Studies carried out in humans have consistently demonstrated that the endocannabinoid system is central to emotional homeostasis and cognitive function. Present findings point specifically to the endocannabinoid system, part of the body’s neurological cell-signaling system, as a critical pathway in depression and schizophrenia and other psychiatric disorders. Cannabidiol (CBD) is a promising drug in potential therapy, due to its wide spectrum of pharmacological actions within and ancillary to the endocannabinoid system.
Why the endocannabinoid system
On the evidence of positron emission tomography and post-mortem studies, the endocannabinoid system, homoeostatic in cortical excitation and inhibition, is dysfunctional in mood and related disorders
that include depression, schizophrenia, and suicide. One notable abnormality is in the gene that codes for the cannabinoid-1 receptor (CB1). In prefrontal cortex homogenates from suicide victims with major depression and matched control subjects, stimulation of [35S]GTPγS binding, activation of Gα protein subunits, inhibition of adenylyl cyclase by the cannabinoid agonist WIN55,212-2, and [3H]CP55,940 binding have all shown that CB1 receptor-stimulated [35S]GTPγS binding is significantly elevated in depressed patients.
Investigatory efforts like this have largely focused on evaluating CB1 binding, but new radiotracers that target enzymes involved in endocannabinoid degradation, notably fatty acid amide hydrolase (FAAH), will allow for illumination of other mechanisms at work too.
CB2, as well, and also GPR55, may play a relevant role in the neurobiology specific to suicide. In the dorsolateral prefrontal cortex of 18 suicide victims with no clinical psychiatric history or treatment with anxiolytics or antidepressants, CB2 and GPR55 gene expressions have been noted to be significantly low. CB2 protein expression was high, however, as were CB2-GPR55 heteroreceptor complexes. There were also CB2-GPR55 receptor heteromers in neurons and astrocytes, though microglial cells showed no expression.
It is the preclinical evidence overall that cannabinoid agonists and endocannabinoid enhancers such as the fatty acid amide hydrolase inhibitors can impact mood regulation that have opened new lines of investigation in possible depression therapy. These agents are known to increase serotonin and noradrenergic neuronal firing activity and increase serotonin release in the hippocampus. Cannabinoid-derived drugs appear to potentiate monoaminergic neurotransmission and hippocampal neurogenesis through different pathways than classical antidepressants.
Experimental intervention with agonists
The effects of exogenous cannabinoid agonists, which do affect emotional reactivity in dose- and context-dependant ways, have been studied, and so has the related approach of amplifying the effects of endogenous cannabinoids, specifically anandamide (AEA) and 2-arachidonoylglycerol (2-AG), by preventing their deactivation. Anandamide, tetrahydrocannabinol (THC) and CBD combine antidepressant, antipsychotic, anxiolytic, analgesic, anticonvulsant actions, and FAAH has been the target of research looking for selective inhibitors that might prolong AEA actions in vivo. Among the inhibitors developed, the compound URB597 has been shown to inhibit FAAH activity in vivo and cause brain AEA levels to increase. This elicits marked anxiolytic and antidepressant effects in animal models. Similar results come with pharmacologically blocking the AEA transport system, which is responsible for the intracellular uptake of AEA from the synaptic cleft. This could amplify CB1 activation mainly where AEA release is higher.
As expected, it appears to be principally the CB1 receptors, in the medial prefrontal cortex and ventral hippocampus, that are responsible for the antidepressant- and anxiolytic-like phenotype brought about by systemic receptor agonists. This parallels biochemical studies showing that endocannabinoids are downregulated in these two regions following exposure to chronic stress. Conversely, CB1 receptor activation within distinct amygdalar nuclei yields opposing behavioral effects; local stimulation of CB1 receptors in the basolateral amygdala and central amygdala is, respectively, anxiogenic and anxiolytic.
What these experimental interventions with cannabinoid agonists may show is that schizophrenia and depression are actually two poles of endocannabinoid system deregulation. It is possible that an altered endocannabinoid system contributes to both, by modifying the HINT1-NR1 C1/GPCR ratio, thereby altering GPCR-NMDAR cross-regulation.
Among the exogenous cannabinoids under investigation, CBD has the widest therapeutic potential yet known, over a wide range of psychiatric disorders, that includes anxiety and depression, and even psychosis. THC associates with acute and neurodevelopmental propsychotic side effects, CBD displays antipsychotic properties, and can also prevent the acquisition of emotionally irrelevant memories, and reverse amphetamine-induced neuronal sensitization through selective phosphorylation of the rapamycin (mTOR) pathway.
Why CBD has particular promise in schizophrenia is not clear, but it has been shown to have beneficial effects in patients. These effects do not appear to depend on dopamine receptor antagonism, so CBD probably represents a new class of treatment for the disorder. Similarities to the effects of clinical antidepressant or atypical antipsychotic drugs are plain. For example, CBD attenuates the decrease in hippocampal neurogenesis and dendrite spines density induced by chronic stress and prevents microglia activation and the decrease in the number of parvalbumin-positive GABA neurons in at least one pharmacological model of schizophrenia.
These mechanisms, which are not entirely understood yet, depend on the behavioral response being measured. Acute anxiolytic and antidepressant effects appear to be a function of 5-HT1A-mediated neurotransmission in brain areas governing defense responses, including the dorsal periaqueductal gray, bed nucleus of the stria terminalis and medial prefrontal cortex. Activation of TRPV1 channels may help explain the antipsychotic effect of CBD, and the bell-shaped dose-response curves commonly observed with it. More study is warranted to investigate other possible mechanisms, such as inhibition of adenosine uptake, inverse agonism at the CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, or intracellular Ca(2+).
The developmental horizon
Efficacy trials of cannabinoids in psychiatric disorders are still limited, but they are encouraging. Ample experimental evidence shows overall beneficial effects in endocannabinoid modulation, even if scarce clinical indication still limits the use of cannabis-based treatments. To better define the possible clinical indications of cannabinoid-based drugs in psychiatry, a number of issues will need to be better addressed, including genetic variability and psychosocial factors that may affect individual responses.
Cannabidiol, it is safe to say, does have positive effects on attenuating behavior associated with psychosis, anxiety, and depression. As a post-script to the translational medicine narrative, the fluorinated CBD derivative 4'-F-CBD (HUF-101) (1) is even more potent than CBD in behavioral assays in mice predictive of anxiolytic, antidepressant, antipsychotic, and anti-compulsive activity. This may point the way to precision medicine in treatment of these disorders in time.
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The foregoing is a report on trends and developments in the cannabinoid industry. No product described herein is intended to diagnose, treat, cure or prevent any disease or syndrome.
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