Marijuana and cocaine interactions in humans: cardiovascular consequences

Seven adult male volunteers residing on a research ward received intravenous cocaine and smoked marijuana, alone and in combination, during daily experimental sessions. Following the determination of baseline cardiovascular indexes, a one gram marijuana cigarette (0-2.7% delta 9-THC w/w) was smoked. Cocaine hydrochloride (0-32 mg) was administered intravenously 13 minutes after the start of marijuana smoking. Cocaine alone produced dose-dependent increases in heart rate, while both low and high THC blood levels produced a similar increase in heart rate. Both doses of cocaine increased mean arterial pressure (MAP) similarly, while THC alone produced blood level dependent increases in MAP. Combinations of cocaine and marijuana increased heart rate above levels seen with either drug alone, with increases plateauing at nearly 50 bpm for all dose-blood level combinations. Increases in mean arterial pressure following combinations of cocaine and marijuana were equivalent to those produced by cocaine alone.     

Ethanol and cocaine interactions in humans: cardiovascular consequences

Intranasal cocaine (COC) and oral ethanol (ETOH) were administered to nine research volunteers during daily experimental sessions. Following the determination of baseline cardiovascular indexes, an ETOH cocktail (0, 19.4, 38.7, or 58.1 g of ETOH in lemonade) was consumed over a ten-minute period. Cocaine hydrochloride (4, 48, 96 mg) was inhaled 25 minutes after the start of ETOH drinking. Breath samples were collected 50 minutes after the start of ETOH drinking to estimate blood alcohol level (BAL). The effect of these doses, alone and in combination, on heart rate (HR) and blood pressure (BP), while resting and while performing a serial acquisition task, were determined. COC and ETOH alone significantly increased HR up to 6 bpm without affecting BP. Combining the two highest doses of COC with the highest BAL increased HR by 20 bpm. During task performance, in the absence of drug, HR was increased up to 5 bpm, and BP was unchanged. Combining the highest COC dose and BAL with task performance increased HR by 40 bpm. Small increases in BP were also observed under these conditions. These results indicate that combinations of ETOH, COC and task performance produce greater increases in HR than BP, and, in addition, this increase in HR is greater than that observed following COC, ETOH, or task performance alone.     

Effects of marijuana on the task-elicited physiological response

Ten healthy male marijuana users smoked either a placebo or active (1.8% delta 9-THC) marijuana cigarette during five daily testing sessions. Ten minutes after drug administration, six subjects (Group I) performed a 10-min serial acquisition task and four subjects (Group II) rested quietly. Blood pressure was sampled at 2-min intervals and heart rate (HR) was recorded continuously. Marijuana alone increased HR by 18 beats/min and mean arterial pressure (MAP) by 3 mmHg, while task performance alone increased HR by 4 beats/min and MAP by 5 mmHg. The combination of drug and task performance had greater cardiovascular effects than either task performance or marijuana alone, with HR increased by 29 beats/min and MAP increased by 15 mmHg. These results suggest that marijuana smoking may increase cardiovascular responsivity.     

Effects of smoked marijuana on heart rate, drug ratings and task performance by humans

Six subjects, reporting marijuana use between two and 30 times per month, participated in studies of the acute effects of smoked marijuana (0.0%, 2.0% and 3.5% Delta(9)-THC, w/w) on heart rate, ratings of drug effect and task performance. Marijuana was administered using a uniform-puffing procedure with monetary contingencies associated with puff and breathhold duration. In general, heart rate and ratings, of "High" and dose "Potency" were increased by marijuana, and performance on some tasks was altered by drug administration. The relative sensitivity of the measures varied across subjects, and no single measure, such as heart rate or verbal rating of drug effect, could be used to predict the behavioral effects of marijuana. Marijuana puff durations were decreased at the highest dose, but dose-related changes in heart rate and task performance indicated that the change in smoking topography did not result in complete compensation for increased cannabinoid concentrations in marijuana smoke.     

Gabapentin maintenance decreases smoked cocaine-related subjective effects, but not self-administration by humans

Data from research with laboratory animals indicate that cocaine self-administration can be reduced by lambda-aminobutyric acid (GABA) agonists. Yet, the effectiveness of GABA agonists to decrease human cocaine self-administration has not been investigated under controlled laboratory conditions. The purpose of this study was to assess the effects of gabapentin, a GABA agonist, on cocaine-related behaviors, including self-administration, in human research participants under controlled laboratory conditions. During this 48-day double-blind, crossover design study, the effects of gabapentin (0, 600, and 1200 mg/d) maintenance on response to cocaine (0, 12, 25, and 50 mg) were investigated in seven cocaine abusers. Active cocaine significantly increased choice to self-administer cocaine, subjective-effect ratings (e.g., "Good Drug Effect"), blood pressure and heart rate (HR). Gabapentin did not reduce cocaine choice or cardiovascular measures, but it did decrease some subjective effects of cocaine (e.g., "Good Drug Effect" and "Anxious"). These data suggest that the cocaine-gabapentin combination was well-tolerated, and because some cocaine-related subjective effects were reduced by maintenance on relatively low gabapentin doses, future studies should test higher gabapentin doses.     

Self-administration of heroin, cocaine and their combination under a discrete trial schedule of reinforcement in rats

Several self-administration models have been used to study the interactions between cocaine and heroin, and the schedule of reinforcement used is an important consideration for these studies. Behavior maintained by cocaine, heroin or their combination was studied using a discrete trial schedule that has been described for cocaine self-administration previously. This schedule permits 24 h access to drug without mortality associated with unlimited access to cocaine, and provides unique measures related to the circadian pattern of drug self-administration. Cocaine and heroin combined maintained higher rates of responding compared to either drug alone when a maximum of three infusions were available each hour (DT3), and decreased food intake compared to cocaine alone. There were significantly greater numbers of hours in both the light and dark cycles during which animals self-administered heroin or the combination of cocaine/heroin compared to cocaine alone. When the FR was increased to 4 under the DT3 access conditions, responding maintained by cocaine or heroin extinguished to levels not different than those maintained by saline while food reinforcement remained intact. The combination of cocaine and heroin maintained robust responding under these conditions. This schedule of reinforcement appears to elucidate behavioral interactions between cocaine and heroin that are more complex than rate of drug consumption and may provide a procedure to address some of the issues related to co-abuse of these drugs.     

Effects of acute smoked marijuana on complex cognitive performance.

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

Effects of tetrahydrocannabinol content on marijuana smoking behavior, subjective reports, and performance

This study investigated the smoking topography of marijuana and its effect on heart rate, subjective reports, and cognitive/psychomotor task performance. Male subjects (N = 12) with histories of moderate marijuana use smoked ad lib one cigarette containing 0, 1.3, or 2.7% delta 9-THC on separate days. Smoking topography measures revealed smaller puff and inhalation volumes and shorter puff duration for the high marijuana dose compared to the low dose. No other smoking behavior differed between the active doses. Heart rate was increased dose dependently over placebo levels. Active marijuana also increased subjective reports of drug effect over placebo, but not dose dependently. Significant memory impairment was observed on a forward and reverse digit span task, and performance was impaired on the digit symbol substitution task by the high, but not low, dose of marijuana. Performance on a divided attention task was not affected by marijuana. Thus, although subjects adjusted their smoking of cigarettes varying in THC content, dose-related effects of marijuana were obtained on several measures. The observed differences and individual variation in smoking topography measures suggest that precise control of smoking behavior would improve the accuracy of marijuana dose delivery.     

Clonidine partially blocks the physiologic effects but not the subjective effects produced by smoking marijuana in male human subjects

Clonidine, an alpha 2-agonist, was studied in three male human subjects in a multi-dose pilot study in combination with smoking marijuana cigarettes. Marijuana alone caused increases in responses on subjective effect questionnaires and increased heart rate. Pretreatment with single oral doses of clonidine three hours prior to marijuana induced no changes in subjective effects prior to smoking marijuana and did not diminish the subjective effects produced by marijuana. Clonidine did substantially reduce but did not abolish the marijuana-induced rise in heart rate. Based on these preliminary data from three subjects, it is concluded that clonidine does not have therapeutic value in the clinical management of active marijuana abuse.     

Discriminative and reinforcing stimulus effects of nicotine, cocaine, and cocaine + nicotine combinations in rhesus monkeys

Concurrent cigarette smoking and cocaine use is well documented. However, the behavioral pharmacology of cocaine and nicotine combinations is poorly understood, and there is a need for animal models to examine this form of polydrug abuse. The purpose of this study was twofold: first to assess the effects of nicotine on the discriminative stimulus effects of cocaine, and second, to study self-administration of nicotine/cocaine combinations in a novel polydrug abuse model. In drug discrimination experiments, nicotine increased the discriminative stimulus effects of low cocaine doses in two of three monkeys, but nicotine did not substitute for cocaine in any monkey. Self-administration of cocaine and nicotine alone, and cocaine + nicotine combinations was studied under a second-order fixed ratio 2, variable ratio 16 (FR2[VR16:S]) schedule of reinforcement. Cocaine and nicotine alone were self-administered in a dose-dependent manner. The combination of marginally reinforcing doses of cocaine and nicotine increased drug self-administration behavior above levels observed with the same dose of either cocaine or nicotine alone. These findings indicate that nicotine may increase cocaine's discriminative stimulus and reinforcing effects in rhesus monkeys, and illustrate the feasibility of combining cocaine and nicotine in a preclinical model of polydrug abuse. Further studies of the behavioral effects of nicotine + cocaine combinations will contribute to our understanding the pharmacology of dual nicotine and cocaine dependence, and will be useful for evaluation of new treatment medications.     

Effects of THC and lofexidine in a human laboratory model of marijuana withdrawal and relapse

Introduction Individuals seeking treatment for their marijuana use rarely achieve sustained abstinence. Objectives The objectives of the study are to determine if THC, a cannabinoid agonist, and lofexidine, an α₂-adrenergic receptor agonist, given alone and in combination, decreased symptoms of marijuana withdrawal and relapse, defined as a return to marijuana use after a period of abstinence. Materials and methods Nontreatment-seeking, male volunteers (n = 8), averaging 12 marijuana cigarettes/day, were maintained on each of four medication conditions for 7 days: placebo, tetrahydrocannabinol (THC) (60 mg/day), lofexidine (2.4 mg/day), and THC (60 mg/day) combined with lofexidine (2.4 mg/day); each inpatient phase was separated by an outpatient washout phase. During the first three inpatient days, placebo marijuana was available for self-administration (withdrawal). For the next 4 days, active marijuana was available for self-administration (relapse). Participants paid for self-administered marijuana using study earnings. Self-administration, mood, task performance, food intake, and sleep were measured. Results THC reversed the anorexia and weight loss associated with marijuana withdrawal, and decreased a subset of withdrawal symptoms, but increased sleep onset latency, and did not decrease marijuana relapse. Lofexidine was sedating, worsened abstinence-related anorexia, and did not robustly attenuate withdrawal, but improved sleep and decreased marijuana relapse. The combination of lofexidine and THC produced the most robust improvements in sleep and decreased marijuana withdrawal, craving, and relapse in daily marijuana smokers relative to either medication alone. Conclusions These data suggest the combination of lofexidine and THC warrant further testing as a potential treatment for marijuana dependence.     

Behavioral and subjective effects of marijuana following partial sleep deprivation

This study tested whether performance would be more impaired when marijuana use followed partial sleep deprivation (PSD) than when marijuana use followed a typical night of sleep. Seven recreational marijuana users (mean 15 of last 30 days) completed six test sessions in a double-blind randomized within-subject design. Each session began with an overnight stay in a sleep laboratory. Bed and wake times were calculated from mean data on individual sleep diaries. Time-in-bed was either regular (mean=8.2 h) or shortened (first 65% of regular time-in-bed deprived). At 3 and 5 h after waking, daytime sleepiness was measured with self-report questionnaires and a sleep latency test. Approximately 6.5 h after waking, subjects smoked a marijuana cigarette (0.003, 2, or 3.5% delta-9 tetrahydrocannabinol [THC]). Test batteries were completed 2, 62, and 122 min after smoking ended. Sleepiness was significantly greater following PSD than after regular sleep. Following regular sleep, heart rate increases with active THC doses were comparable, but heart rate with 2% THC was significantly less elevated following PSD. Ratings of ‘impaired’ and ‘stoned’ increased with both THC doses after regular sleep and were further increased with 3.5% THC after PSD. High-potency marijuana increased body sway similarly across sleep conditions. There were no significant effects of marijuana or PSD, alone or in combination, on brake latency. Thus, while PSD increased the dose-dependence of THC effects on heart rate and subjective impairment, it did not enhance the effects of marijuana on standing balance and brake latency.     

Voluntary self-administration of both morphine and cocaine by rats

Voluntary self-administration of cocaine and/or morphine was studied in rats. Male rats were offered water bottles or bottles containing either cocaine or morphine, both cocaine and morphine (combination) or cocaine and morphine as a mixture. Alternating the three drug-containing bottles had no effect on drug choice. When offered alone, rats consumed about 12 +/- 8 mg/kg/day of cocaine or 0.3 +/- 0.3 mg/kg/day of morphine. When both drugs were offered in combination, they consumed a higher amount of cocaine (22 +/- 7), but the same amount of morphine (0.4 +/- 0.3). Availability of cocaine/morphine mixture kept morphine consumption constant (0.3 +/- 0.1), but markedly decreased cocaine intake (0.3 +/- 0.2). Addition of saccharin to the drug solutions only slightly increased consumption of both drugs, whereas saccharin added as a competitor or distracter to the drug solution reduced cocaine but not morphine self-administration. Animals showed wide interindividual variations but surprisingly small intraindividual variations in self-administration of cocaine or morphine under all conditions. No correlation between cocaine and morphine intake was apparent in the combination situation. Forcing animals first with cocaine had no effect on subsequent intake of cocaine or morphine presented in combination. However, forcing animals first with morphine subsequently increased morphine and reduced cocaine intake. In conclusion, morphine intake was the same if offered alone, in combination or as a mixture, whereas cocaine intake increased during a combination but decreased in the mixture situation. Cocaine pre-exposure had no effect on subsequent voluntary morphine or cocaine choice, whereas morphine pre-exposure increased subsequent voluntary morphine but decreased cocaine intake. These results suggest the possibility of two reward centers, one for each drug, the morphine center exerting a dominant influence over the cocaine center.     

Acute and residual effects of marijuana: profiles of plasma THC levels, physiological, subjective, and performance measures

Three experienced marijuana smokers participated in four 2-day experimental sessions in which they smoked either 0, 1, or 2 marijuana cigarettes containing 2.57% delta 9-tetrahydrocannabinol (THC) at two different times on the first day. A battery of physiological, subjective, and performance measures was repeated throughout day 1 to assess acute effects and on day 2 to measure any residual effects of marijuana. Blood samples were also repeatedly collected to examine the relationship between plasma levels and pharmacological effects of THC. Acutely, marijuana increased heart rate and subjective ratings of drug effects and slightly impaired performance on a circular lights task in all subjects. Performance was also impaired (decreased accuracy and increased response time) on serial addition/subtraction and digit recall tasks on day 1 in two subjects. On day 2, tachycardia and subjective effects of marijuana were not observed. Performance remained impaired on the arithmetic and recall tasks on day 2, although the decrements were not as large as those observed on day 1. In general, plasma THC levels covaried with the other measures. These preliminary results suggest that marijuana can adversely affect complex human performance up to 24 hours after smoking.     

Comparative effects of cocaine and pseudococaine on EEG activities,cardiorespiratory functions,and self-administration behavior in the rhesus monkey

The effects of cocaine and pseudococaine on the EEGs, heart and respiratory rates, and self-administration behavior were studied in rhesus monkeys. An intravenous injection of cocaine (2.5 and 4.0 mg/kg) in the monkey produced low-voltage fast waves (LVFWs) in the EEGs and behavioral hyperexcitation accompanied by marked increases in the heart and respiratory rates with mydriasis and excessive salivation. In contrast, pseudococaine produced high-voltage slow waves (HVSWs) in the EEGs and behavioral depression accompanied by the same symptoms of the autonomic functions as those produced by cocaine. Both isomers were self-administered by the monkeys. During cocaine self-administration sessions, the animals showed hyperexcitation in their overall behavior, while with pseudococaine thay showed almost normal behavioral responses. These results suggest that cocaine produced excitatory effects and pseudococaine inhibitory effects on the EEGs and behavior. Both isomers stimulate the heart and respiratory rates, and were self-administered by the monkeys.     

Reinforcing and subjective effects of oral Δ9-THC and smoked marijuana in humans

The reinforcing and subjective effects of oral delta-9-tetrahydrocannabinol (THC) and smoked marijuana were studied in two groups of regular marijuana users. One group (N=10) was tested with smoked marijuana and the other (N=11) with oral THC. Reinforcing effects were measured with a discrete-trial choice procedure which allowed subjects to choose between the self-administration of active drug or placebo on two independent occasions. Subjective effects and heart rate were measured before and after drug administration. Smoked active marijuana was chosen over placebo on both choice occasions by all subjects. Similarly, oral THC was chosen over placebo on both occasions by all but one subject. Both active drug treatments produced qualitatively and quantitatively similar subjective effects, and both significantly increased heart rate, although the time course of effects differed substantially between the two treatments. The results demonstrate that both smoked marijuana and oral THC can serve as positive reinforcers in human subjects under laboratory conditions. The experimental paradigm used here should prove useful for identifying factors that influence the self-administration of marijuana and other cannabinoids by humans.     

Opioid and cocaine combined effect on cocaine-induced changes in HPA and HPG axes hormones in men

Nalbuphine, a mixed micro-/kappa-opioid analgesic, may have potential as a new medication for the treatment of cocaine abuse. Kappa-opioid agonists functionally antagonize some abuse-related and locomotor effects of cocaine, and both kappa-selective and mixed micro-/kappa-opioids reduce cocaine self-administration by rhesus monkeys. Because cocaine's interactions with the hypothalamic-pituitary-adrenal and (HPA) hypothalamic-pituitary-gonadal (HPG) axes may contribute to its reinforcing properties, we examined the effects of cocaine alone and in combination with nalbuphine. Neuroendocrine effects of a single dose of cocaine alone (0.2 mg/kg, IV), with nalbuphine (5 mg/70 kg, IV)+cocaine (0.2 mg/kg, IV) in combination were compared in seven adult men (ages 18-35) who met DSM-IV criteria for current cocaine abuse. Cocaine alone, and in combination with nalbuphine was administered on separate test days under placebo-controlled, double blind conditions. Cocaine stimulated ACTH, cortisol, and LH, whereas cocaine+nalbuphine in combination produced a smaller increase in ACTH, and decreased cortisol and LH. Thus it appears that nalbuphine attenuated cocaine's effects on ACTH, cortisol, and LH. These data are consistent with our earlier report that nalbuphine modestly attenuated cocaine's positive subjective effects, and that the subjective and cardiovascular effects of cocaine+nalbuphine in combination were not additive.     

Acute administration of the GABA reuptake inhibitor tiagabine does not alter the effects of oral cocaine in humans

Drugs affecting central gamma-aminobutyric acid (GABA) systems may have promise as treatments for cocaine addiction. In the present study, tiagabine (Gabatril), a GABA reuptake inhibitor, was investigated for its ability to modify the discriminative-stimulus, reinforcing, subject-rated, performance and cardiovascular effects of oral cocaine in non-treatment seeking cocaine users. Initially, acute doses of 4 mg tiagabine were tested alone and in combination with oral cocaine in four participants to establish the safety of cocaine-tiagabine combinations. A higher dose of tiagabine (8 mg) was then tested in a larger group (n = 6). Participants learned to discriminate 150 mg of oral cocaine. The effects of cocaine (0-150 mg, p.o.) administered alone and in combination with tiagabine were then determined. Subject-rated, performance and cardiovascular measures were obtained at regular intervals. The reinforcing effects of cocaine, tiagabine and cocaine-tiagabine combinations were assessed using the Multiple-Choice Procedure. Cocaine alone produced prototypical behavioral and physiological effects (i.e., functioned as a discriminative and reinforcing stimulus, produced stimulant-like subject-rated effects, improved performance and increased heart rate). In general, acute administration of tiagabine did not alter the effects of oral cocaine. These findings suggest that tiagabine would not be effective at preventing continued cocaine use by blocking its acute, abuse-related effects.     

Acute behavioral and cardiac effects of cocaine and alcohol combinations in humans

Subjects received acute doses of orally administered alcohol (0–1.0 g/kg) and intranasal cocaine (4–96 mg/70 kg) alone and in combination in two experiments. Results generally were consistent across both experiments. Cocaine administered alone improved Digit Symbol Substitution Test (DSST) performance, increased subject ratings of stimulant-like effects, heart rate and blood pressure, and decreased skin temperature. Alcohol administered alone disrupted DSST performance, increased ratings of drunkenness, heart rate and skin temperature, and decreased blood pressure. Combining cocaine and alcohol attenuated the disruptions in DSST performance observed with alcohol alone, and either did not change or attenuated the improvements in performance observed with cocaine alone. Combining the drugs also attenuated effects observed with the drugs alone on skin temperature and, to a lesser extent, blood pressure. By contrast, drug combinations increased heart rate above levels observed when cocaine or alcohol were administered alone. Effects of the drug combinations on subject ratings were variable.     

Comparison of subjective,pharmacokinetic, and physiological effects of marijuana smoked as joints and blunts

Recent increases in marijuana smoking among the young adult population have been accompanied by the popularization of smoking marijuana as blunts instead of as joints. Blunts consist of marijuana wrapped in tobacco leaves, whereas joints consist of marijuana wrapped in cigarette paper. To date, the effects of marijuana smoked as joints and blunts have not been systematically compared. The current within-subject, randomized, double-blind, placebo-controlled study sought to directly compare the subjective, physiological, and pharmacokinetic effects of marijuana smoked by these two methods. Marijuana blunt smokers (12 women and 12 men) were recruited and participated in a 6-session outpatient study. Participants were blindfolded and smoked three puffs from either a blunt or a joint containing marijuana with varying Δ⁹-tetrahydrocannabinol (THC) concentrations (0.0, 1.8, and 3.6%). Subjective, physiological (heart rate, blood pressure, and carbon monoxide levels) and pharmacokinetic effects (plasma THC concentration) were monitored before and at specified time points for 3 h after smoking. Joints produced greater increases in plasma THC and subjective ratings of marijuana intoxication, strength, and quality compared to blunts, and these effects were more pronounced in women compared to men. However, blunts produced equivalent increases in heart rate and higher carbon monoxide levels than joints, despite producing lower levels of plasma THC. These findings demonstrate that smoking marijuana in a tobacco leaf may increase the risks of marijuana use by enhancing carbon monoxide exposure and increasing heart rate compared to joints.