Endocannabinoid System and Exogenous Cannabinoids in Depression and Anxiety: A Review.
- Authors
- Hasbi, Ahmed; Madras, Bertha K; George, Susan R
- Year
- 2023
- Journal
- Brain sciences
- PMID
- 36831868
- DOI
- 10.3390/brainsci13020325
- PMCID
- PMC9953886
There is a growing liberalization of cannabis-based preparations for medical and recreational use. In multiple instances, anxiety and depression are cited as either a primary or a secondary reason for the use of cannabinoids. The purpose of this review is to explore the association between depression or anxiety and the dysregulation of the endogenous endocannabinoid system (ECS), as well as the use of phytocannabinoids and synthetic cannabinoids in the remediation of depression/anxiety symptoms. After a brief description of the constituents of cannabis, cannabinoid receptors and the endocannabinoid system, the most important evidence is presented for the involvement of cannabinoids in depression and anxiety both in human and from animal models of depression and anxiety. Finally, evidence is presented for the clinical use of cannabinoids to treat depression and anxiety. Although the common belief that cannabinoids, including cannabis, its main studied components-tetrahydrocannabinol (THC) and cannabidiol (CBD)-or other synthetic derivatives have been suggested to have a therapeutic role for certain mental health conditions, all recent systematic reviews that we report have concluded that the evidence that cannabinoids improve depressive and anxiety disorders is weak, of very-low-quality, and offers no guidance on the use of cannabinoids for mental health conditions within a regulatory framework. There is an urgent need for high-quality studies examining the effects of cannabinoids on mental disorders in general and depression/anxiety in particular, as well as the consequences of long-term use of these preparations due to possible risks such as addiction and even reversal of improvement.
Schematic representation of the endocannabinoid signaling system. Endocannabinoids (eCBs) 2AG (2-arachidonoylglycerol) and AEA (anandamide) are synthesized in postsynaptic neurons and act pre-synaptically at their receptors (CB1Rs) in a retrograde mode (A). eCBs can also activate CB1R localized post-synaptically in some cases. In general, activation of CB1 receptors by eCBs decreases the probability of neurotransmitter release through multiple mechanisms, comprising inhibition of calcium influx and activation of potassium channels These effects are terminated by eCB reuptake followed by degradation: 2AG by MAGL pre-synaptically and AEA by FAAH post-synaptically. A large proportion (45–48%) of synapses in different brain regions is tripartite (B), formed by pre-synaptic and post-synaptic neurons, and a glial cell—an astrocyte—which expresses CB1R. In response to neuronal activation, eCBs released by the postsynaptic neurons can activate CB1R expressed on astrocytes. The astrocytes respond with an increase in intracellular calcium leading to release of gliotransmitters (B).
LLM interpretation
This figure is a schematic diagram illustrating the endocannabinoid signaling system in two scenarios: (A) a bipartite synapse and (B) a tripartite synapse involving an astrocyte. The diagrams show the synthesis of 2-AG and AEA in the postsynaptic neuron, their retrograde transport to activate pre-synaptic CB1 receptors (CB1R) to inhibit neurotransmitter release, and their subsequent degradation by MAGL and FAAH. Panel B further depicts eCBs activating CB1R on an astrocyte, triggering an increase in intracellular calcium ($\text{Ca}^{2+}$) and the release of gliotransmitters.
Modulation of neuronal activity by the endocannabinoid system. Endocannabinoids modulate neuronal activity as illustrated for dopamine (DA) neurons with cell bodies in the ventral tegmental area (VTA). CB1 receptors on GABAergic terminals (A) can facilitate dopaminergic activity through suppression of the inhibitory input onto the GABA receptors present on DA neurons, leading to an increase of DA release. Further, the activation of mGluR5 receptor by released glutamate (B) leads to the synthesis and release of 2-arachidonoylglycerol (2-AG), which then retrogradely activates CB1 receptors to inhibit additional glutamate release.
LLM interpretation
This figure is a schematic diagram illustrating the modulation of dopamine (DA) neurons in the ventral tegmental area (VTA) by the endocannabinoid system. Panel A shows how 2-AG activates CB1 receptors on GABAergic terminals to suppress inhibitory input, resulting in increased DA release at the nucleus accumbens (NAc) terminal. Panel B depicts a retrograde signaling pathway where glutamate activates mGluR5 receptors, triggering the synthesis of 2-AG via PLC and DAGL to inhibit further glutamate release through CB1 receptors.
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