Cannabinoids are compounds obtained from cannabis, a product of the hemp plant Cannabis sativa. This has been used extensively and for a very long time as a recreational drug, as well as for medicine.
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Cannabinoids that are found abundantly in cannabis (the herbal form) or hashish (the resin form) include the 21-carbon alkaloid Δ9-tetrahydrocannabinol (Δ9 -THC) and cannabidiol (CBD). Endogenous cannabinoids (ECs) have also been identified, such as anandamide (N-arachidonylethanolamine) and 2-arachidonylglycerol (2-AG) and its ether form, noladin ether.
Cannabinoids act mainly at the level of two receptors: the type 1 cannabinoid receptor (CB1R) and the type 2 cannabinoid receptor (CB2R). These are G-protein-linked receptors.
Cannabinoid (CB) receptors form part of the important endocannabinoid system (ECS). CB1 receptors are mostly in key brain areas like the cortex, cerebellum, and basal ganglia, besides the hippocampus, but also in peripheral tissues like the intestine, liver, immune cells, and fatty tissue.
CB2 receptors are mostly in the peripheral lymphoid tissue and immune cells, but also in the brain. They have distinct anti-inflammatory or immunosuppressive effects. Other ligands also bind to CB receptors, while ECs and their precursors may also interact with important metabolic regulators such as the nuclear receptor, the peroxisome proliferator-activated receptor-gamma (PPARγ).
PPARs are transcription factors and affect gene expression in several regions of the genome, modulating lipid and glucose metabolism, vascular tone, and inflammation. PPARγ improves insulin sensitivity and reduces cardiovascular events and inflammation.
The discovery that CB receptor ligands (ECs) were produced in the human brain led to the theory that there was a central endocannabinoid neuromodulatory system (ECS). This is today thought to regulate multiple brain functions such as pain, memory, neuroendocrine function, opiate dependence, appetite for food, psychomotor control, and brain development.
Notably, anandamide is expressed most abundantly in the hippocampal cells.
Activation of CB1 receptors modulates the release of a variety of neurotransmitters in the CNS, both excitatory and inhibitory neurotransmitters, glutamate and GABA, respectively, in key regions such as the hippocampus, basal ganglia, cerebellum, and brainstem.
These compounds also affect the release of slower-acting neurotransmitters such as opioids, acetylcholine, and dopamine or norepinephrine. Overall, they reduce synaptic plasticity, which could affect learning and memory.
The effect of EC tone on movement control could mean that the ECS could benefit from specifically-directed cannabinoids in movement disorders like Parkinson’s disease or Tourette’s syndrome, or even multiple sclerosis (MS).
Cannabinoids also stimulate the medial forebrain bundle (MFB) that is the reward system, but indirectly, while their interactions with leptins may stimulate food intake by producing a hedonistic perception of food. These compounds can also reduce the perception of pain by inhibiting activity in the rostral ventromedial medulla (RVM) in the brainstem, somewhat like the opioid morphine.
Cannabinoids may protect neurons against hyperexcitation by glutamate, ischemia, or oxidative damage, but more research is necessary to confirm these hypotheses, or to confirm their potential use as anticonvulsants. Conversely, Δ9-THC has been demonstrated to be toxic in cultured neurons, causing shrinkage and DNA breakdown via CB1 receptor activity.
Adverse effects in humans
Many recent studies are showing that cannabis, used over the long term, causes several side effects in animals, but in humans, more needs to be known.
Cannabis typically produces euphoria, called a “high”, but may also sharpen sensory perception, increase the heart rate, impair concentration, reduce nausea and enhance the appetite. Cognitive skills are impaired, including thinking, memory, and psychomotor skills.
Panic attacks and depersonalization are also frequently associated, with young people especially being prone to loss of motivation. Using cannabis at high dosages over a long period can cause cognitive skills to deteriorate slowly but permanently, perhaps because of neuronal toxicity.
Adolescent use and chronic damage
Hippocampal shrinkage is linked to lifetime cannabis exposure and the occurrence of psychotic symptoms, along with a drop in amygdala volume. These brain regions are involved in memory and executive/effective processing.
The long-term effects are likely to be still more complex and drastic, given that cannabis is almost always first used in adolescence, while the brain is still maturing. During this period of rapid growth and pivotal maturational changes, CB receptors are expressed abundantly in the white matter of the brain, making it peculiarly prone to aberrant development following chronic high cannabis exposure.
Prolonged cannabis exposure from adolescence can reduce ECS development, causing aberrant white matter development. The gray matter of the central nervous system may also be reduced by regular cannabis use. In both these situations, the age at which regular use begins is key to the extent of eventual damage, as well as the dosage.
These changes occur in regions that are linked to mood and emotions, as well as to personality and social behavior. Hippocampal changes may lead to impaired memory and psychosis, while gray matter increase in the cerebellum found in regular cannabis users could be due to abnormalities of brain development during adolescence triggered by early drug exposure.
The medical utility of cannabinoids
Cannabinoids also interact with neurotransmitters including dopamine, glutamate, serotonin, and gamma-aminobutyric acid (GABA), which suggests they may have a medical use. For instance, cannabinoids might help treat neuropathic pain, or the pain of cancers, relieve the spasticity of multiple sclerosis (MS), and are already being used to treat nausea and vomiting in chemotherapy.
Other uses include helping patients with human immunodeficiency virus (HIV) to gain weight, restore sleep and treat Tourette’s syndrome. However, these benefits come at a price.
Cannabinoids are linked to acute side effects, such as weakness, confusion, balance issues, sleepiness, hallucinations, euphoria, dizziness, and dry mouth. They can also, paradoxically, cause anxiety in some individuals. However, the high cannabidiol (CBD) content of cannabis, known to reduce anxiety, is responsible for the self-treatment with cannabis in many anxiety disorder patients.
CBD is also known to have anticonvulsant effects, along with its derivative cannabidivarin, though the mechanism remains to be resolved. CBD may act by modulating neuronal excitability and neurotransmission, as well as via its anti-inflammatory effects. Further studies are required.
Cannabinoids and neuroinflammation
The ECS is important in modulating inflammation in the central nervous system. Many drugs that affect the ECS reduce cytokine and chemokine levels, besides blocking the proliferation and activation of B and T cells. Moreover, they drive T cells and dendritic cells, representing adaptive and innate immunity, into apoptosis, leading to immunosuppression.
THC has been shown to prevent the activation of T helper cells as well by its ability to block macrophage-mediated antigen presentation. ECs elicit the anti-inflammatory microglial phenotype.
While microglial cells always express CB1 receptors, CB2 receptors are expressed only after cell activation. The upregulation of the ECS during inflammation helps protect the cells from damage by preventing the surge of inflammatory signaling molecules from activated microglia and other immune cells.
The ECS also regulates anti-inflammatory signaling by activated immune cells, chiefly via CB2. Thus, CB2 agonists could help block inflammatory mediator production like nitric oxide or TNF-α during acute injury, thus preventing acute neuronal damage due to excitation.
Arachidonyl-2’-chloroethylamide (ACEA), a selective CB1 receptor agonist, was able to prevent neuronal degeneration and neuronal death. The latter effect was linked to reduced endoplasmic reticulum stress.
Cannabinoids may help reduce neuroinflammation
The role played by inflammation in Alzheimer’s disease (AD) and Parkinson’s disease, MS, and HIV encephalitis explains why cannabinoids can protect the brain against the damage due to this phenomenon. This is due to prevent microglial activation.
Two CB receptor agonists have been able to prevent the apoptosis of lymphocytes in peripheral blood in the presence of beta-amyloid, characteristic of AD, or hydrogen peroxide. In human MS, the spinal cord shows high expression of CB2 macrophages and microglia, with ECS perturbation. ECs act via both CB1 and CB2 receptors to exert their anti-inflammatory actions via mitogen-activated protein kinase phosphatase-1 (MAPK1).
While much more evidence is required, the promise offered by cannabinoids in managing inflammation within the brain needs to be explored. Scientists are working on developing CB2 selective agonists that may avoid psychotropism while delivering anti-inflammatory benefits.