systolic blood pressure, and diastolic blood pressure were obtained before MDMA administration and at 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 7, and 8 hours after MDMA administration. The ratepressure product (heart rate systolic blood pressure) was calculated. Metabolite and MDMA pharmacokinetics, neuroendocrine measures, subjective mood ratings, and structured psychiatric measurements are reported in detail elsewhere (Jones and colleagues. In preparation). Echocardiography was performed 1 hour after MDMA administration by using a commercially available Doppler echocardiography machine (Sequoia, Acuson, Mountain View, California). End-diastolic and end-systolic volumes were calculated by using the bi-plane method of discs (9). From these measurements, standard calculations of stroke volume, ejection fraction, and cardiac output were made. Meridional systolic wall stress was calculated by using previously defined formulas (10). The response to MDMA (0.5 mg/kg, 1.5 mg/kg, or placebo) was compared with the response to dobutamine (5, 20, and 40 g/kg per minute) by using repeated-measures analysis of variance. Drug condition and observation times were considered within-participant factors. After a significant F test, pairwise comparisons were performed by using the least-squares means analysis. Effects were considered statistically significant at a Pvalue less than or equal to 0.05. Data were adjusted for sphericity by using the HuynhFeldt adjustment factor. The funding sources had no role in the collection, analysis, or interpretation of the data or in the decision to submit the manuscript for publication. Results The mean age (SD) of the five men and three women who completed the study was 29 5 years (range, 24 to 39 years). The participants had reportedly used MDMA 49 65 times (range, 5 to 200 times). After completing part of the first MDMA session, one additional participant chose to withdraw from the study because of professional obligations. Data from this participant are excluded from analysis. Peak hemodynamic effects (defined as the maximal observed value) occurred 1 to 1.5 hours after MDMA administration. Because all echocardiograms were obtained at least 1 hour after the MDMA dose and required approximately 15 minutes to complete, we used peak hemodynamic effects for comparison with echocardiographic data. Except for diastolic blood pressure, there were no significant differences between the peak hemodynamic effects and those measured 1 hour after administration of MDMA. Although diastolic blood pressure 1 hour after administration of 1.5 mg/kg of MDMA was statistically less than the peak (69 5 mm Hg vs. 76 10 mm Hg; P<0.01), the absolute magnitude was small and does not substantially change the results. The cardiovascular effects of MDMA and dobutamine are summarized in the Table. Table. Comparative Cardiovascular Effects of MDMA and Dobutamine in Eight Participants We found that MDMA, 1.5 mg/kg, and dobutamine, 20 and 40 g/kg per minute, increased heart rate (by 28 beats/min), systolic and diastolic blood pressures (by 25 mm Hg and 7 mm Hg, respectively), and ratepressure product, whereas MDMA, 0.5 mg/kg, and dobutamine, 5 g/kg per minute, did not. Peak heart rate changes after administration of MDMA or dobutamine are shown in the top part of the Figure. The peak increases in heart rate, systolic blood pressure, and ratepressure product after 1.5 mg/kg of MDMA were significantly greater than after 20 g/kg per minute of dobutamine but less than after 40 g/kg of dobutamine. Figure. Comparison of the effects of dobutamine or 3,4-methylenedioxymethamphetamine ( MDMA ) on peak heart rate ( top ), cardiac output ( middle ), and ratio of meridional wall stress to ejection fraction ( bottom ). Changes in cardiac output after administration of MDMA or dobutamine are shown in the middle part of the Figure. We found that 1.5 mg/kg of MDMA and 20 and 40 g/kg per minute of dobutamine increased cardiac output, but 0.5 mg/kg of MDMA and 5 g/kg per minute of dobutamine did not. The increase of 2 L/min in cardiac output after 1.5 mg/kg of MDMA was similar to that after 20 g/kg per minute of dobutamine but less than that after 40 g/kg per minute of dobutamine. Neither dobutamine nor MDMA changed left ventricular end-diastolic volume. Consistent with its inotropic properties, dobutamine decreased left ventricular end-systolic volume and produced dose-dependent increases in ejection fraction. In contrast, neither dose of MDMA significantly decreased end-systolic volume. Consequently, ejection fraction was unchanged after MDMA administration. Meridional wall stress was used to compare the inotropic effects of MDMA and dobutamine by correcting for ejection fraction. Meridional wall stress did not change significantly with any dose of either agent. Consistent with the inotropic properties of dobutamine, the ratio of meridional wall stress to ejection fraction progressively decreased with each successive dobutamine dose and was significantly reduced at a dose of 40 g/kg per minute. This variable was unchanged with either dose of MDMA (Figure, bottom). Subjective effects of MDMAfeelings of relaxation, well-being, and improved moodreached their maximum between 1.5 and 3 hours. Most participants felt that 0.5 mg/kg of MDMA produced very weak effects (although two felt that it was of medium strength), whereas 1.5 mg/kg was considered a medium to somewhat strong dose. Further details on the pharmacokinetic and dynamic effects of MDMA will be reported elsewhere (Mendelson and colleagues. In preparation). Discussion We compared the effects of a well-known cardiostimulatory -agonist to those of an uncharacterized illicit compound by using clinically validated outcome measures. Contrasting the effects of these compounds may help physicians better understand the cardiovascular risks associated with illicit MDMA use. Dobutamine and MDMA both produce dose-dependent increases in heart rate, blood pressure, and cardiac output. Although both compounds are cardiostimulants, dobutamine has positive inotropic effects whereas MDMA has no measurable inotropic effects. In the absence of inotropism, incremental increases in afterload produce proportional increases in force or tension per unit of cross-sectional area of the ventricular wall. This i

Buprenorphine and naloxone combinations: the effects of three dose ratios in morphine-stabilized, opiate-dependent volunteers.

Abstract 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.

Use of salvia divinorum, an unscheduled hallucinogenic plant: a web‐based survey of 500 users

Salvia divinorum (SD) is a legal psychoactive plant that produces hallucinogen‐like effects through a putative kappa opiate mechanism. We characterized the reasons, methods, and reported consequences of SD use in a sample of 500 users (92.6% male, 23.4±8.7, range 13–68 years) with an on‐line questionnaire. They had used 13.3±22.9 (range 1–250) times, usually to explore altered consciousness or to have a spiritual/mystical experience. 80.6% probably or definitely would use SD again. 92.6% smoked SD with 61.4% using a concentrated extract and 37.3% using dried leaf; effects were estimated to last 14.1±12.8 minutes. Compared to other methods of altering consciousness, SD effects were felt to be unique. Common (>25%) after‐effects of SD included feelings of increased insight (47%), improved mood (44.8%), calmness (42.2%), increased sense of connection with the universe or nature (39.8%), weird thoughts (36.4%), things seem unreal (32.4%), floating feeling (32%), increased sweating (28.2%) and body felt warm or hot (25.2%). 25.8% reported persisting (>24 hr) positive effects (usually an increased sense of well‐being) on at least 1 occasion. 4.4% had persisting negative effects (most often anxiety). 0.6% had sought professional help for a SD‐related problem. At some point, 0.6% felt addicted to or dependent upon SD; 1.2% reported strong cravings for SD; 0.4% endorsed three DSM‐IV dependence criteria. We conclude that SD is commonly used and merits further study.

Estimating the intake of abused methamphetamines using experimenter-administered deuterium labeled R-methamphetamine: selection of the R-methamphetamine dose.

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.

Effects of 3,4-methylenedioxymethamphetamine on socioemotional feelings, authenticity, and autobiographical disclosure in healthy volunteers in a controlled setting

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.

The effects of inhaled L-methamphetamine on athletic performance while riding a stationary bike: a randomised placebo-controlled trial

Objective: L-methamphetamine (the non-abused isomer of methamphetamine) is banned in athletic competition because it may improve athletic performance, but there are no studies assessing its effects on performance. In the United States L-methamphetamine is formulated in the non-prescription Vick’s Vapor Inhaler (VVI) nasal decongestant. VVIs sold elsewhere (we used ones from the UK) contain similar inactive ingredients (menthol, camphor and Siberian pine oil) but no L-methamphetamine. This study tested the effects of inhaled L-methamphetamine delivered from a widely available non-prescription product on athletic performance. Design: In a 2-session double-blind placebo-controlled study 12 participants (ages 14–17) were dosed with 4 (session 1) and 12 (session 2) inhalations from VVIs with (USA) or without (UK) L-methamphetamine and then performed two 20 minute rides on a stationary bike with rides separated by a 30 minute rest. Outcome measure: The main outcome measure was miles travelled during each 20 minute ride. Secondary outcome measures included postride urine toxicology; heart rate and blood pressure before, 1, 5 and 10 minutes postride; energy, performance, endurance, and ability to breathe; and VVI preference. Data were analysed using Excel statistical macros. Results: After ∼16 μg L-methamphetamine distance travelled was 5.26 (SD 0.53) miles vs 5.30 (0.55) with placebo; p = 0.81. After ∼48 μg L-methamphetamine distance travelled was 5.30 (0.51) vs 5.35 (0.43) with placebo; p = 0.85. The ∼16 μg dose increased systolic blood pressure from 72.6 (4.3) to 79.6 (6.6) mm Hg (p = 0.03) at 5 minutes postride but there were no other differences in outcomes. Conclusions: Modest doses of inhaled L-methamphetamine probably do not improve athletic performance but do minimally raise diastolic blood pressure.

Developing biomarkers for methamphetamine addiction.

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.

MDMA Impairs Response to Water Intake in Healthy Volunteers.

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.

A Method to Quantify Illicit Intake of Drugs from Urine: Methamphetamine

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-d3) we have developed a simple, robust method that reliably estimates changes in MA intake. Twelve subjects were dosed with 5 mg of l-MA-d3 daily and challenged with 15, 30, and 45 mg of nonlabeled d-MA (d-MA-d0) after reaching plasma steady status of l-MA-d3. Urinary concentration ratios of d-MA-d0 to l-MA-d3 provided clear separation of the administered doses with as little as 15-mg dose increments. Administered doses could not be resolved using d-MA-d0 concentrations alone. In conclusion, the urinary [d-MA-d0]:[l-MA-d3] 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.