Tuesday, February 5, 2013

Medical use of cannabis. Cannabidiol: A new light for schizophrenia? - Deiana - 2012 - Drug Testing and Analysis - Wiley Online Library

Medical use of cannabis. Cannabidiol: A new light for schizophrenia? - Deiana - 2012 - Drug Testing and Analysis - Wiley Online Library


Section of Article"

Cannabis use to cure schizophrenia: a matter of ratio

There are 19 clinical trials registered in 2012 for the use of CBD for a variety of medical conditions.[60] ‘Perhaps no other signalling system (the cannabinoid) discovered during the past 15 years is raising as many expectations for the development of new therapeutic drugs, encompassing such a wide range of potential strategies for treatments.’[61]
Cannabis use has highly variable physiological effects, but the biochemical basis for this remains a matter of contention. The numerous cannabinoids present in the plant have distinct actions, not all detrimental to mental health. Cannabis effects depend primarily on the content of THC and CBD, and other minor cannabinoids, which in turn depends on the plants’ strain, regional origin, and how the plant is processed. For instance, leaves of Cannabis sativa (marijuana) have a THC content of 4–6%, whereas the resin (hashish) provides 10–15% THC. Indoor-cultivated plants (skunk) can contain up to 20% THC, while oil formulated as an alcoholic resin extract has up to 60% THC.[2, 62-65]
The origin of the plant can also make considerable difference in terms of THC content. For example, marijuana produced in the Netherlands in 2008 contained about 16% THC and virtually no CBD, whereas strains imported from Nepal, Afghanistan, or Morocco contained a similar proportion of THC (17%) but also contained 9% CBD.[64] In 1982, it was found that schizophrenic patients in South Africa experienced an increased frequency of acute psychotic episodes after the use of a variety of Cannabis sativa virtually devoid of CBD.[66] Psychotic effects in some instances are closely related to the THC:CBD ratio: a higher proportion of THC is linked to psychotropic effects, whereas high CBD level is linked to antipsychotic effects. A study conducted by Zuardi et al. demonstrated the interactions between THC and CBD in healthy volunteers, with the latter drug inhibiting THC-induced anxiety and subjective alterations.[67]
In 2008,[68] it was reported that psychosis and delusions were correlated with the smoked CBD:THC ratio found in hair. Higher levels of anhedonia, hallucinations, and delusions were observed in individuals with only THC in their hair compared with those with both THC and CBD, and those with no cannabinoid. This further supports the concept that the presence of CBD in smoked cannabis counteracts to some extent the psychotropic effects of THC.
High THC and low CBD concentrations have also been associated with a higher risk of a first psychotic episode,[69] while cannabis with high CBD content was associated with fewer psychotic experiences.[70] Cognitive deficits emerged in individuals who smoked cannabis with a low-CBD content, whereas high-CBD cannabis smokers tested in memory tasks under acute intoxication performed similarly than when tested in a drug-free state.[71] Conflicting findings were reported by the same authors in different studies. Zuardi[72] reported significant improvement of the symptomatology in a 19-year-old schizophrenic girl given increasing doses of oral CBD up to 1500 mg/day for four weeks. However, ten years, later the same group reported negative results in three 22–23-year-old boys with treatment-resistant schizophrenia administered CBD monotherapy for four weeks.[73] The discrepancy may be due to the short CBD treatment and/or to the fact that in the second study the patients were also insensitive to clozapine, an atypical antipsychotic. Even at high doses, CBD was well tolerated and minimal side effects were reported. Intriguingly, psychotic symptoms in acute schizophrenia have been found to be reduced by CBD with a potency similar to amisulpiride, an atypical antipsychotic D2 and D3 receptor antagonist, but with fewer side effects such as extrapyramidal symptoms (movement disorders such as dystonia, pseudo-parkinsonism, akinesia, and akathisia) and weight gain.[74]
Results reported in the clinical domain were consistent with pre-clinical evidence. CBD reduces stereotypes and hyper-locomotion induced by apomorphine and amphetamine, respectively, with no undesired effects, such as the extrapyramidal effects induced by classical antipsychotics,[75-77] thus showing a pharmacological profile resembling that of clozapine. Interestingly, both drugs induce c-fos expression (a proto-oncogene commonly employed to detect specific neuronal functional activation) in the lateral septal nucleus and the nucleus accumbens, in which antipsychotics exert some of their effects.[78] No induction of c-fos is seen in motor-related brain areas like the basal ganglia,[79] explaining the lack of extra-pyramidal motor effects of CBD.
In addition to DA-based models, CBD effects have also been explored in glutamate-based models, as it can reverse the hyperlocomotion induced by the NMDA receptor antagonist ketamine.[77] CBD also reverses disruption of pre-pulse inhibition induced by NMDA receptor antagonist MK-801 administration.[80] Moreover, it was reported to restore the deficit in social interactions induced by MK-801.[81]
The ability of CBD to inhibit the fatty acid amide hydrolase (FAAH, the enzyme that catalyses anandamide degradation) has been suggested as a possible mechanism to explain its antipsychotic effects. Schizophrenic patients have higher levels of anandamide,[28-30] and the intensity of symptoms is known to be negatively correlated with cerebrospinal levels of anandamide.[29, 82] Accordingly, in animals, the pharmacological blockade of anandamide degradation attenuates psychotic-like behaviours induced by amphetamine and phencyclidine.[83] Such elevation of anandamide levels observed in schizophrenia has been suggested to reflect a compensatory adaptation to the disease state. Based on this view, the use of FAAH inhibitors has gained growing interest as a possible treatment. Recently, a clinical study conducted by Leweke, suggested that by indirectly enhancing anandamide signalling, CBD alleviates psychotic symptoms in schizophrenic patients.[84]
The association between improved clinical symptoms and serum anandamide levels observed in CBD-treated schizophrenics, suggests that the ability of CBD to indirectly enhance anandamide signalling might represent a possible mechanism contributing to its antipsychotic properties.
Alternatively, CBD's ability to bind TRPV1Rs has also been suggested as a possible alternative mechanism to explain its anti-psychotic-like effects using a model of impaired sensory gait (pre-pulse inhibition) induced by the glutamate receptor antagonist MK801.[81]
Whether CBD may alleviate psychotic symptoms through complementary or alternative mechanisms, including interactions with serotonin 5-HT1A receptors,[13, 14] and GPR55 receptors[17] should also be taken in consideration, and at present awaits further clarification.
CBD effects have been investigated mainly focusing on positive and negative symptoms of schizophrenia, yet little is known about its potential effects on cognitive symptoms. This is of great interest as schizophrenics are cognitively impaired, primarily in attention, working memory, and executive functions. Unfortunately, currently prescribed anti-psychotics have limited efficacy in ameliorating these cognitive deficits, increasing the scientific and clinical interest on possible CBD effects on these symptoms.
The high density of cannabinoid receptors in the hippocampus suggests that the endocannabinoid system is involved in superior cognitive functioning; hence, it is reasonable to expect some modification of cognitive symptoms following cannabinoid pharmacological manipulation. CBD increases c-fos expression in brain areas often impaired in schizophrenia and involved in attention processes (including medial pre-frontal cortex and the cingulate gyrus),[85] indicating increased activity in these regions. Hence, there is a rationale to believe that CBD treatment might be beneficial for cognitive symptoms; however, initial pre-clinical and clinical results have not been promising. For instance, in schizophrenic patients treated with 300 or 600 mg CBD, no beneficial effects were documented in the Stroop Color Word Test attentional task, and the highest dose being even detrimental.[86]
In one animal study, a CBD-rich extract was found to be ineffective in a spatial memory task in animals treated with MK801 and scopolamine;[87] however, this extract also contained a significant concentration of THC, which could have counterbalanced the positive effect of CBD. In previous work, the same group showed that CBD-enriched extracts had no effects on working and short-term memory, and that at high doses it antagonizes THC-induced memory deficit.[88] This suggests that CBD could counteract memory deficits induced by cannabinoids, but not cholinergic or glutamatergic disruption. CBD effects on cognitive function are currently under investigation in a phase II clinical trial,[89] in which CBD is administered together with anti-psychotics to treat cognitive symptoms in schizophrenic patients.
These studies indicate that CBD possess anti-psychotic properties, but whether they extend to the cognitive domain awaits further investigation.

Conclusion

In conclusion, there is mounting evidence supporting the therapeutic use of CBD to treat schizophrenic symptoms; however, medical use of cannabinoid extracts is met with opposition in many countries based on legislation, and social traditions.
The unpredictability of the physiological effects of cannabis promotes the perception that there is a potential risk of anti-social behaviour. The fact that cannabis effects also depend upon endogenous cannabinoid tone may account for such variability between users, along with the variety of cannabis strains, provenance, and THC:CBD content. All these variables certainly render the endorsement of cannabis for medical use a conundrum.
Research offers an overwhelming body of data supporting its therapeutic value. Undeniably, the habitual use of cannabis increases the risk of developing schizophrenia, especially in vulnerable subjects, but evidence suggests that this may be largely attributed to THC. Conversely, preclinical and clinical studies suggest a potential anti-psychotic activity of CBD, with a pharmacological profile resembling that of atypical anti-psychotics. Being devoid of psychotropic activity, CBD could represent a reliable medication for schizophrenia, especially in view of its lack of extra-pyramidal side effects.
Particular attention should be paid, however, when supporting the idea of using ‘cannabinoids to treat schizophrenia’. This could lead to the misconception, especially among adolescents, that smoking cannabis is always good for you.
‘In terms of harm reduction, users should be made aware of the higher risk of memory impairment associated with smoking low cannabidiol strains of cannabis like ‘skunk’ and encouraged to use strains containing higher levels of cannabidiol’.[71]
It might sound somewhat idealistic, but I value Morgan's statement. According to the definition of Catullo, cannabis inspires a feeling of Odi et Amo (hate and love). I feel that balanced information should be favoured within the media to inform the cannabis-smoking community (especially adolescents), of both the good and the bad aspects of cannabis.

Acknowledgements

I express my deepest gratitude to Dr Liana Fattore, Laura Shuelert, and Catherine Sweatman for their fruitful comments and English review of the manuscript.

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