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cbd cause psychosis

The study did have limitations. Aside from being a small study with a methodology unable to account for every factor that might influence the outcome, the researchers also noted that they can’t be sure the results weren’t caused by “the rapid changes in cerebral perfusion that are known to occur with a single dose of psychoactive drugs.” In other words, they may have witnessed a short-term effect that won’t last. Quoting from the study: “It is also unclear whether the effects of CBD will persist after longer-term dosing.”

Psychosis is not a single condition or disorder, but is rather a symptom of other disorders characterized by detachment from reality. Seeing, hearing or believing things that aren’t real, including hallucinations, is typical of a psychotic episode. While the exact causes of psychosis aren’t known, it’s thought to be triggered by mental illness, trauma, substance abuse and extreme stress. Even lack of sleep can spark an episode.

“The results have started unravelling the brain mechanisms of a new drug that works in a completely different way to traditional anti-psychotics,” said the study’s lead author Dr. Sagnik Bhattacharyya from the Institute of Psychiatry, Psychology & Neuroscience at King’s College, London.

Cannabidiol (CBD), the non-intoxicating compound in marijuana, continues drawing attention as a potential treatment for disorders and illnesses ranging from epilepsy to cancer. Now a new brain imaging study suggests that a single dose of CBD can reduce symptoms of psychosis by “resetting” activity in three brain areas. If replicable, the study offers the first evidence-based explanation for how CBD works in the brain to counteract psychosis, with results that could help generate new treatments.

This was a small study of 33 participants who were experiencing psychotic symptoms. A smaller group of healthy participants served as a control group. Half the psychosis group was given one 600 mg oral dose of CBD (a dose that was “previously effective in established psychosis” according to the study), the other half received an identical placebo capsule. The control group didn’t receive any drug. Then all of the participants completed a memory task designed to engage three brain areas that have been linked to the onset of psychosis (specifically the striatum, medial temporal cortex, and midbrain) while their brains were examined with an fMRI scanner.

The study represents another move forward for CBD as a treatment for brain-based disorders. Earlier this year, the US FDA approved the first drug comprised of CBD to treat severe forms of epilepsy. While CBD derived from cannabis is a Schedule 1 controlled substance under federal law in the US, hemp-derived CBD is more widely accessible, though its legality in terms of federal law is still murky at best.

“There is an urgent need for a safe treatment for young people at risk of psychosis,” added Dr. Bhattacharyya. “One of the main advantages of cannabidiol is that it is safe and seems to be very well tolerated, making it in some ways an ideal treatment.”

The scans showed abnormal activity in the brains of the participants experiencing symptoms, as compared to the healthy control group – that much was expected. But the brains of those who had taken a dose of CBD showed less severe abnormalities than the brains of those who had taken a placebo, suggesting that the compound was “resetting” abnormal activity in the key brain areas.

There are a number of specific factors that convey increased risk of developing a psychotic disorder after cannabis exposure. A family history of schizophrenia has been shown to increase the risk of psychosis following cannabis exposure [24, 25]. For example, one study comparing 54 cannabis-using patients with schizophrenia to 71 patients who did not use cannabis found cannabis-using patients to have higher rates of psychosis in their family histories, especially if cannabis use preceded their psychotic symptoms [24]. Another population registry-based study found that family history of schizophrenia increased both the risk of schizophrenia and of acute cannabis-induced psychosis [25]. A history of child abuse (including sexual, physical, and/or emotional abuse) or neglect also increases the risk of developing schizophrenia after cannabis use [26–31]. Two large, population-based, longitudinal studies, in Greece and the Netherlands, both replicated findings that childhood maltreatment and cannabis use precede and are independently associated with increased risk of later psychosis, and that the combination of the 2 risk factors is synergistically associated with an increased risk of psychosis [28]. Finally, being born in and growing up in an urban environment is positively associated with the combination of cannabis use and psychosis. For instance, a large prospective study in and around Munich, Germany, found that the increased risk of psychosis following cannabis use was much greater for those who grew up in the city of Munich than for those raised in surrounding rural areas [32].

Four genes have emerged as possibly modulating the risk of developing a psychotic illness following exposure to cannabis, in increasing order of replication in the literature: the brain-derived neurotrophic factor (BDNF) gene, the cannabinoid receptor 1 (CNR1) gene, the catechol O-methyltransferase (COMT) gene, and AKT1 [40]. A single nucleotide polymorphism (SNP) of the gene encoding brain-derived neurotrophic factor, Val66Met (rs6265), has been shown to moderate the relationship between cannabis use and age of onset of psychosis. The interaction may be limited to females for unknown reasons; female cannabis users who carry the Val/Val polymorphism displayed psychotic symptoms on average 7 years earlier than female Met carriers [41]. CNR1 encodes the cannabinoid receptor 1 (CB1R), which is widespread throughout the central nervous system (CNS), including the brain. In a functional magnetic resonance imaging study of working memory in healthy subjects, those carrying a G allele in a SNP (rs1406977) of CNR1 associated with lower receptor expression levels in the prefrontal cortex who also had a history of cannabis use demonstrated decreased working memory and abnormally increased ventromedial prefrontal connectivity than those with AA alleles, as well as to those with a G allele but no history of cannabis use [42]. A variation of CNRI involving AAT triplet repeats has been associated with a “hebephrenic” type of schizophrenia, characterized by prominent negative symptoms and disorganization [43, 44]. Catechol O-methyltransferase is one of the enzymes responsible for degrading catecholamines, including dopamine. A Val158Met SNP (rs4680) in COMT has been found to increase the risk of schizophrenia amongst people with premorbid cannabis use [45], although this finding has not been consistently replicated [46]. The Val/Val genotype has also been associated with increased symptom severity in individuals with schizophrenia who are using cannabis [45]. Two studies found a 3-way interaction between the COMT SNP, cannabis use, and a history of child abuse. Carriers of the COMT Val/Val genotype who were exposed to both childhood abuse and cannabis had more severe psychotic symptoms, whereas amongst carriers of a Met allele, childhood abuse was associated with more severe psychotic symptoms in noncannabis users [26, 27]. AKT1 encodes for a protein kinase involved in second messenger transduction at the CB1R, and has also been implicated in increasing the risk for psychosis in cannabis users. An SNP (rs2494732) has been associated with a greatly increased risk of developing a psychotic disorder amongst cannabis users: compared with T/T carriers, C/C carriers demonstrated 7-fold odds of developing psychosis [47]. In a study examining potential mechanisms behind this gene-by-cannabis exposure interaction, it was found that subjects with schizophrenia carrying the C/C genotype with premorbid cannabis use performed worse on cognitive measures of sustained attention as than C/C genotype subjects without premorbid cannabis use, even after long-term abstinence from cannabis. T/T carriers with cannabis use performed as well or better than T/T carriers without cannabis use, suggesting a differential effect on brain functioning and psychosis risk of cannabis use depending on underlying genetic vulnerability [48].

Cannabis and Schizophrenia

Five published clinical studies have examined the antipsychotic effects of CBD in humans. In 1995, Zuardi et al. [91] published a case report in which a patient with treatment-resistant schizophrenia was administered up to 1500 mg orally per day of CBD for 26 days, with symptomatic improvement and no adverse effects. In a follow-up report, the same group studied the effects of up to 1280 mg orally per day of CBD for 4 weeks in 3 patients with treatment-resistant psychosis. Only 1 of the 3 patients improved, but none had adverse effects [92]. In another study, CBD up to 600 mg orally per day for 6 weeks significantly reduced psychotic symptoms in 6 patients with Parkinson’s disease and was well tolerated [93]. Hallak et al. studied the acute effects of CBD on selective attention, as well as electrodermal responsiveness to auditory stimuli, in 28 medication-free schizophrenic patients. They found no differences on any measure between patients who received a single oral dose of CBD 300 mg, CBD 600 mg, or placebo [94]. Finally, the largest clinical study of the effects of CBD on psychosis to date was a 4-week, double-blind, randomized trial comparing CBD, up to 800 mg per day (n = 20), to the antipsychotic amisulpride (n = 19). Both groups significantly improved on ratings of positive and negative symptoms with no significant differences between treatment groups. However, the CBD group experienced significantly fewer side effects, including prolactin elevations, extrapyramidal symptoms, and weight gain [76]. Further analysis showed that CBD treatment led to a significant increase in serum anandamide levels, which correlated with improvement in symptoms [76]. If replicated in larger samples, such findings could suggest that CBD may have significant antipsychotic properties with superior tolerability to currently available antipsychotic drugs [73]. However, further larger scale, placebo-controlled trials are needed to determine whether CBD would make an effective and safe alternative to available antipsychotic treatments.

Whereas CBD is very well tolerated and has few psychoactive effects on its own [79], it counteracts several effects of THC and other CB1R agonists in healthy subjects [80], including anxiety, euphoria, and psychosis [3, 73, 81]. CBD has also been shown to attenuate THC-induced memory impairment [80]. However, in mice and rats, CBD inhibits metabolism of THC, so that pretreatment with CBD can increase brain concentrations of THC and thereby potentiate its behavioral effects [82]. In a series of functional magnetic resonance imaging experiments in which CBD and THC were administered to healthy human subjects, the 2 compounds produced largely opposite patterns of activation during tasks involving memory, emotional processing, salience, and response inhibition in key brain regions implicated in schizophrenia, such as the striatum, prefrontal cortex, and hippocampus [3, 81]. There is also evidence that using cannabis with a higher CBD/THC ratio is associated with a lower risk of psychotic disorders, subthreshold psychotic symptoms, and cognitive changes related to psychosis [3], from both studies analyzing THC and CBD concentrations in hair samples [83, 84], and from a study analyzing the content of the cannabis that subjects reported regularly using [85]. Cannabis users have been found to have evidence for neurotoxicity in the prefrontal cortex based on lower levels of N-acetylaspartic acid measured by proton magnetic spectroscopy, which reflects neuronal integrity [86]. A higher ratio of CBD to THC concentrations in hair samples of cannabis users was associated with higher levels of N-acetylaspartic acid in the putamen/globus pallidus region [86], as well as larger hippocampal volume [87, 88].

Gene-by-Environment Interactions

The ECS comprises 2 cannabinoid receptors, CB1R in the CNS and CB2R in the periphery [49]; 2 main endogenous ligands, anandamide and arachidonoylglycerol (2-AG) [50]; 2 main endocannabinoid synthesizing enzymes, N-acyl phosphatidylethanolamine phospholipase and diacylglycerol lipase; and 2 degradation enzymes, fatty acid amide hydrolase and monoacylglycerol lipase [51]. The system is involved in complex regulation of emotion, reward, and cognition, and has been implicated in both inflammatory and neuroprotective processes [51]. 2-AG is a full agonist at both CB1R and CB2R, whereas anandamide is a partial agonist at CB1R. Both 2-AG and anandamide are retrograde messengers; they are released postsynaptically and act presynaptically to inhibit release of many excitatory and inhibitory neurotransmitters, including dopamine, glutamate, and γ-aminobutyric acid (GABA) [52]. Several other molecules also act at cannabinoid receptors, including N-arachidonoyl-dopamine, noladin ether, oleamide, N-oleoylethanolamide, N-palmitoylethanolamide, and virodhamine. In addition, endocannabinoids may also modulate neuroplasticity and exert other effects by acting at transient receptor potential vanilloid 1channels, G protein-coupled receptor 55, and peroxisome proliferator-activated receptors α and γ [53]. CB1R expression is high in brain areas with a greater density of dopaminergic neurons, such as frontal regions, basal ganglia, cerebellum, hippocampus, amygdala, and substantia nigra, and interactions between the endocannabinoid and dopaminergic systems have been thought to play a role in the relationships between cannabinoids and psychosis [54]. CB1R are expressed on GABA-ergic and glutamatergic axon terminals in the hippocampus where they modulate long-term potentiation, which is involved in memory and plasticity [55]. The effect of CB1R agonists on long-term potentiation may be biphasic, producing enhancement at low concentrations and inhibition at higher concentrations; vanilloid receptors, which are co-localized with CB1R, may play a role in this modulatory function [56].