Marijuana Cigarettes Research Articles

Effects of marijuana on temporal discriminations in humans

Marijuana has been reported to alter the discrimination of time. The present study used a psychophysical approach to examine the effects of marijuana on temporal discrimination in humans. Research participants were required to push one of two buttons depending on the duration of a conditional stimulus (a blue square on a computer monitor). Correct choices ('C' button after a 2-s stimulus; 'A' button after a 4-s stimulus) resulted in an increase in session earnings of 0.12 dollars. Intermediate durations (probe stimuli between 2 and 4 s) were also presented. Psychophysical functions relating the probability of judging a duration as 'long' (4 s) as a function of actual stimulus durations were characterized by a logistic function fitted to the data. Administration of both low (1/2 placebo and 1/2 2.2% Delta (9)-tetrahydrocannabinol cigarette) and high (3.89% Delta(9)-tetrahydrocannabinol) potency marijuana cigarettes produced a bias of judging intervals as long, consistent with an interpretation that subjective time passes more quickly when an individual is intoxicated by marijuana. Deliberation time, operationally defined as response latency, peaked on trials with sample durations that corresponded to the measure of central tendency, and shifted in a similar manner after marijuana administration. The data are consistent with other studies on the effects of marijuana on time estimation.

The cannabinoid CB1 receptor antagonist rimonabant attenuates the hypotensive effect of smoked marijuana in male smokers

Animal studies suggest that cannabinoid CB1 receptors play a role in regulating blood pressure (BP). In human studies, activation of CB1 receptors by cannabis or its active ingredient, Delta9-tetrahydrocannabinol (THC), has modest and inconsistent effects on BP. We evaluated this phenomenon in 63 male cannabis smokers (mean [SD] age 27.7 +/- 5.4 years, 70% African American, 10.3 +/- 5.9 years of lifetime cannabis use) by administering escalating oral doses (1, 3, 10, 30, 90 mg) of the selective CB1 receptor antagonist rimonabant (or placebo) in a randomized, parallel-group, double-blind, placebo-controlled design. Subjects smoked an active (2.64% THC) or placebo marijuana cigarette 2 and 6 hours after rimonabant dosing. Blood pressure and symptoms were monitored for 90 minutes after smoking while subjects remained seated. Marijuana smoking alone (ie, after placebo rimonabant) had no consistent effect on BP, but 22% of subjects experienced symptomatic (dizziness, lightheadedness) hypotension, as did 20% to 33% of subjects who received pretreatment with rimonabant, 1, 3, or 10 mg. No subject receiving rimonabant, 30 or 90 mg, before marijuana smoking experienced symptomatic hypotension. The 7 subjects who experienced symptomatic hypotension had significantly higher mean (SD) peak plasma THC concentrations (181.6 +/- 80.2) than did the 33 subjects who did not (109.0 +/- 62.6). Rimonabant by itself had no effects on BP and did not alter THC pharmacokinetics. These findings indicate that CB1 receptors play a role in mediating effects of cannabis smoking on BP in humans.

Inhaled marijuana smoke disrupts mitochondrial energetics in pulmonary epithelial cells in vivo

Habitual marijuana smoking is associated with inflammation and atypia of airway epithelium accompanied by symptoms of chronic bronchitis. We hypothesized that Delta(9)-tetrahydrocannabinol (THC), the primary psychoactive component of marijuana, might contribute to these findings by impairing cellular energetics and mitochondrial function. To test this hypothesis, we examined particulate smoke extracts from marijuana cigarettes, tobacco cigarettes, and placebo marijuana (0% THC) cigarettes for their effects on the mitochondrial function of A549 cells in vitro. Only extracts prepared from marijuana cigarettes altered mitochondrial staining by the potentiometric probe JC-1. With the use of a cross-flow, nose-only inhalation system, rats were then exposed for 20 min to whole marijuana smoke and examined for its effects on airway epithelial cells. Inhalation of marijuana smoke produced lung tissue concentrations of THC that were 8-10 times higher than those measured in blood (75 +/- 38 ng/g wet wt tissue vs. 9.2 +/- 2.0 ng/ml), suggesting high local exposure. Intratracheal infusion of JC-1 immediately following marijuana smoke exposure revealed a diffuse decrease in lung cell JC-1 red fluorescence compared with tissue from unexposed or placebo smoke-exposed rats. Exposure to marijuana smoke in vivo also decreased JC-1 red fluorescence (54% decrease, P < 0.01) and ATP levels (75% decrease, P < 0.01) in single-cell preparations of tracheal epithelial cells. These results suggest that inhalation of marijuana smoke has deleterious effects on airway epithelial cell energetics that may contribute to the adverse pulmonary consequences of marijuana smoking.

Transitional cell carcinoma associated with marijuana: Case report and review of the literature

Transitional cell carcinoma of the bladder tends to occur in older patients with a history of tobacco use. We recently evaluated and treated a 45-year-old man with a history of heavy marijuana use. The patient’s only risk factor for transitional cell carcinoma was the inhalation of up to five marijuana cigarettes daily for more than 30 years. We present our case and review the literature.

Neurophysiological and subjective profile of marijuana with varying concentrations of cannabinoids

This study investigated the contribution of different cannabinoids to the subjective, behavioral and neurophysiological effects of smoked marijuana. Healthy marijuana users (12 men, 11 women) participated in four sessions. They were randomly assigned to a low or a high delta9-tetrahydrocannabinol group (THC; 1.8% versus 3.6%). In the four sessions under blinded conditions subjects smoked marijuana cigarettes containing placebo (no active cannabinoids), or cigarettes containing THC with low or high levels of cannabichromene (CBC; 0.1% versus 0.5%) and low or high levels of cannabidiol (CBD; 0.2% versus 1.0%). Dependent measures included subjective reports, measures of cognitive task performance and neurophysiological measures [electroencephalographic (EEG) and event-related potential (ERP)]. Compared to placebo, active THC cigarettes produced expected effects on mood, behavior and brain activity. A decrease in performance, reduction in EEG power and attenuation of ERP components reflecting attentional processes were observed during tests of working memory and episodic memory. Most of these effects were not dose-dependent. Varying the concentrations of CBC and CBD did not change subjects' responses on any of the outcome measures. These findings are consistent with previous studies indicating that THC and its metabolites are the primary active constituents of marijuana. They also suggest that neurophysiological EEG and ERP measures are useful biomarkers of the effects of THC.

Acute Marijuana Effects on Human Risk Taking

Previous studies have established a relationship between marijuana use and risky behavior in natural settings. A limited number of laboratory investigations of marijuana effects on human risk taking have been conducted. The present study was designed to examine the acute effects of smoked marijuana on human risk taking, and to identify behavioral mechanisms that may be involved in drug-induced changes in the probability of risky behavior. Using a laboratory measure of risk taking designed to address acute drug effects, 10 adults were administered placebo cigarettes and three doses of active marijuana cigarettes (half placebo and half 1.77%; 1.77%; and 3.58% Delta9-THC) in a within-subject repeated-measures experimental design. The risk-taking task presented subjects with a choice between two response options operationally defined as risky and nonrisky. Data analyses examined cardiovascular and subjective effects, response rates, distribution of choices between the risky and nonrisky option, and first-order transition probabilities of trial-by-trial data. The 3.58% THC dose increased selection of the risky response option, and uniquely shifted response probabilities following both winning and losing outcomes following selection of the risky option. Acute marijuana administration thereby produced measurable changes in risky decision making under laboratory conditions. Consistent with previous risk-taking studies, shifts in trial-by-trial response probabilities at the highest dose suggested a change in sensitivity to both reinforced and losing risky outcomes. Altered sensitivity to consequences may be a mechanism in drug-induced changes in risk taking. Possible neurobiological sites of action related to THC are discussed.

Cannabinoids: reward, dependence, and underlying neurochemical mechanisms--a review of recent preclinical data.

Starting with the discovery of an endogenous brain cannabinoid system with specific receptors and endogenous ligands, research in the cannabinoid field has accelerated dramatically over the last 15 years. Cannabis is the most used illicit psychotropic substance in the world but only recently have reliable preclinical models become available for investigating the rewarding and dependence-producing actions of its psychoactive constituent, delta9-tetrahydrocannabinol (THC). The goal of this review is to examine the various animal models currently available that are being used to facilitate our understanding of the rewarding and dependence-producing actions of cannabinoids, which are central to their abuse liability, and of the neurochemical mechanisms that may underlie these actions of cannabinoids. Recent demonstrations that strong and persistent intravenous self-administration behavior can be obtained in squirrel monkeys using a range of THC doses that are in agreement with the total intake and the single doses of THC normally self-administered by humans smoking marijuana cigarettes provides a reliable and direct tool for assessing the reinforcing effects of THC that are central to its abuse liability. In addition, recent demonstrations of persistent intravenous self-administration of synthetic cannabinoid CB1 receptor agonists by rats and mice and the development of genetically modified mice lacking specific cannabinoid receptors provide convenient rodent models for exploring underlying neurochemical mechanisms. Repeated demonstrations in rats that THC and synthetic CB1 agonists can induce conditioned place preferences or aversions, depending on details of dose and spacing, can reduce the threshold for intracranial self-stimulation behavior under certain conditions, and can serve as effective discriminative stimuli for operant behavior provide less direct, but more rapidly established, measures for investigating the rewarding effects of cannabinoids. Finally, there have been numerous recent reports of major functional interactions between endogenous cannabinoid, opioid, and dopaminergic neurotransmitter systems in areas such as analgesia, physical dependence and tolerance development, and drug reinforcement or reward. This provides an opportunity to search for drugs with the beneficial therapeutic effects of currently available cannabinoids or opioids but without undesirable adverse effects such as abuse liability.

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.

Drinking Practices and Other Health-Related Behaviors Among Adolescents of São Paulo City, Brazil

Purpose. (a) detect possible demographic and behavioral differences among young episodic heavy drinkers and other young drinkers; (b) investigate the association of youth drinking patterns with other health-compromising behaviors. Methods. The data presented are part of a health behavior survey, which used a modified version of the Youth Health Risk Behavior Survey (YHRBS) questionnaire. Students from public (n = 993) and private schools (n = 815), from 7th to 11th grades were investigated in São Paulo city. Multivariate logistic regression analyses were employed to investigate the association among different drinking practices and the various health-compromising behaviors, controlling for age group, gender, and school system. Odds Ratios (OR) and their 95% Confidence Intervals (CI) were calculated. Episodic Heavy Drinking was defined as having five or more drinks in a 2-hour interval, at least once in the last 30 days. Results. Episodic Heavy Drinkers (EHDs) tend to be older and males and prefer to drink with friends at commercial facilities instead of drinking with their relatives at home. EHDs also reported higher percentages of adverse consequences, such as physical fights, accidents, and school absenteism after drinking. EHDs are more likely to engage in other high-risk behaviors. In the public schools, they were more likely to carry guns (OR = 17.0; CI = 3.9–74.8), get involved in physical fights (OR = 8.9; CI = 4.4–18.0), attempt suicide (OR = 4.2; CI = 2.0–8.7), and use inhalants (OR = 2.7; CI = 1.3–5.7) than abstainers. They are also more likely to use marijuana (OR = 4.7; CI = 2.2–9.9) and smoke cigarettes (OR = 5.3; CI = 2.7–10.4) than moderate drinkers. The results were similar for private schools, with even higher ratios of inhalant use (OR =15.2; CI = 6.2–37.1), when EHDs were compared with abstainers and cigarette (OR = 64.5; CI = 8.6–481.0) and marijuana use (OR = 6.5; CI = 4.3–9.7), when EHDs were compared with moderate drinkers. Conclusions. EHDs display different drinking habits than other adolescents who drink. Also, they are at increased risk for a range of health-compromising behaviors, when compared with both abstainers and moderate drinkers.

Marijuana smoking and head and neck cancer.

A recent epidemiological study showed that marijuana smoking was associated with an increased risk of head and neck cancer. Among high school students and young adults, the prevalence of marijuana use was on the rise in the 1990s, with a simultaneous decline in the perception that marijuana use is harmful. It will be a major public health challenge to make people aware of the harmful effects of marijuana smoking, when some people view it as the illicit drug with the least risk. The carcinogenicity of delta9-tetrahydrocannabinol (THC) is not clear, but according to laboratory studies, it appears to have antitumor properties such as apoptosis as well as tumor-promoting properties such as limiting immune function and increasing reactive oxygen species. Marijuana tar contains similar carcinogens to tar from tobacco cigarettes, but each marijuana cigarette maybe more harmful than a tobacco cigarette since more tar is inhaled and retained when smoking marijuana. More molecular alterations have been observed in bronchial mucosa specimens of marijuana smokers compared to nonsmokers. Field cancerization may be occurring on the bronchial epithelium due to marijuana smoking exposure. Several case studies were suggestive of an association of marijuana smoking with head and neck cancers and oral lesions. However, in a cohort study with 8 years of follow-up, marijuana use was not associated with increased risks of all cancers or smoking-related cancers. Further epidemiological studies are necessary to confirm the association of marijuana smoking with head and neck cancers and to examine marijuana smoking as a risk factor for lung cancer. It will also be of interest to examine potential field cancerization of the upper aerodigestive tract by marijuana and to explore marijuana as a risk factor for oral premalignant lesions.

Canadian Lawmakers Rethink Marijuana Laws

Canadian Lawmakers Rethink Marijuana Laws

Effects of oral THC maintenance on smoked marijuana self-administration

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

Synergistic cytotoxicity of Δ 9-tetrahydrocannabinol and butylated hydroxyanisole

We examined the food additive, butylated hydroxyanisole (BHA), for its capacity to modulate the cytotoxic effects of Δ 9-tetrahydrocannabinol (THC). THC was not cytotoxic when added to cultures of A549 lung tumor cells at concentrations<5 μg/ml, but induced cell necrosis at higher levels with an LC 50=16–18 μg/ml. BHA alone, at concentrations of 10–200 μM, produced limited cell toxicity but significantly enhanced the necrotic death resulting from concurrent exposure to THC. In the presence of BHA at 200 μM, the LC 50 for THC decreased to 10–12 μg/ml. Similar results were obtained with smoke extracts prepared from marijuana cigarettes, but not with extracts from tobacco or placebo marijuana cigarettes (containing no THC). Two different mechanisms for this synergistic cytotoxicity were investigated. Experiments were repeated in the presence of either diphenyleneiodonium or dicumarol as inhibitors of the redox cycling pathway. Neither of these compounds protected cells from the effects of combined THC and BHA, but rather enhanced necrotic cell death. Measurements of cellular ATP revealed that both THC and BHA reduced ATP levels in A549 cells, consistent with toxic effects on mitochondrial electron transport. The combination was synergistic in this respect, reducing ATP levels to <15% of control. Exposure to marijuana smoke in conjunction with BHA, a common food additive, may promote deleterious health effects in the lung.

Marijuana Effects on Sensitivity to Reinforcement in Humans

Under controlled laboratory conditions, eight adult subjects smoked placebo and three different potencies of marijuana cigarettes ranging in Δ9 THC content. Immediately following smoking, subjects were exposed to a laboratory task that provided concurrently available response options. One option systematically decreased in reinforcement frequency throughout the session, and thus required a reallocation of behavior to the non-decreasing option to maximize monetary earnings. After smoking the two highest doses (1.77% and 3.58% Δ9 THC) subjects earned fewer reinforcers and allocated a higher proportion of responding to the decreasing option, compared with placebo and the lowest dose. The difference in reinforcers earned could not be accounted for by a change in response rates. Quantitative and graphical analyses revealed that the higher doses produced considerable periods of time spent on the decreasing option despite earning few reinforcers. The data are discussed with regard to marijuana effects on dopamine/cannabinoid systems and adaptive behavior change.

The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir

The use of cannabinoids for appetite stimulation and the management of wasting and antiretroviral side-effects has become a common practice in the care of HIV-infected individuals. We present pharmacokinetic data from a randomized placebo-controlled study designed to evaluate the metabolic effects of smoked marijuana and dronabinol in HIV-infected patients receiving indinavir (IDV) or nelfinavir (NFV). Subjects on stable regimens containing IDV 800 mg every 8 h (n = 28) or NFV 750 mg three time a day (n = 34) were randomized to one of three treatment arms: 3.95% THC marijuana cigarettes, dronabinol 2.5 mg capsules or placebo capsules administered three times daily. Serial blood sampling was performed at baseline and on day 14 of treatment. The changes in NFV and IDV pharmacokinetics were measured as the median percentage change from baseline. At day 14, the 8-h area under the curve (AUC(8)) changed by -10.2% (P = 0.15), maximum concentration (C(max)) by -17.4% (P = 0.46), and minimum concentration (C(min)) by -12.2% (P = 0.28) for patients in the NFV marijuana arm (n = 11). Similar decreases had occurred by day 14 among patients in the IDV marijuana arm (n = 9): AUC8 had changed by -14.5% (P = 0.074), C(max) by -14.1% (P = 0.039), and C(min) by -33.7% (P = 0.65). Despite a statistically significant decrease in C(max) of IDV in the marijuana arm, the magnitude of changes in IDV and NFV pharmacokinetic parameters in the marijuana arm are likely to have no short-term clinical consequence. The use of marijuana or dronabinol is unlikely to impact antiretroviral efficacy.

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% Δ9-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 Δ9-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 Δ9-THC concentration-dependent manner. These data demonstrate that acute marijuana smoking produced minimal effects on complex cognitive task performance in experienced marijuana users.

Temporal indication of marijuana use can be estimated from plasma and urine concentrations of delta9-tetrahydrocannabinol, 11-hydroxy-delta9-tetrahydrocannabinol, and 11-nor-delta9-tetrahydrocannabinol-9-carboxylic acid.

Current technology establishes marijuana use based upon detection of the pharmacologically inactive cannabinoid metabolite (11-nor-delta9-carboxy-tetrahydrocannabinol-9-carboxylic acid, THC-COOH) in urine. No accurate prediction of time of use is possible because THC-COOH has a half-life of 6 days. To determine if a temporal relationship between marijuana use and metabolite excretion patterns could be established, eight healthy user-volunteers (18-35 years old) smoked marijuana cigarettes containing 0% (placebo), 1.77%, and 3.58% delta9-tetrahydrocannabinol (THC). Plasma and urine were collected prior to smoking, 5 min after smoking, and hourly thereafter for 8 h for measurement of cannabinoid concentrations by gas chromatography-mass spectrometry. Mathematical models proposed for determination of recent marijuana use were applied to data from this study and verified the temporal use of marijuana. One subject, who later admitted chronic marijuana use (urine baseline THCCOOH, 529.2 ng/mL; plasma, 75.5 ng/mL), excreted 8beta-dihydroxy-THC, peaking 2 h postsmoking (92.3 ng/mL). Urinary THC, the psychoactive component of marijuana, concentrations peaked 2 h after smoking and declined to assay limit of detection (LOD) (1.5 ng/mL) by 6 h. 11-Hydroxy-delta9-tetrahydrocannabinol (11-OH-THC) and THCCOOH were detectable for the entire 8-h testing period but continued to decrease. Urinary concentrations of THC greater than 1.5 ng/mL suggests marijuana use during the previous 8-h time period.

Marijuana Smoke and Δ9-Tetrahydrocannabinol Promote Necrotic Cell Death but Inhibit Fas-Mediated Apoptosis

Marijuana smoke shares many components in common with tobacco smoke except for the presence of Δ9-tetrahydrocannabinol (Δ9-THC), the psychotropic compound found only in Cannibis sativa. Δ9-THC has been shown to potentiate smoke-induced oxidative stress and necrotic cell death. In the present study, our objective was to determine the effects of Δ9-THC on the balance between Fas-induced apoptosis and necrosis in A549 lung tumor cells. We found that Fas-induced activation of caspase-3 was inhibited by whole smoke from both tobacco and marijuana cigarettes. Gas-phase smoke, which generates high levels of intracellular reactive oxygen species, had no effect on caspase-3 activity. However, particulate-phase smoke (tar) was a potent inhibitor of Fas-induced caspase-3 activity, with marijuana tar being more potent than either tobacco or placebo marijuana tar (lacking Δ9-THC). Δ9-THC also inhibited Fas-induced caspase-3 activity in A549 cells. In contrast, no inhibition was observed when Δ9-THC was incubated with activated caspase-3 enzyme, suggesting that Δ9-THC acts on the cell pathway(s) leading to caspase-3 activation and not directly on enzyme function. Flow cytometry was used to measure the percentage of cells undergoing apoptosis (staining for annexin V) versus necrosis (staining for propidium iodide) and confirmed that both marijuana tar extract and synthetic Δ9-THC inhibit Fas-induced apoptotis while promoting necrosis. These observations suggest that the Δ9-THC contained in marijuana smoke disrupts elements of the apoptotic pathway, thereby shifting the balance between apoptotic and necrotic cell death. This shift may affect both the carcinogenic and immunologic consequences of marijuana smoke exposure.

Antiemetic efficacy of smoked marijuana: Subjective and behavioral effects on nausea induced by syrup of ipecac

Although the public debate about the legalization of marijuana has continued for as long as 25 years, few controlled studies have been conducted to assess its potential medical benefits. The present study examined the antiemetic effect of smoked marijuana cigarettes (8.4 and 16.9 mg Δ 9-tetrahydrocannabinol [THC]) compared to a highly potent antiemetic drug, ondansetron (8 mg) in 13 healthy volunteers. Nausea and emesis were induced by syrup of ipecac. Marijuana significantly reduced ratings of “queasiness” and slightly reduced the incidence of vomiting compared to placebo. Ondansetron completely eliminated the emetic effects of ipecac. These findings support and extend previous results, indicating that smoked marijuana reduces feelings of nausea and also reduces emesis in this model. However, its effects are very modest relative to ondansetron, and the psychoactive effects of marijuana are likely to limit its clinical usefulness in the general population.

Blockade of Effects of Smoked Marijuana by the CB1-Selective Cannabinoid Receptor Antagonist SR141716

SR141716, a recently developed CB1 cannabinoid receptor antagonist, blocks acute effects of Delta-9-tetrahydrocannabinol (THC) and other CB1 cannabinoid agonists in vitro and in animals. These findings suggest that CB1 receptors mediate many of the effects of marijuana, but this has not been evaluated in humans. Sixty-three healthy men with a history of marijuana use were randomly assigned to receive oral SR141716 or a placebo in an escalating dose (1, 3, 10, 30, and 90 mg) design. Each subject smoked an active (2.64% THC) or placebo marijuana cigarette 2 hours later. Psychological effects associated with marijuana intoxication and heart rate were measured before and after antagonist and marijuana administration. Single oral doses of SR141716 produced a significant dose-dependent blockade of marijuana-induced subjective intoxication and tachycardia. The 90-mg dose produced 38% to 43% reductions in visual analog scale ratings of "How high do you feel now?" "How stoned on marijuana are you now?" and "How strong is the drug effect you feel now?" and produced a 59% reduction in heart rate. SR141716 alone produced no significant physiological or psychological effects and did not affect peak THC plasma concentration or the area under the time x concentration curve. SR141716 was well tolerated by all subjects. SR141716 blocked acute psychological and physiological effects of smoked marijuana without altering THC pharmacokinetics. These findings confirm, for the first time in humans, the central role of CB1 receptors in mediating the effects of marijuana.