Delta(9)-Tetrahydrocannabinol (THC) is the main source of the pharmacological effects caused by the consumption of cannabis, both the marihuana-like action and the medicinal benefits of the plant. However, its acid metabolite THC-COOH, the non-psychotropic cannabidiol (CBD), several cannabinoid analogues and newly discovered modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoids exert many effects through activation of G-protein-coupled cannabinoid receptors in the brain and peripheral tissues. Additionally, there is evidence for non-receptor-dependent mechanisms. Natural cannabis products and single cannabinoids are usually inhaled or taken orally; the rectal route, sublingual administration, transdermal delivery, eye drops and aerosols have only been used in a few studies and are of little relevance in practice today. The pharmacokinetics of THC vary as a function of its route of administration. Pulmonary assimilation of inhaled THC causes a maximum plasma concentration within minutes, psychotropic effects start within seconds to a few minutes, reach a maximum after 15-30 minutes, and taper off within 2-3 hours. Following oral ingestion, psychotropic effects set in with a delay of 30-90 minutes, reach their maximum after 2-3 hours and last for about 4-12 hours, depending on dose and specific effect. At doses exceeding the psychotropic threshold, ingestion of cannabis usually causes enhanced well-being and relaxation with an intensification of ordinary sensory experiences. The most important acute adverse effects caused by overdosing are anxiety and panic attacks, and with regard to somatic effects increased heart rate and changes in blood pressure. Regular use of cannabis may lead to dependency and to a mild withdrawal syndrome. The existence and the intensity of possible long-term adverse effects on psyche and cognition, immune system, fertility and pregnancy remain controversial. They are reported to be low in humans and do not preclude legitimate therapeutic use of cannabis-based drugs. Properties of cannabis that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, sedation, improvement of mood, stimulation of appetite, antiemesis, lowering of intraocular pressure, bronchodilation, neuroprotection and induction of apoptosis in cancer cells.

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No abstract available
Psychopharmacology (Berl). 2002 Jun;161(4):331-9. Epub 2002 Apr 19. Related Articles, Links

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RATIONALE: There has been controversy about whether the subjective, behavioral or therapeutic effects of whole plant marihuana differ from the effects of its primary active ingredient, Delta(9)-tetrahydrocannabinol (THC). However, few studies have directly compared the effects of marihuana and THC using matched doses administered either by the smoked or the oral form.

OBJECTIVE: Two studies were conducted to compare the subjective effects of pure THC to whole-plant marihuana containing an equivalent amount of THC in normal healthy volunteers. In one study the drugs were administered orally and in the other they were administered by smoking.

METHODS: In each study, marihuana users (oral study: n=12, smoking study: n=13) participated in a double-blind, crossover design with five experimental conditions: a low and a high dose of THC-only, a low and a high dose of whole-plant marihuana, and placebo. In the oral study, the drugs were administered in brownies, in the smoking study the drugs were smoked. Dependent measures included the Addiction Research Center Inventory, the Profile of Mood States, visual analog items, vital signs, and plasma levels of THC and 11-nor-9-
carboxy-THC.

RESULTS: In both studies, the active drug conditions resulted in dose-dependent increases in plasma THC levels, and the levels of THC were similar in THC-only and marihuana conditions (except that at the higher oral dose THC-only produced slightly higher levels than marihuana). In both the oral study and the smoking study, THC-only and whole plant marihuana produced similar subjective effects, with only minor differences.

CONCLUSION: These results support the idea that the psychoactive effects of marihuana in healthy volunteers are due primarily to THC.

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Cannabinoids have a long history of consumption for recreational and medical reasons. The primary active constituent of the hemp plant Cannabis sativa is delta9-tetrahydrocannabinol (delta9-THC). In humans, psychoactive cannabinoids produce euphoria, enhancement of sensory perception, tachycardia, antinociception, difficulties in concentration and impairment of memory. The cognitive deficiencies seem to persist after withdrawal. The toxicity of marihuana has been underestimated for a long time, since recent findings revealed delta9-THC-induced cell death with shrinkage of neurons and DNA fragmentation in the hippocampus. The acute effects of cannabinoids as well as the development of tolerance are mediated by G protein-coupled cannabinoid receptors. The CB1 receptor and its splice variant CB1A, are found predominantly in the brain with highest densities in the hippocampus, cerebellum and striatum. The CB2 receptor is found predominantly in the spleen and in haemopoietic cells and has only 44% overall nucleotide sequence identity with the CB1 receptor. The existence of this receptor provided the molecular basis for the immunosuppressive actions of marihuana. The CB1 receptor mediates inhibition of adenylate cyclase, inhibition of N- and P/Q-type calcium channels, stimulation of potassium channels, and activation of mitogen-activated protein kinase. The CB2 receptor mediates inhibition of adenylate cyclase and activation of mitogen-activated protein kinase. The discovery of endogenous cannabinoid receptor ligands, anandamide (N-arachidonylethanolamine) and 2-arachidonylglycerol made the notion of a central cannabinoid neuromodulatory system plausible. Anandamide is released from neurons upon depolarization through a mechanism that requires calcium-dependent cleavage from a phospholipid precursor in neuronal membranes. The release of anandamide is followed by rapid uptake into the plasma and hydrolysis by fatty-acid amidohydrolase. The psychoactive cannabinoids increase the activity of dopaminergic neurons in the ventral tegmental area-mesolimbic pathway. Since these dopaminergic circuits are known to play a pivotal role in mediating the reinforcing (rewarding) effects of the most drugs of abuse, the enhanced dopaminergic drive elicited by the cannabinoids is thought to underlie the reinforcing and abuse properties of marihuana. Thus, cannabinoids share a final common neuronal action with other major drugs of abuse such as morphine, ethanol and nicotine in producing facilitation of the mesolimbic dopamine system.

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Dronabinol (Delta 9-tetrahydocannabinol, THC), the main source of the pharmacological effects caused by the use of cannabis, is an agonist to both the CB1 and the CB2 subtype of cannabinoid receptors. It is available on prescription in several countries. The non-psychotropic cannabidiol (CBD), some analogues of natural cannabinoids and their metabolites, antagonists at the cannabinoid receptors and modulators of the endogenous cannabinoid system are also promising candidates for clinical research and therapeutic uses. Cannabinoid receptors are distributed in the central nervous system and many peripheral tissues including spleen, leukocytes; reproductive, urinary and gastrointestinal tracts; endocrine glands, arteries and heart. Five endogenous cannabinoids have been detected so far, of whom anandamide and 2-arachidonylglycerol are best characterized. There is evidence that besides the two cannabinoid receptor subtypes cloned so far additional cannabinoid receptor subtypes and vanilloid receptors are involved in the complex physiological functions of the cannabinoid system that include motor coordination, memory procession, control of appetite, pain modulation and neuroprotection. Strategies to modulate their activity include inhibition of re-uptake into cells and inhibition of their degradation to increase concentration and duration of action. Properties of cannabinoids that might be of therapeutic use include analgesia, muscle relaxation, immunosuppression, anti-inflammation, anti-allergic effects, sedation, improvement of mood, stimulation of appetite, anti-emesis, lowering of intraocular pressure, bronchodilation, neuroprotection and antineoplastic effects.

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The many studies that have been included in this review suggest that cannabinoids have ubiquitous effects on biological systems. These results also underscore the intensity to which cannabinoids have been studied. While there are numerous reasons for the prodigious amount of cannabinoid research, a major stimulus has been the desire to identify a specific biochemical event or pathway that is responsible for the expression of delta 9-THC's unique psychoactivity. It is the hope that delta 9-THC, as with all centrally acting drugs, might serve as an important tool for achieving a better understanding of the central nervous system. As discussed in this review, the psychoactivity of cannabinoids might best be described as a composite of numerous effects. If that is indeed the case, then it would seem logical that these centrally mediated effects do not arise from a single biochemical alteration, but rather from multiple actions. Of course, a major problem arises when one attempts to establish a relationship between cause and effect when multiple mechanisms and effects are involved. An initial approach to reducing the complexity of elucidation of mechanism of action should involve attempts to distinguish those cannabinoid actions which result in specific effects (psychoactivity) from those which produce non-psychoactive effects (such as general depression). There are several fundamental principles that can be used to assess specificity, including concentration or dose of the drug that is required to produce a given effect. Low doses of delta 9-THC are capable of producing the psychoactivity that is unique to cannabinoids, whereas higher doses may produce effects that are both specific and nonspecific for cannabinoids. Unfortunately, establishing this basic tenet for delta 9-THC has proven to be difficult. It has not been possible to establish the concentration of delta 9-THC at its site of action that is necessary to produce a given pharmacological effect. While it is a simple matter to measure the concentration of cannabinoids in either a whole tissue or an incubation medium, the hydrophobicity of cannabinoids dramatically affects their affinity for, and hence concentration in, the biochemical components of the tissue. If the concentration of delta 9-THC could be measured at its site of action, then the relevance of many of its pharmacological effects could be adequately determined. Two possible mechanisms by which cannabinoids might produce psychoactivity are membrane perturbation and receptor interactions, and indeed, both mechanisms have received considerable attention.

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It is known that an individual's drug use history affects the quality of subjective effects experienced following administration of several clinically used psychoactive drugs such as barbiturates, diazepam, and morphine. However, it is not known whether drug use history also affects responses to therapeutic cannabinoids such as delta9-THC. The current experiment compared the subjective and behavioral effects of oral delta9-THC in two groups of volunteers: frequent users (FREQ; n = 11), who reported using marihuana at least 100 times, and infrequent users (INF; n = 10) who reported using marihuana 10 or fewer times. Subjects participated in three sessions during which they received delta9-THC (7.5 and 15 mg) and placebo. They completed subjective effects questionnaires for 5 h following administration. In the FREQ group, the lower dose (7.5 mg) increased ratings of "feel drug," relative to placebo, whereas it had no effect in the INF group. In contrast, at the higher dose (15 mg), ratings of "feel drug" were lower in the FREQ group than in the INF group, suggestive of tolerance. In addition, the INF group reported greater sedative effects than the FREQ group following the higher dose of delta9-THC, again suggesting tolerance to delta9-THC's sedative effects. These findings demonstrate that marihuana use history may affect the subjective effects of oral delta9-THC, but that the influence of drug use history depends on the dose of drug administered. These findings may have implications for the clinical use of delta9-THC and other cannabinoids.

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Understanding of cannabinoid (CB) actions has been remarkably advanced during the last decade, due mainly to the identification of the G-protein-coupled cannabinoid receptors, namely, CB1 receptors that are predominantly found in the brain and CB2 receptors that are exclusively found in peripheral tissues. Endogenous ligands for these receptors have also been identified. Research to date suggests that the analgesic effect of cannabinoids and the enhancement of opioid analgesia by cannabinoids are both CB1 receptor-mediated via the activation of opioid receptors. The involvement of the CB1 receptor in mediating reinforcing and physical dependence-producing effects of opioids has also been suggested, with the former being considered the result of interaction with the dopaminergic neurotransmission in the midbrain dopamine system. However, the discriminative stimulus effects of cannabinoids have been reported to be highly specific in that the effects were not substituted by other classes of compounds including opioidergic and dopaminergic agents nor were they antagonized by antagonists of various neurotransmission systems, suggesting that the discriminative stimulus effects only involve the cannabinoid system. Thus the cannabinoid actions appear to be classifiable into at least two kinds: 1) those mediated directly through cannabinoid receptors and 2) those mediated indirectly through other systems such as opioidergic systems. Detailed research into these actions may help to elucidate not only the mechanisms of action of exogenous cannabinoids but also the role of endogenous cannabinoids, especially in the brain reward system.

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Nabilone is a modified cannabinol derivative with central nervous system activity. Administration of nabilone in single doses of 1 to 5 mg results in dose-related pharmacologic effects in man. One and 2.5 mg doses of nabilone induced relaxant and sedative effects in all subjects. No euphoria, dry mouth, tachycardia, or postural hypotension was seen after 1 mg, minimal effects were seen after 2.5 mg, and marked effects were seen after 5 mg. Effects were evident within 60 to 90 min and persisted for 8 to 12 hr. Nabilone produced no significant tachycardia. There were no changes in supine blood pressure; however, marked postural hypotension occurred after the 5-mg dose. The administration of nabilone at doses of 1 mg or 2 mg two times daily resulted in euphoria and dry mouth during the first two days of drug; thereafter tolerance developed to these effects but there was no apparent decrease in relaxation. Subjects challenged with a single 5-mg dose of nabilone showed a 66% reduction in symptoms and signs after the 7-day drug period compared to that of the same dose after 1 wk of placebo. Comparison of nabilone with other cannabinol derivatives suggests that some of the undesirable pharmacologic effects can be separated within the group.

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Cannabinoids and opioids both produce analgesia through a G-protein-coupled mechanism that blocks the release of pain-propagating neurotransmitters in the brain and spinal cord. However, high doses of these drugs, which may be required to treat chronic, severe pain, are accompanied by undesirable side effects. Thus, a search for a better analgesic strategy led to the discovery that delta 9-tetrahydrocannabinol (THC), the major psychoactive constituent of marihuana, enhances the potency of opioids such as morphine in animal models. In addition, studies have determined that the analgesic effect of THC is, at least in part, mediated through delta and kappa opioid receptors, indicating an intimate connection between cannabinoid and opioid signaling pathways in the modulation of pain perception. A host of behavioral and molecular experiments have been performed to elucidate the role of opioid receptors in cannabinoid-induced analgesia, and some of these findings are presented below. The aim of such studies is to develop a novel analgesic regimen using low dose combinations of cannabinoids and opioids to effectively treat acute and chronic pain, especially pain that may be resistant to opioids alone.

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Opioids and cannabinoids are among the most widely consumed drugs of abuse in humans. A number of studies have shown that both types of drugs share several pharmacological properties, including hypothermia, sedation, hypotension, inhibition of both intestinal motility and locomotor activity and, in particular, antinociception. Moreover, phenomena of cross-tolerance or mutual potentiation of some of these pharmacological effects have been reported. In recent years, these phenomena have supported the possible existence of functional links in the mechanisms of action of both types of drugs. The present review addresses the recent advances in the study of pharmacological interactions between opioids and cannabinoids, focusing on two aspects: antinociception and drug addiction. The potential biochemical mechanisms involved in these pharmacological interactions.

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Opioids and cannabinoids are two major classes of drugs with important clinical uses as well as significant side effects. Recently, the three major subtypes of opioid receptors, delta, kappa and mu, have been cloned. Both the endogenous cannabinoids and their receptors have also recently been cloned. These advances are facilitating attempts to understand the structural features of these receptors that are involved in their functioning, which should lead to the development of new and improved clinically useful opioids and cannabinoid-like drugs.

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The reinforcing properties of delta 9THC (17.5 mg), a 1 g marihuana 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 marihuana-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 marihuana 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 marihuana users reported a significant increase in elation following marihuana smoking, but this was not associated with a significant increment in pulse rate. Intermittent and occasional marihuana smokers had significant increases in pulse rate, but no significant marihuana-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 marihuana cigarette in an operant work choice paradigm. These data indicate that smoked marihuana was significantly more reinforcing than all other cannabis compounds studied, regardless of past drug-use history.

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Dronabinol is an oral form of delta-9-tetrahydrocannabinol indicated for treatment of anorexia associated with weight loss in individuals with AIDS, and nausea and vomiting associated with cancer chemotherapy. The authors reviewed the literature and conducted surveys and interviews among addiction medicine specialists, oncologists, researchers in cancer and HIV treatment, and law enforcement personnel to determine the abuse liability of dronabinol. There is no evidence of abuse or diversion of dronabinol. Available prescription tracking data indicates that use remains within the therapeutic dosage range over time. Healthcare professionals have detected no indication of "scrip-chasing" or "doctor-shopping" among the patients for whom they have prescribed dronabinol. Cannabis-dependent populations, such as those treated in our Clinic and seen by the addiction medicine specialists we interviewed, have demonstrated no interest in abuse of dronabinol. There is no street market for dronabinol, and no evidence of any diversion of dronabinol for sale as a street drug. Furthermore, dronabinol does not provide effects that are considered desirable in a drug of abuse. The onset of action is slow and gradual, it is at most only weakly reinforcing, and the overwhelming majority of reports of users indicate that its effects are dysphoric and unappealing. This profile of effects gives dronabinol a very low abuse potential.

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No abstract available

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