Phytocannabinoids and epilepsy.

WHAT IS KNOWN AND OBJECTIVE: Antiepileptic drugs often produce serious adverse effects, and many patients do not respond to them properly. Phytocannabinoids produce anticonvulsant effects in preclinical and preliminary human studies, and appear to produce fewer adverse effects than available antiepileptic drugs. The present review summarizes studies on the anticonvulsant properties of phytocannabinoids. METHODS: Literature search using the PubMed database to identify studies on phytocannabinoids and epilepsy. RESULTS AND DISCUSSION: Preclinical studies suggest that phytocannabinoids, especially cannabidiol and cannabidivarin, have potent anticonvulsant effects which are mediated by the endocannabinoid system. Human studies are limited in number and quality, but suggest that cannabidiol has anticonvulsant effects in adult and infantile epilepsy and is well tolerated after prolonged administration. WHAT IS NEW AND CONCLUSION: Phytocannabinoids produce anticonvulsant effects through the endocannabinoid system, with few adverse effects. Cannabidiol and cannabidivarin should be tested in randomized, controlled clinical trials, especially in infantile epileptic syndromes.

Cannabidiol can improve complex sleep-related behaviours associated with rapid eye movement sleep behaviour disorder in Parkinson's disease patients: a case series.

WHAT IS KNOWN AND OBJECTIVE: Cannabidiol (CBD) is the main non-psychotropic component of the Cannabis sativa plant. REM sleep behaviour disorder (RBD) is a parasomnia characterized by the loss of muscle atonia during REM sleep associated with nightmares and active behaviour during dreaming. We have described the effects of CBD in RBD symptoms in patients with Parkinson's disease. CASES SUMMARY: Four patients treated with CBD had prompt and substantial reduction in the frequency of RBD-related events without side effects. WHAT IS NEW AND CONCLUSION: This case series indicates that CBD is able to control the symptoms of RBD.

Cannabis affects people differently: inter-subject variation in the psychotogenic effects of Δ9-tetrahydrocannabinol: a functional magnetic resonance imaging study with healthy volunteers.

BACKGROUND: Cannabis can induce transient psychotic symptoms, but not all users experience these adverse effects. We compared the neural response to Δ9-tetrahydrocannabinol (THC) in healthy volunteers in whom the drug did or did not induce acute psychotic symptoms. Method In a double-blind, placebo-controlled, pseudorandomized design, 21 healthy men with minimal experience of cannabis were given either 10 mg THC or placebo, orally. Behavioural and functional magnetic resonance imaging measures were then recorded whilst they performed a go/no-go task. RESULTS: The sample was subdivided on the basis of the Positive and Negative Syndrome Scale positive score following administration of THC into transiently psychotic (TP; n = 11) and non-psychotic (NP; n = 10) groups. During the THC condition, TP subjects made more frequent inhibition errors than the NP group and showed differential activation relative to the NP group in the left parahippocampal gyrus, the left and right middle temporal gyri and in the right cerebellum. In these regions, THC had opposite effects on activation relative to placebo in the two groups. The TP group also showed less activation than the NP group in the right middle temporal gyrus and cerebellum, independent of the effects of THC. CONCLUSIONS: In this first demonstration of inter-subject variability in sensitivity to the psychotogenic effects of THC, we found that the presence of acute psychotic symptoms was associated with a differential effect of THC on activation in the ventral and medial temporal cortex and cerebellum, suggesting that these regions mediate the effects of the drug on psychotic symptoms.

Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report.

WHAT IS KNOWN AND OBJECTIVE:   Cannabis withdrawal in heavy users is commonly followed by increased anxiety, insomnia, loss of appetite, migraine, irritability, restlessness and other physical and psychological signs. Tolerance to cannabis and cannabis withdrawal symptoms are believed to be the result of the desensitization of CB1 receptors by THC. CASE SUMMARY:   This report describes the case of a 19-year-old woman with cannabis withdrawal syndrome treated with cannabidiol (CBD) for 10 days. Daily symptom assessments demonstrated the absence of significant withdrawal, anxiety and dissociative symptoms during the treatment. WHAT IS NEW AND CONCLUSION:   CBD can be effective for the treatment of cannabis withdrawal syndrome.

Social anxiety disorder: what are we losing with the current diagnostic criteria?

OBJECTIVE: To assess the rate of comorbidities and the functional impairment associated with the social anxiety disorder (SAD), with an emphasis on the so-called subthreshold clinical signs and symptoms. METHOD: Psychiatric comorbidities and psychosocial functioning were evaluated in 355 volunteers (college students) who had been diagnosed as SAD (n = 141), Subthreshold SAD (n = 92) or Controls (n = 122). RESULTS: The rate of comorbidities was 71.6% in the SAD group and 50% in subjects with Subthreshold SAD, both significantly greater than Controls (28.7%). Concerning psychosocial functioning, the SAD group had higher impairment than the other two groups in all domains evaluated, and subjects with Subthreshold SAD presented intermediate values. CONCLUSION: The rates of psychiatric comorbidities and the impairment of psychosocial functioning increase progressively along the spectrum of social anxiety. The fact that Subthreshold SAD causes considerable disability and suffering in comparison with control subjects justifies a review of the validity of the diagnostic criteria.

Maternal administration of cannabidiol promotes an anti-inflammatory effect on the intestinal wall in a gastroschisis rat model.

Gastroschisis (GS) is an abdominal wall defect that results in histological and morphological changes leading to intestinal motility perturbation and impaired absorption of nutrients. Due to its anti-inflammatory, antioxidant, and neuroprotective effects, cannabidiol (CBD) has been used as a therapeutic agent in many diseases. Our aim was to test the effect of maternal CBD in the intestine of an experimental model of GS. Pregnant rats were treated over 3 days with CBD (30 mg/kg) after the surgical induction of GS (day 18.5 of gestation) and compared to controls. Fetuses were divided into 4 groups: 1) control (C); 2) C+CBD (CCBD); 3) gastroschisis (G), and 4) G+CBD (GCBD). On day 21.5 of gestation, the fetuses were harvested and evaluated for: a) body weight (BW), intestinal weight (IW), and IW/BW ratio; b) histometric analysis of the intestinal wall; c) immunohistochemically analysis of inflammation (iNOS) and nitrite/nitrate level. BW: GCBD was lower than CCBD (P<0.005), IW and IW/BW ratio: GCBD was smaller than G (P<0.005), GCBD presented lower thickness in all parameters compared to G (P<0.005), iNOS and nitrite/nitrate were lower concentration in GCBD than to G (P<0.005). Maternal use of CBD had a beneficial effect on the intestinal loops of GS with decreased nitrite/nitrate and iNOS expression.

Cannabidiol, a Cannabis sativa constituent, as an antipsychotic drug.

A high dose of delta9-tetrahydrocannabinol, the main Cannabis sativa (cannabis) component, induces anxiety and psychotic-like symptoms in healthy volunteers. These effects of delta9-tetrahydrocannabinol are significantly reduced by cannabidiol (CBD), a cannabis constituent which is devoid of the typical effects of the plant. This observation led us to suspect that CBD could have anxiolytic and/or antipsychotic actions. Studies in animal models and in healthy volunteers clearly suggest an anxiolytic-like effect of CBD. The antipsychotic-like properties of CBD have been investigated in animal models using behavioral and neurochemical techniques which suggested that CBD has a pharmacological profile similar to that of atypical antipsychotic drugs. The results of two studies on healthy volunteers using perception of binocular depth inversion and ketamine-induced psychotic symptoms supported the proposal of the antipsychotic-like properties of CBD. In addition, open case reports of schizophrenic patients treated with CBD and a preliminary report of a controlled clinical trial comparing CBD with an atypical antipsychotic drug have confirmed that this cannabinoid can be a safe and well-tolerated alternative treatment for schizophrenia. Future studies of CBD in other psychotic conditions such as bipolar disorder and comparative studies of its antipsychotic effects with those produced by clozapine in schizophrenic patients are clearly indicated.

5-HT-related drugs and human experimental anxiety.

Clinical observations and double-blind studies demonstrated an anxiolytic effect of drugs that facilitate serotonergic transmission on several anxiety disorders. There is a latency of several weeks for their anxiolytic effect to take place. There may be, in addition, a biphasic effect, i.e., an acute anxiogenic effect followed by an anxiolytic effect after chronic use. In addition, acute administration of m-chlorophenylpiperazine (MCPP), an agonist of 5-HT-1 receptors, increased anxiety in normal volunteers as well as in patients with panic or obsessive-compulsive disorders. Studies in health volunteers have been performed in our laboratory to explore the acute effect on human anxiety of drugs that selectively influence 5-HT neurotransmission. We observed that acute administration of chlorimipramine enhanced the rise in anxiety induced in healthy volunteers by speaking in front of a video camera. With a similar experimental design, we also demonstrated an anxiogenic effect of metergoline, a nonselective 5-HT receptor blocker. It is suggested that the proanxiogenic effect of acute administration of 5-HT uptake inhibitors may be due to impaired 5-HT neurotransmission.

Comparison between two models of experimental anxiety in healthy volunteers and panic disorder patients.

To further investigate the role of serotonin (5-HT) in anxiety, two tests were used in human subjects. The first was the conditioning of skin conductance response (CSCR) that associates a tone to a loud noise. The second was simulated public speaking (SPS), which is believed to represent unconditioned fear. In healthy volunteers the 5-HT(2A) receptor blocker and 5-HT reuptake inhibitor nefazodone reduced subjective anxiety and the number of spontaneous fluctuations of skin conductance during CSCR, but enhanced anxiety induced by SPS. Opposite effects had been reported with the 5-HT releasing and uptake-inhibiting agent D-fenfluramine. Panic patients behaved like controls in the CSCR. However, they had a higher level of baseline anxiety and were insensitive to SPS. This profile resembles the reported effect of the non-selective 5-HT receptor blocker metergoline in healthy volunteers. Therefore, panic patients seem to process unconditioned fear abnormally, which may be due to lack of 5-HT inhibition in brain structures commanding flight from proximal danger stimuli.

Effects of cannabidiol in animal models predictive of antipsychotic activity.

The effects of cannabidiol (CBD) were compared to those produced by haloperidol in rats submitted to experimental models predictive of antipsychotic activity. Several doses of CBD (15-480 mg/kg) and haloperidol (0.062-1.0 mg/kg) were tested in each model. First, CBD increased the effective doses 50% (or) ED50 of apomorphine for induction of the sniffing and biting stereotyped behaviors. In addition, both CBD and haloperidol reduced the occurrence of stereotyped biting induced by apomorphine (6.4 mg/kg), increased plasma prolactin levels and produced palpebral ptosis, as compared to control solutions. However, CBD did not induce catalepsy even at the highest doses, in contrast to haloperidol. Such a pharmacological profile is compatible with that of an "atypical" antipsychotic agent, though the mechanism of action is uncertain and may not be identical to that of the dopamine antagonists.

Action of cannabidiol on the anxiety and other effects produced by delta 9-THC in normal subjects.

The object of the experiment was to verify whether cannabidiol (CBD) reduces the anxiety provoked by delta 9-THC in normal volunteers, and whether this effect occurs by a general block of the action of delta 9-THC or by a specific anxiolytic effect. Appropriate measurements and scales were utilized and the eight volunteers received, the following treatments in a double-blind procedure: 0.5 mg/kg delta 9-THC, 1 mg/kg CBD, a mixture containing 0.5 mg/kg delta 9-THC and 1 mg/kg CBD and placebo and diazepam (10 mg) as controls. Each volunteer received the treatments in a different sequence. It was verified that CBD blocks the anxiety provoked by delta 9-THC, however this effect also extended to marihuana-like effects and to other subjective alterations induced by delta 9-THC. This antagonism does not appear to be caused by a general block of delta 9-THC effects, since no change was detected in the pulse-rate measurements. Several further effects were observed typical of CBD and of an opposite nature to those of delta 9-THC. These results suggest that the effects of CBD, as opposed to those of delta 9-THC, might be involved in the antagonism of effects between the two cannabinoids.

Antianxiety effect of cannabidiol in the elevated plus-maze.

In order to assess the presence of anxiolytic properties in cannabidiol (CBD) the drug was tested in an elevated plus-maze model of anxiety, in rats. Doses of 2.5, 5.0 and 10.0 mg/kg significantly increased the entry ratio (open/total number of entries), an anxiolytic-like effect. CBD at a dose of 20.0 mg/kg was no longer effective. None of the doses of CBD used changed total number of entries, a measure of total exploratory activity. Diazepam (2.0 mg/kg) also caused an anxiolytic-like effect in this model. These results indicate that CBD causes a selective anxiolytic effect in the elevated plus-maze, within a limited range of doses.

Effect of d-fenfluramine on human experimental anxiety.

To investigate the role of 5-HT in human anxiety, the 5-HT releaser and uptake blocker d-fenfluramine (FEN) was administered to healthy volunteers under two models of experimental anxiety. The first was a simulated public speaking (SPS) test consisting of talking in front of a video camera, anxiety being evaluated mainly by self-rating scales. The second was a conditioned fear test, in which the changes in skin electrical conductance caused by a tone associated once with an aversive white noise were measured. The doses of 15 and 30 mg FEN, PO, decreased anxiety induced by SPS in a dose-dependent way, as indicated by the anxiety factor of Norris Visual Analogue Mood Scale. In the conditioned fear test, however, the amplitude and level of skin conductance responses to the conditioned aversive stimulus were not significantly changed by FEN. The differential effects of FEN in these human experimental models of anxiety, together with similar results reported in rats, support the view that 5-HT exerts a dual action on brain mechanisms regulating anxiety, facilitating conditioned while inhibiting unconditioned fear. The presumed reduction in unconditioned fear caused by FEN may have implications for the treatment of panic disorder.

Effect of metergoline on human anxiety.

In order to assess the role played by serotonin (5-HT) in subjective anxiety, three groups of 12 healthy volunteers were given 12 mg metergoline (MET), 10 mg diazepam (DZ) or placebo (PB), under double-blind conditions, and submitted to a simulated public speaking (SPS) test. MET increased state-anxiety scores, measured by Spielberg's State-Trait Anxiety Inventory. The effect of MET was significantly different from both the PB and DZ groups immediately before the SPS test (prestress) as well as 24 h after medication, and from the DZ group only, 2.5 h after the test (poststress). In contrast, DZ did not significantly affect subjective anxiety. The SPS test significantly increased anxiety in DZ- or PB-treated subjects as compared to prestress scores, whereas the increases in the MET group were not significant, probably because pretest levels were already high. No drug effect on heart rate, skin electrical conductance and quality of sleep during the night following medication was found. In addition, the drugs did not cause bodily symptoms that could secondarily affect mood. Since MET is a 5-HT receptor antagonist, active on the central nervous system, an inhibitory role of 5-HT on subjective anxiety might be suggested.

Effect of chlorimipramine and maprotiline on experimental anxiety in humans.

In order to assess the role played by serotonin (5-HT) and noradrenaline in anxiety, four groups of healthy volunteers were given 25 mg of the selective inhibitor of 5-HT uptake chlorimipramine, 50 mg of the selective inhibitor of noradrenaline uptake maprotiline, 1 mg of the benzodiazepine anxiolytic lorazepam or placebo, and submitted to a simulated public speaking (SPS) test, consisting of speaking in front of a videocamera. Subjective anxiety was evaluated by the visual analog mood scale (VAMS) of Norris as well as by the state-trait anxiety inventory (STAI) of Spielberger. Chlorimipramine enhanced SPS-induced anxiety, whereas maprotiline and lorazepam reduced anxiety during as well as outside the test period. Mental and physical sedation (VAMS) were increased by either maprotiline or lorazepam. In a scale of bodily symptoms, chlorimipramine tended to increase muscle tension, agitation and palpitation, whereas maprotiline caused lethargy. The rise in blood pressure induced by the SPS procedure outlasted the period of stress in the group treated with chlorimipramine. In contrast, the SPS-induced increase in heart rate was enhanced by lorazepam. Chlor imipramine and maprotiline reduced salivation to the same extent. Pupillary diameter, however, was significantly increased by chlorimipramine alone. It may be tentatively sug gested that the proanxiogenic effect of chlorimipramine is related to changes in central 5-HT neurotransmission while the anxiolytic effect of maprotiline is associated with alteration of noradrenergic mechanisms. Increased peripheral sympathetic tone may also contribute to the proanxiety action of chlorimipramine.

Effects of ipsapirone and cannabidiol on human experimental anxiety.

The effects of ipsapirone and cannabidiol (CBD) on healthy volunteers submitted to a simulated public speaking (SPS) test were compared with those of the anxiolytic benzodiazepine diazepam and placebo. Four independent groups of 10 subjects received, under a double-blind design, placebo or one of the following drugs: CBD (300 mg), diazepam (10 mg) or ipsapirone (5 mg). Subjective anxiety was evaluated through the Visual Analogue Mood Scale (VAMS) and the State-trait Anxiety Inventory (STAI). The VAMS anxiety factor showed that ipsapirone attenuated SPS-induced anxiety while CBD decreased anxiety after the SPS test. Diazepam, on the other hand, was anxiolytic before and after the SPS test, but had no effect on the increase in anxiety induced by the speech test. Only ipsapirone attenuated the increase in systolic blood pressure induced by the test. Significant sedative effects were only observed with diazepam. The results suggest that ipsapirone and CBD have anxiolytic properties in human volunteers submitted to a stressful situation.

Do panic patients process unconditioned fear vs. conditioned anxiety differently than normal subjects?

Panic patients were evaluated with two models of experimental anxiety that are believed to generate distinct emotional states: (1) a stimulated public speaking test (SPS), a presumed indicator of unconditioned fear, and (2) conditioning of skin conductance responses (CSCR) to a tone associated with an aversive white noise, an index of conditioned anxiety. Subjective states were evaluated through the visual analogue mood scale (VAMS) and a bodily symptoms scale (BSS). In the SPS test, panic patients showed higher baseline levels of VAMS-measured anxiety than controls. Unlike controls, panic patients failed to show increased anxiety before and during speech. Although baseline levels of arousal were similar in both groups, VAMS mental sedation decreased in controls, but not in panic patients during the SPS. Panic patients showed more discontent than controls throughout the whole experimental session. They also scored higher than controls on several items of the BSS. In the CSCR test, panic patients showed more spontaneous fluctuations of skin conductance than controls. Nevertheless, conditioning of skin conductance responses to the tone was similar in both groups. Therefore, panic patients seemed to process unconditioned fear abnormally.

Effects on variable-interval performance in rats of delta 9-tetrahydrocannabinol and cannabidiol, separately and in combination.

The objective of this investigation was to study the influence of the dose ratio between cannabidiol (CBD) and delta 9-tetrahydrocannabinol (delta 9-THC) on the effects of mixtures of the two cannabinoids on variable-interval (VI) schedule performance in rats. The effect on VI performance of a control solution, 10 mg/kg CBD, delta 9-THC (0.125, 0.5, 2 and 8 mg/kg) and a mixture of 10 mg/kg CBD + delta 9-THC (0.125, 0.5, 2 and 8 mg/kg) was investigated in 10 rats, with a different sequence of treatments for each animal. The results were expressed in terms of rate-dependency. The control solution, 10 mg/kg CBD, 0.125 mg/kg delta 9-THC, or 10 mg/kg CBD + delta 9-THC (0.125 mg/kg) did not cause rate-dependent effects. Delta 9-THC (0.5 and 2 mg/kg) produced rate-dependent effects. The dose of 8 mg/kg delta 9-THC almost suppressed responding. The combination of 10 mg/kg CBD + 0.5 mg/kg delta 9-THC did not cause rate-dependent effects but produced a response pattern similar to that obtained with 0.125 mg/kg delta 9-THC. At these doses CBD antagonized delta 9-THC. The combination of 10 mg/kg CBD + 2 mg/kg delta 9-THC caused rate-dependent effects. The rate-dependent regression line determined by this mixture was parallel to that produced by 2 mg/kg delta 9-THC. However, the lower intercept of the mixture with the y axis suggested potentiation of the depressant effects of delta 9-THC by CBD.(ABSTRACT TRUNCATED AT 250 WORDS)

Reliability of the Portuguese version of the structured clinical interview for DSM-III-R (SCID) in a Brazilian sample of psychiatric outpatients.

The objective of the present study was to determine the reliability of psychiatric diagnoses using a translation and adaptation of Portuguese of the "Structured Clinical Interview for DSM-III-R-patient version" (SCID-P) and the "Structured Clinical Interview for DSM-III-R Personality Disorders" (SCID-II), using the joint interviews methodology. Thirty-nine subjects were evaluated using the SCID-P and 20 of them using the SCID-II. Interrater reliability was analyzed statistically by means of the Kappa Coefficient. Agreement between results obtained with SCID-P was statistically significant for the major diagnostic categories of DSM-III-R and for 10 of the 12 specific diagnostic categories studied (a minimum of 4 subjects per diagnosis). Agreement was not statistically significant for Psychotic Disorder Not Otherwise Specified (NOS) and for Other Bipolar Disorder. The Weighted Kappa for the main diagnoses and the Overall Kappa for the entire set of 25 specific diagnostic categories proposed by the SCID-P were statistically significant. The general agreement for Personality Disorders with SCID-II was statistically significant. The Kappa Coefficient was determined for the Avoidant, Paranoid, Histrionic and Borderline Personality Disorders and for the Conduct Disorder. The remaining Personality Disorders were not analyzed statistically because of their low prevalence in the sample. Agreement was not significant only for the Histrionic Personality Disorder. These data suggest that the translation and adaptation of the SCID-P and SCID-II to Portuguese presents, in general, good reliability indices, and thus its use is recommended.

Effect of cannabidiol on plasma prolactin, growth hormone and cortisol in human volunteers.

In the present study, we investigated the effects of cannabidiol (CBD) on plasma prolactin, growth hormone and cortisol of 11 normal volunteers who received placebo or CBD at the doses of 300 mg (N = 7) or 600 mg (N = 4), po, in a double-blind manner during two experimental sessions separated by an interval of at least one week. The sessions were held in the morning and consisted of blood collection and application of self-evaluation scales before and after drug injection (-35 to 180 min). Hormonal measurements were performed by radioimmunoassay. Basal prolactin (11.5 +/- 4.3 ng/ml) and growth hormone (1.5 +/- 0.7 ng/ml) levels were unchanged after placebo and CBD. In contrast, plasma cortisol levels decreased significantly during the placebo sessions (basal measurement = 11.0 +/- 3.7 micrograms/dl; 120 min after placebo = 7.1 +/- 3.9 micrograms/dl), in agreement with the normal circadian rhythm of this hormone. This decrease in cortisol levels was significantly attenuated after CBD (basal measurement = 10.5 +/- 4.9 micrograms/dl; 120 min after 300 mg CBD = 9.9 +/- 6.2 micrograms/dl; 120 min after 600 mg CBD = 11.6 +/- 11.6 micrograms/dl). CBD was also found to have a sedative effect as determined by the self-evaluation scales. The present results suggest that CBD interferes with cortisol secretion.