The anxiolytic properties of nabilone, a synthetic cannabinoid resembling the natural cannabinoids, were studied in 25 outpatients suffering from anxiety. The drug was compared with a placebo in a double-blind manner over a 28-day treatment period. Patients were seen weekly by the physician and were rated by the Hamilton Rating Scale for Anxiety and the Patient's Global Evaluation as well as by patient-rated evaluations. The results of the study showed a dramatic improvement in anxiety in the nabilone group when compared with placebo (P less than 0.001). Side effects reported were dry mouth, dry eyes, and drowsiness. Patients did not report any of the subjective "altered state" experience of marihuana.

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The effects of single oral doses of nabilone, a synthetic cannabinoid, were studied in eight anxious volunteer subjects. Each subject had two exposures to placebo and three dose levels of nabilone at one-week intervals in a single-blind balanced Latin-square design after the nabilone dose range was determined by each subject's response to a test dose. Heart rate and blood pressure were monitored. The Profile of Mood States (POMS), a self-rating adjective checklist, was used as the quantitative measure of subjective effects. Four subjects performed a continuous avoidance procedure. High doses (4 or 5 mg) of nabilone produced orthostatic hypotension in these subjects. Mild dose-related increases in heart rate also occurred. Despite the occurrence of highly significant levels of sedation, there were no significant effects of nabilone on the continuous avoidance procedure. Two of these four subjects experienced an antianxiety effect from low (1 or 2 mg) nabilone doses. Four other subjects received comparatively lower doses of nabilone and performed on three behavioral tasks at intervals before and after drug: a recognition memory procedure, a task requiring spaced responding at a controlled rate, and a reaction time task. In these subjects there were no reliable effects on blood pressure or heart rate, no significant subjective effects on the POMS, and no antianxiety effects. Drug effects were also minimal on the three behavioral tasks.

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RATIONALE: Endogenous and exogenous cannabinoids acting through the CB1 cannabinoid receptors are implicated in the control of a variety of behavioural and neuroendocrine functions, including emotional responses, and learning and memory processes. Recently, knockout mice deficient in the CB1 cannabinoid receptor have been generated, and these animals result in an excellent tool to evaluate the neurophysiology of the endogenous cannabinoid system.

OBJECTIVES: To establish the role of the CB1 cannabinoid receptor in several emotional-related behavioural responses, including aggressiveness, anxiety, depression and learning models, using CB1 knockout mice.

METHODS: We evaluated the spontaneous responses of CB1 knockout mice and wild-type controls under different behavioural paradigms, including the light/dark box, the chronic unpredictable mild stress, the resident-intruder test and the active avoidance paradigm.

RESULTS: Our findings showed that CB1 knockout mice presented an increase in the aggressive response measured in the resident-intruder test and an anxiogenic-like response in the light/dark box. Furthermore, a higher sensitivity to exhibit depressive-like responses in the chronic unpredictable mild stress procedure was observed in CB1 knockout mice, suggesting an increased susceptibility to develop an anhedonic state in these animals. Finally, CB1 knockout mice showed a significant increase in the conditioned responses produced in the active avoidance model, suggesting an improvement of learning and memory processes.

CONCLUSIONS: Taken together these findings demonstrate that endogenous cannabinoids through the activation of CB1 receptors are implicated in the control of emotional behaviour and participate in the physiological processes of learning and memory.

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In the last decade, a large number of studies using Delta(9)-tetrahydrocannabinol (THC), the main active principle derivative of the marihuana plant, or cannabinoid synthetic derivatives have substantially contributed to advance the understanding of the pharmacology and neurobiological mechanisms produced by cannabinoid receptor activation. Cannabis has been historically used to relieve some of the symptoms associated with central nervous system disorders. Nowadays, there are anecdotal evidences for the use of cannabis in many patients suffering from multiple sclerosis or chronic pain. Following the historical reports of the use of cannabis for medicinal purposes, recent research has highlighted the potential of cannabinoids to treat a wide variety of clinical disorders. Some of these disorders that are being investigated are pain, motor dysfunctions or psychiatric illness. On the other hand, cannabis abuse has been related to several psychiatric disorders such as dependence, anxiety, depression, cognitive impairment, and psychosis. Considering that cannabis or cannabinoid pharmaceutical preparations may no longer be exclusively recreational drugs but may also present potential therapeutic uses, it has become of great interest to analyze the neurobiological and behavioral consequences of their administration. This review attempts to link current understanding of the basic neurobiology of the endocannabinoid system to novel opportunities for therapeutic intervention and its effects on the central nervous system.

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Evidence suggests that cannabinoid receptors, the pharmacologcial target of cannabis-derived drugs, and their accompanying system of endogenous activators may be dysfunctional in schizophrenia. To test this hypothesis, we examined whether endogenous cannabinoid concentrations in cerebrospinal fluid of schizophrenic patients are altered compared to nonschizophrenic controls. Endogenous cannabinoids were purified from cerebrospinal fluid of 10 patients with schizophrenia and 11 non-schizophrenic controls by high-performance liquid chromatography, and quantified by isotope dilution gas-chromatography/mass-spectrometry. Cerebrospinal concentrations of two endogenous cannabinoids (anandamide and palmitylethanolamide) were significantly higher in schizophrenic patients than non-schizophrenic controls (p < 0.05). By contrast, levels of 2-arachidonylglycerol, another endogenous cannabinoid lipid, were below detection in both groups. The findings did not seem attributable to gender, age or medication. Elevated anandamide and palmitylethanolamide levels in cerebrospinal fluid of schizophrenic patients may reflect an imbalance in endogenous cannabinoid signaling, which may contribute to the pathogenesis of schizophrenia.

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There has been considerable debate about the reasons for the association observed between cannabis use and psychosis in both clinical and general population samples. Among the hypotheses proposed to explain the association are the following: 1) common factors explain the co-occurrence; 2 cannabis causes psychosis that would not have occurred in the absence of cannabis use; 3) cannabis precipitates psychosis among persons who were vulnerable to developing the disorders; 4) cannabis use worsens or prolongs psychosis among those who have already developed the disorder; and 5) that persons with psychosis are more likely to become regular or problematic cannabis users than persons without psychosis. This article evaluates the evidence on each of these hypotheses, including recent research on the role of the cannabinoid receptor system in schizophrenia. The evidence suggests that common factors do not explain the comorbidity between cannabis use and psychosis, and it is unlikely that cannabis use causes psychosis among persons who would otherwise not have developed the disorder. The evidence is more consistent with the hypotheses that cannabis use may precipitate psychosis among vulnerable individuals, increase the risk of relapse among those who have already developed the disorder, and may be more likely to lead to dependence in persons with schizophrenia.

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In-patients with psychotic symptoms and cannabis-positive urine analysis were assessed by PSE within one week of admission and again at one and six months. Concurrently admitted psychotic patients with drug-free urine analysis were controls. At one week the two groups differed significantly on only five PSE items: changed perception, thought insertion, non-verbal auditory hallucinations, delusions of control, and delusions of grandiose ability. One item (delayed sleep) differed at one month, and none at six months. The symptom cluster at one week is consistent with acute cannabis intoxication. Subjects and controls were mostly single, poorly educated, unemployed people with histories of psychotic disorders, and given major tranquillisers on admission. Compared with controls, subjects were younger, less likely to have psychiatric histories, more often male, Afro-Caribbeans with a history of convictions and compulsory admissions. The commonest diagnosis was schizophrenia. Use of the label 'cannabis-induced psychosis' may obscure a diagnosis of paranoid schizophrenia. A short-lived psychotic episode does occur in clear consciousness after cannabis intoxication, but chronic cannabis-induced psychosis was not found.

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