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Cannabidiol for the treatment of schizophrenic psychoses

A hemp compound has been shown to increase the effect of the endogenous cannabinoid anandamide in the human brain, thus reducing the delusions associated with psychotic diseases. Studies carried out by Prof. Markus Leweke from the Central Institute of Mental Health in Mannheim involving patients with acute schizophrenic attacks show that the plant compound is better tolerated than currently approved antipsychotic drugs.

Prof. Dr. med. F. Markus Leweke, Director of the Excellence Centre for Clinical Studies at the Central Institute of Mental Health in Mannheim. © Central Institute of Mental Health

Delusions cannot be treated with marijuana. Professor Dr. Markus Leweke warns people with schizophrenia against the use of cannabis for treating the disease. Leweke, senior physician in the Department of Psychiatry and Psychotherapy at the Central Institute of Mental Health in Mannheim, has focused for many years on the effects of endogenous and exogenous cannabinoids for the treatment of schizophrenic psychoses. In a study published in the renowned journal “Translational Psychiatry”, Leweke reports that cannabidiol, a marijuana component, inhibits the degradation of the endogenous neurotransmitter anandamide in the brain. Leweke and his team had previously shown that higher anandamide levels in the cebrospinal fluid correlated with the reduction of the psychotic symptoms associated with schizophrenia. The binding of large amounts of anandamide, a signalling molecule of the endogenous cannabinoid system, to the respective receptors in the brain delays or completely suppresses the transition from early stages of schizophrenia to acute psychoses. The administration of hemp cannabidiol maintains the high anandamide levels in the cerebrospinal fluid, resulting in the alleviation of psychoses.

Chemical structure of cannabidiol © Efferth, Molecular Pharmacology and Toxicology

Cannabidiol, which is the predominant cannabinoid in hemp plants, does not have an intoxicating effect nor does it make people “high”. This effect is due to the compound tetrahydrocannabinole (THC) which is contained in the leaves of the hemp plant and in other cannabis preparations (marijuana, hashish, etc.). Any schizophrenia patient who tried to treat the disease with cannabis would simply make their delusions worse. However, purified cannabidiol is regarded as a drug that has the potential to reduce the symptoms. Professor Leweke explains that purified cannabidiol is better tolerated by patients and hence more suited to the treatment of schizophrenic psychoses than approved psychopharmaceuticals such as amisulpride, which has been shown to lead to movement disorders, weight gain and an elevated risk of diabetes. In a controlled, double-blind randomized clinical trial involving 42 patients with acute schizophrenic psychoses, half of the patients were given amisulpride and the other half cannabidiol. The study found that the plant-derived cannabinoid was better tolerated by the patients at well as having an antipsychotic effect comparable to that of amisulpride.

The endogenous cannabinoid system

The identification of receptors for the major cannabis constituent THC led to the discovery of an endogenous cannabinoid system involving the receptors CB1 and CB2 as well as endocannabinoid ligands such as anandamide (arachidonylethanolamide) and the enzymes involved in the synthesis and degradation of the compound. A large number of CB1 receptors is present in the central nervous system and these receptors belong to the most common G-protein coupled receptors. CB2 receptors, which are part of the same protein family, are mainly expressed by immune cells. However, they also occur in small concentrations in other tissues. The major function of the endogenous cannabinoid system seems to be the maintenance and restoration of the body’s equilibrium. Endocannabinoids are involved in many physiological processes and have been found to lower blood pressure and body temperature, stimulate the appetite and reduce the perception of pain and anxiety. A Swabian chocolate company advertises on its homepage that anandamide, which binds to the same receptors as those that are stimulated by THC, makes people happy: “anandamide, happily it’s in chocolate”. As a matter of fact, small concentrations of anandamide (“ananda” is the Sanskrit word for felicity) are found in cocoa beans.

Endocannabinoids are highly lipophylic (fat-soluble) substances that are synthesized by special enzymes (e.g. acyltransferases, phospholipases) from phospholipids in the cell membrane. During neurotransmission, the endocannabinoids are released from the post-synaptic membrane following the depolarization of the neuron, and activate the CB1 receptors on the pre-synaptic membrane. This suppresses the release of neurotransmitters such as serotonin, glutamate, dopamine and GABA. Following the activation of their receptors, the endocannabinoids are taken up by the cells by way of specific membrane transport proteins and degraded. Cannabidiol inhibits the degradation of the neurotransmitters.

A long way to go before marketing authorization is obtained

Central Institute of Mental Health, Mannheim © Central Institute of Mental Health, Mannheim

Little information is yet available on the molecular relationships between the endocannabinoid system and psychiatric diseases such as schizophrenia. Professor Leweke and the Translational Psychosis Research team at the Central Institute of Mental Health use rats with experimentally impaired social behaviour, perception capacity and movement. Changes in behaviour are recorded and their effect on the animals’ brain metabolism and the endogenous cannabinoid system investigated, for example by measuring the cannabinoid concentrations in body fluids and using positron emission tomography (PET-CT). In order to be able to draw parallels between the animal experiments and the neurobiological and psychopathological alterations in humans, the researchers from Mannheim use exogenous cannabinoids that are given to healthy volunteers under controlled conditions. The specific pharmacological manipulation of the endocannabinoid system and its effect on the neurotransmitter systems in the brain triggers symptoms that are similar to those associated with schizophrenic psychoses. The researchers are then able to investigate the neurobiological alterations in relation to psychopathological abnormalities and behavioural changes.

It is still not known when cannabidiol is likely to be approved as a drug for the treatment of schizophrenic psychoses. Expensive investigations on the compound’s efficiency in different patient populations are needed in order to provide medical evidence about the postulated effect. However, the pharmaceutical industry is somewhat reluctant to sponsor such trials for the simple reason that cannabidiol cannot be patented. Researchers will therefore have to acquire public funds from sources such as the European Commission. However, Leweke is optimistic that he is on the right track, even though it will be a long time before the compound is approved as a drug for the treatment of schizophrenic psychoses.

Original publication:
F.M.Leweke, D. Piomelli, F.Pahlisch, D.Muhl, C.W.Gerth, C.Hoyer, J.Klosterkötter, M.Hellmich, D.Koethe: Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Translational Psychiatry, 2012 March 2(3): e94)

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