Tag Archives: THC

Cannabis reinforcement and dependence: role of the cannabinoid CB1 receptor.

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Abstract

“Awareness of cannabis dependence as a clinically relevant issue has grown in recent years. Clinical and laboratory studies demonstrate that chronic marijuana smokers can experience withdrawal symptoms upon cessation of marijuana smoking and have difficulty abstaining from marijuana use. This paper will review data implicating the cannabinoid CB1 receptor in regulating the behavioral effects of Δ9-tetrahydrocannobinol (THC), the primary psycho-active component of cannabis, across a range of species. The behavioral effects that will be discussed include those that directly contribute to the maintenance of chronic marijuana smoking, such as reward, subjective effects, and the positive and negative reinforcing effects of marijuana, THC and synthetic cannabinoids. The role of the CB1 receptor in the development of marijuana dependence and expression of withdrawal will also be discussed. Lastly, treatment options that may alleviate withdrawal symptoms and promote marijuana abstinence will be considered.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2731704/

Dronabinol for the Treatment of Cannabis Dependence: A Randomized, Double-Blind, Placebo-Controlled Trial

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   “The purpose of this study was to evaluate the safety and efficacy of dronabinol, a synthetic form of delta-9-tetrahydrocannabinol, a naturally occurring pharmacologically active component of marijuana, in treating cannabis dependence… This is the first trial using an agonist substitution strategy for treatment of cannabis dependence. Dronabinol showed promise, it was well-tolerated, and improved treatment retention and withdrawal symptoms. Future trials might test higher doses, combinations of dronabinol with other medications with complementary mechanisms, or with more potent behavioral interventions.

The agonist substitution strategy has been effective for other substance use disorders, mainly nicotine (nicotine patch, other nicotine replacement products, varenicline) and opioid dependence (methadone, buprenorphine). Therefore, dronabinol, an orally bioavailable synthetic form of delta-9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana acting at the cannabinoid 1 (CB1) receptor, seems a logical candidate medication for cannabis dependence. An ideal agonist medication has low abuse potential, reduces withdrawal symptoms and craving, and decreases the reinforcing effects of the target drug, thereby facilitating abstinence. Dronabinol has been shown to reduce cannabis withdrawal symptoms in laboratory settings among non-treatment seeking cannabis users. Although dronabinol produced modest positive subjective effects among cannabis users in the laboratory, there is little evidence of abuse or diversion of dronabinol in community settings. We conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of dronabinol for patients seeking treatment for cannabis dependence. This is, to our knowledge, the largest clinical trial to date to evaluate a pharmacologic intervention for cannabis dependence, and the first to attempt agonist substitution.

.In conclusion, agonist substitution pharmacotherapy with dronabinol, a synthetic form of THC, showed promise for treatment of cannabis dependence, reducing withdrawal symptoms and improving retention in treatment, although it failed to improve abstinence. The trial showed that among adult cannabis-dependent patients, dronabinol was well accepted, with good adherence and few adverse events. Future studies should consider testing higher doses of dronabinol, with longer trial lengths, combining dronabinol with other medications acting through complementary mechanisms or more potent behavioral interventions. Moreover, the field should particularly seek to develop high affinity CB1 partial agonists.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3154755/

Marijuana Withdrawal in Humans: Effects of Oral THC or Divalproex

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   “Abstinence following daily marijuana use can produce a withdrawal syndrome characterized by negative mood (eg irritability, anxiety, misery), muscle pain, chills, and decreased food intake. Two placebo-controlled, within-subject studies investigated the effects of a cannabinoid agonist, delta-9-tetrahydrocannabinol (THC: Study 1), and a mood stabilizer, divalproex (Study 2), on symptoms of marijuana withdrawal. Participants (n=7/study), who were not seeking treatment for their marijuana use, reported smoking 6–10 marijuana cigarettes/day, 6–7 days/week. Study 1 was a 15-day in-patient, 5-day outpatient, 15-day in-patient design. During the in-patient phases, participants took oral THC capsules (0, 10 mg) five times/day, 1 h prior to smoking marijuana (0.00, 3.04% THC). Active and placebo marijuana were smoked on in-patient days 1–8, while only placebo marijuana was smoked on days 9–14, that is, marijuana abstinence. Placebo THC was administered each day, except during one of the abstinence phases (days 9–14), when active THC was given. Mood, psychomotor task performance, food intake, and sleep were measured. Oral THC administered during marijuana abstinence decreased ratings of ‘anxious’, ‘miserable’, ‘trouble sleeping’, ‘chills’, and marijuana craving, and reversed large decreases in food intake as compared to placebo, while producing no intoxication. Study 2 was a 58-day, outpatient/in-patient design. Participants were maintained on each divalproex dose (0, 1500 mg/day) for 29 days each. Each maintenance condition began with a 14-day outpatient phase for medication induction or clearance and continued with a 15-day in-patient phase. Divalproex decreased marijuana craving during abstinence, yet increased ratings of ‘anxious’, ‘irritable’, ‘bad effect’, and ‘tired.’ Divalproex worsened performance on psychomotor tasks, and increased food intake regardless of marijuana condition. Thus, oral THC decreased marijuana craving and withdrawal symptoms at a dose that was subjectively indistinguishable from placebo. Divalproex worsened mood and cognitive performance during marijuana abstinence. These data suggest that oral THC, but not divalproex, may be useful in the treatment of marijuana dependence.

To conclude, there are currently no effective pharmacotherapies for cannabinoid dependence, yet the large number of nonresponders in marijuana treatment studies emphasizes the importance of increasing treatment options for marijuana dependence. We have developed a laboratory model to predict medications that may show promise clinically for the treatment of marijuana dependence. The present findings, in combination with earlier studies, suggest that nefazodone and oral THC show promise as potential treatment medications, while bupropion and divalproex do not…”

http://www.nature.com/npp/journal/v29/n1/full/1300310a.html

Adverse effects of cannabis. (2011)

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Abstract

“Cannabis, Cannabis sativa L., is used to produce a resin that contains high levels of cannabinoids, particularly delta9-tetrahydrocannabinol (THC), which are psychoactive substances. Although cannabis use is illegal in France and in many other countries, it is widely used for its relaxing or euphoric effects, especially by adolescents and young adults. What are the adverse effects of cannabis on health? During consumption? And in the long term? Does cannabis predispose users to the development of psychotic disorders? To answer these questions, we reviewed the available evidence using the standard Prescrire methodology. The long-term adverse effects of cannabis are difficult to evaluate. Since and associated substances, with or without the user’s knowledge. Tobacco and alcohol consumption, and particular lifestyles and behaviours are often associated with cannabis use. Some traits predispose individuals to the use of psychoactive substances in general. The effects of cannabis are dosedependent.The most frequently report-ed adverse effects are mental slowness, impaired reaction times, and sometimes accentuation of anxiety. Serious psychological disorders have been reported with high levels of intoxication. The relationship between poor school performance and early, regular, and frequent cannabis use seems to be a vicious circle, in which each sustains the other. Many studies have focused on the long-term effects of cannabis on memory, but their results have been inconclusive. There do not * About fifteen longitudinal cohort studies that examined the influence of cannabis on depressive thoughts or suicidal ideation have yielded conflicting results and are inconclusive. Several longitudinal cohort studies have shown a statistical association between psychotic illness and self-reported cannabis use. However, the results are difficult to interpret due to methodological problems, particularly the unknown reliability of self-reported data. It has not been possible to establish a causal relationship in either direction, because of these methodological limitations. In Australia, the marked increase in cannabis use has not been accompanied by an increased incidence of schizophrenia. On the basis of the available data, we cannot reach firm conclusions on whether or not cannabis use causes psychosis. It seems prudent to inform apparently vulnerable individuals that cannabis may cause acute psychotic decompensation, especially at high doses. Users can feel dependent on cannabis, but this dependence is usually psychological. Withdrawal symptoms tend to occur within 48 hours following cessation of regular cannabis use, and include increased irritability, anxiety, nervousness, restlessness, sleep difficulties and aggression. Symptoms subside within 2 to 12 weeks. Driving under the influence of cannabis doubles the risk of causing a fatal road accident. Alcohol consumption plays an even greater role. A few studies and a number of isolated reports suggest that cannabis has a role in the occurrence of cardiovascular adverse effects, especially in patients with coronary heart disease. Numerous case-control studies have investigated the role of cannabis in the incidence of some types of cancer. Its role has not been ruled out, but it is not possible to determine whether the risk is distinct from that of the tobacco with which it is often smoked. Studies that have examined the influence of cannabis use on the clinical course of hepatitis C are inconclusive. Alcohol remains the main toxic agent that hepatitis C patients should avoid. In practice, the adverse effects of low-level, recreational cannabis use are generally minor, although they can apparently be serious in vulnerable individuals. The adverse effects of cannabis appear overall to be less serious than those of alcohol, in terms of neuropsychological and somatic effects, accidents and violence.”

http://www.ncbi.nlm.nih.gov/pubmed/21462790

Cannabis–1988.

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Abstract

“In this updating review of research on cannabis particular attention has been paid to the increasing number of studies of the disposition of the components of cannabis in man, as well as possible effects on health. Specific binding sites for cannaboids have not been demonstrated. Approximately 80 metabolites of tetrahydrocannabiol (THC) have been discovered, of which 11-OH-THC is the main metabolite, but it contributes little to the overall effect when the drug is smoked or given intravenously. The minimum plasma level of THC associated with the psychotropic effect is 25 ng/ml. Cannabis may produce directly an acute panic reaction, a toxic delirium, and acute paranoid state, or acute mania. Cannabis use may aggrevate schizophrenia, but it is much less certain whether it can lead to sociopathy or even to “amotivational syndrome”. Despite widespread use of cannabis in virtually all parts of the world, no catastrophic effects on health have been noted. Cannabis appears to be relatively safe as compared with current social drugs. It is, however, still too early in the history of the present episode of cannabis use to be sanguine about possible bad effects.”

http://www.ncbi.nlm.nih.gov/pubmed/2852450

Reinforcing properties of oral delta 9-tetrahydrocannabinol, smoked marijuana, and nabilone: influence of previous marijuana use.

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Abstract

“The reinforcing properties of delta 9THC (17.5 mg), a 1 g marijuana cigarette containing 1.83% delta 9-THC, a synthetic cannabis compound (Nabilone 2 mg orally), and their respective placebos were assessed with self-report and operant work-contingent choice procedures. Three groups of eight subjects were selected on the basis of a history of regular, intermittent, or occasional marijuana-smoking behavior. All subjects served as their own controls for each drug condition and studies were carried out under double-blind and “double-dummy” conditions in a controlled, residential research ward. Placebo responding did not vary as a function of history of marijuana use, but the past history of drug use had a significant influence on the reinforcing properties of cannabis compounds as well as the behavioral and physiological effects of these drugs. Regular marijuana users reported a significant increase in elation following marijuana smoking, but this was not associated with a significant increment in pulse rate. Intermittent and occasional marijuana smokers had significant increases in pulse rate, but no significant marijuana-induced elation. Nabilone and delta 9-THC produced a significant increase in pulse rate for all subject groups, but there was no significant increase in elation following ingestion of these compounds. Given a choice between the three drugs and three placebos, 18 of 23 subjects worked to obtain a marijuana cigarette in an operant work choice paradigm. These data indicate that smoked marijuana was significantly more reinforcing than all other cannabis compounds studied, regardless of past drug-use history.”

http://www.ncbi.nlm.nih.gov/pubmed/6149589

Reinforcing and subjective effects of oral delta 9-THC and smoked marijuana in humans.

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Abstract

“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.”

http://www.ncbi.nlm.nih.gov/pubmed/1319601

Substitution profile of the cannabinoid agonist nabilone in human subjects discriminating δ9-tetrahydrocannabinol.

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Abstract

“OBJECTIVES:

The central effects of Δ-tetrahydrocannabinol (Δ-THC), the primary active constituent of cannabis, are attributed to cannabinoid CB1 receptor activity, although clinical evidence is limited. Drug discrimination has proven useful for examining the neuropharmacology of drugs, as data are concordant with the actions of a drug at the receptor level. The aim of this study was to determine the profile of behavioral and physiological effects of the cannabinoid agonist nabilone in humans trained to discriminate Δ-THC.

METHODS:

Six cannabis users learned to identify when they received oral Δ-THC (25 mg) or placebo and then received a range of doses of the cannabinoid agonists nabilone (1, 2, 3, and 5 mg) and Δ-THC (5, 10, 15, and 25 mg). The dopamine reuptake inhibitor methylphenidate (5, 10, 20, and 30 mg) was included as a negative control. Subjects completed the Multiple-Choice Procedure, and self-report, task performance, and physiological measures were collected.

RESULTS:

Nabilone shared discriminative-stimulus effects with the training dose of Δ-THC, produced subject-rated drug effects that were comparable to those of Δ-THC, and increased heart rate. Methylphenidate did not engender Δ-THC-like discriminative-stimulus effects.

CONCLUSIONS:

These data demonstrate that the interoceptive effects of nabilone are similar to Δ-THC in cannabis users. The overlap in their behavioral effects is likely due to their shared mechanism as CB1 receptor agonists. Given the relative success of agonist replacement therapy to manage opioid, tobacco, and stimulant dependence, these results also support the evaluation of nabilone as a potential medication for cannabis-use disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/20838217

Separate and combined effects of the cannabinoid agonists nabilone and Δ9-THC in humans discriminating Δ9-THC

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“Background

Agonist replacement treatment is a promising strategy to manage cannabis-use disorders. The aim of this study was to assess the combined effects of the synthetic cannabinoid agonist nabilone and Δ9-tetrahydrocannabinol (Δ9-THC) using drug-discrimination procedures, which are sensitive to drug interactions. Testing the concurrent administration of nabilone and Δ9-THC was also conducted to provide initial safety and tolerability data, which is important because cannabis users will likely lapse during treatment.”

“Conclusions

These results replicate a previous study demonstrating that nabilone shares agonist effects with the active constituent of cannabis in cannabis users, and contribute further by indicating that nabilone would likely be safe and well tolerated when combined with cannabis. These data support the conduct of future studies to determine if nabilone treatment would produce cross-tolerance to the abuse-related effects of cannabis and reduce cannabis use.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3089804/

Recent advantages in cannabinoid research.

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Abstract

“Although the active component of cannabis Delta9-THC was isolated by our group 35 years ago, until recently its mode of action remained obscure. In the last decade it was established that Delta9-THC acts through specific receptors – CB1 and CB2 – and mimics the physiological activity of endogenous cannabinoids of two types, the best known representatives being arachidonoylethanolamide (anandamide) and 2-arachidonoylglycerol (2-AG). THC is officially used against vomiting caused by cancer chemotherapy and for enhancing appetite, particularly in AIDS patients. Illegally, usually by smoking marijuana, it is used for ameliorating the symptoms of multiple sclerosis, against pain, and in a variety of other diseases. A synthetic cannabinoid, HU-211, is in advanced clinical tests against brain damage caused by closed head injury. It may prove to be valuable against stroke and other neurological diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/10575284