New study highlights positive effects of CBD in treating psychoses such as schizophrenia
Psychotic disorders such as schizophrenia are heterogeneous and often debilitating conditions.
The introduction of dopamine D2 receptor antagonists in the 1950s revolutionized the treatment of psychotic disorders and they remain the mainstay of the therapeutic arsenal against psychosis.
However, traditional antipsychotics are associated with a number of side effects and a significant proportion of patients do not achieve adequate remission of symptoms. It is therefore necessary to develop new treatments, in particular those whose mechanism of action is not an antagonist of D2 receptors. Cannabidiol (CBD), a non-toxic constituent of the cannabis plant, has emerged as a potential new class of antipsychotics with a unique mechanism of action.
A recent analysis concluded that patients with psychosis had significantly higher levels of endocannabinoid anandamide in cerebrospinal fluid and blood, and higher expression of the major central cannabinoid 1 receptor (CB1) on peripheral immune cells. This high endocannabinoid tone has been observed at all stages of the disease, from prodrome to chronic psychosis. Alterations in CB1 receptor expression have also been observed in postmortem tissues and in vivo in patients with psychosis. While the endocannabinoid system plays a role in psychotic pathophysiology, it is interesting to note that pharmaceutical compounds that modulate this system may have therapeutic value.
Cannabidiol (CBD), a phytocannabinoid constituting cannabis sativa, has been announced as one of these potential treatments. Although the main psychoactive ingredient in cannabis, delta-9-tetrohydrocannabinol (THC), has anxiogenic, psychotomimetic and amnesic effects, CBD is non-toxic and has anxiolytic, antipsychotic and anticonvulsant properties, without harmful effects on memory. The epidemiological findings support these opposing effect profiles; numerous data indicate that cannabis is a risk factor in the development of psychoses and adverse outcomes in cannabis users. However, the detrimental effects of cannabis use on the risk of the onset and subsequent course of psychosis are particularly evident in people who consume cannabis that is high in THC and low in CBD, rather than in those who consume hash-type cannabis (with a lower THC level and a higher CBD level). This trend is consistent with the evidence that CBD not only has opposite effects to THC, but can also block some of its unwanted (and particularly psychotomimetic) effects.
It is important to note that CBD has a different mechanism of action than dopamine receptor antagonists and therefore could represent a completely new class of antipsychotic therapy. This would be associated with many advantages. First, by avoiding antagonism of dopamine receptors, one can avoid unwanted effects such as extrapyramidal symptoms and an increase in prolactin. Second, if CBD works through different molecular pathways to current antipsychotics, it could be used not only as monotherapy, but also potentially as an adjunct treatment alongside existing antipsychotics, with potential additional efficacy gains. While CBD is currently in trials for a number of psychiatric disorders and physical health issues, the study synthesizes and summarizes current evidence regarding the therapeutic potential of CBD in the treatment of psychosis.
Evidence for the antipsychotic potential of cannabidiol
The accumulated evidence regarding the antipsychotic potential of CBD comes from several different sources. These include preclinical work, experimental studies in healthy human volunteers comparing the neurocognitive effects of THC and CBD, as well as studies to determine whether CBD can block or lessen the symptomatic effects of THC. .
Indirect evidence for the antipsychotic and anxiolytic effects of CBD comes from preclinical studies, where the specific characteristics of psychotic disorders are modeled in animals and allow the examination of potential therapeutic effects at the molecular and behavioral levels.
Hyperlocomotion is considered a model of positive psychotic symptoms and can be treated with antipsychotics. CBD has been shown to reduce amphetamine (dopamine agonist) and ketamine [N-methyl-d-aspartate (NMDA) receptor antagonist (NMDA) -induced hyperlocomotion without inducing catalepsy, suggesting that it has antipsychotic-like beneficial effects without the harmful motor side effects, with a profile similar to that of the atypical antipsychotic clozapine.
Experimental and neuroimaging studies in humans
Neuroimaging studies, which non-invasively examine the neuronal substrate systems, on which CBD can act to produce its antipsychotic and anxiolytic effects in vivo, complement our knowledge of the antipsychotic potential of CWD.
THC and CBD have been shown to have opposing effects on regional brain activation in a variety of cognitive tasks in healthy individuals. Interestingly, this phenomenon has been observed in areas of the brain where patients with psychosis experience dysfunction and during tasks known to be impaired by cannabis use.
Further evidence for the protective effects of CBD against the psychotomimetic, anxiogenic and cognitive effects of THC comes from experimental studies where the two cannabinoids were co-administered. THC can be used as an experimental model of psychosis in humans because its acute administration in healthy people can induce transient psychotic symptoms (including positive and negative symptoms), as well as cognitive deficits resembling those seen in schizophrenics.
In summary, a growing body of research suggests that CBD attenuates the propsychotic, anxiety, and cognitive effects induced by THC in healthy individuals, both neurophysiologically and behaviorally (psychopathologically). Additionally, CBD has opposing effects to THC on regional brain activation and functional connectivity in a range of cognitive tasks (including processing salience, learning and memory, inhibition of responses, and treatment of fear) in areas known to be disturbed in patients with psychosis. Taken together, this accumulated evidence supports the potential therapeutic role of CBD in the treatment of psychosis and is consistent with the independent evidence that CBD has antipsychotic effects in patients with this disease (see below).
Early clinical trials suggest that CBD is safe, well tolerated and may have antipsychotic effects in patients with psychosis. There is some evidence that CBD may be particularly effective in the early stages of the disorder, such as in patients at high clinical risk and those with a first psychotic episode.
Neuroimaging research suggests that CBD may exert its therapeutic effects by modulating brain function in regions known to be altered in patients with psychosis according to various cognitive paradigms. Questions remain about the full side effect profile of CBD, with reports of increased liver enzymes and potential liver toxicity, but the most commonly reported side effects (such as diarrhea and sedation) are probably both mild and mild. Since CBD has antipsychotic effects without directly acting on dopamine receptors, it could represent a new type of treatment for psychosis.