Cannabinoids: Therapeutic mechanisms

This is a short review about cannabis therapeutic usage and potential mechanisms of action. 

While the endocannabinoid system is relatively new discovery some of its components are already studied and could provide insight on cannabis effects.

Simplified scheme of Endocannabinoid components
The purpose of the scheme is to visualise some components of the endocannabinoid system. It does not represent all components or their interactions.

Receptors 

The main receptors identified so far are CB1 and CB2. It is known that CB1 cannabinoid receptor is found in very high levels in the central nervous system and in lower densities in peripheral neural and other tissues. On the other hand CB2 cannabinoid receptor is known to be associated with the immune system.

However, there are some membrane receptors known as G protein-coupled receptors (GPRs), which could also be involved in the endocannabinoid system. For example, a member of this group is the receptor GPR 18, which is shown to be activated by THC. GPRs are known to be involved in nervous system, metabolism (reducing weight gain), insulin secretion, etc.

Except CB1 and CB2 there is data that endocannabinoids can activate TRPV1 ion channels – for example, there is data that CBD can activate TRIPV1, which suggests that there could be ionotropic cannabinoid receptor. TRPV1 is found in the nervous system and is associated with pain management.

Endocannabinoids could also activate members of the nuclear hormone receptor family known as PPARs (peroxisome proliferator-activated receptors). PPARs are known to be involved in cancer cells development.

Endocannabinoids

Apart from endocannabinoid receptors the system includes endocannabinoids (for example, anandamide (AEA) and 2-arachidonoylglycerol (2AG)). Ananadamide is involved in different processes like memory, sleep and eating patterns, pain relief. 2-Arachidonoylglycerol participates in the processes of signaling in the brain.

Enzymes

And, of course, enzymes involved in catalytic processes in the endocannabinoid system like:

  • FAAH (fatty acid amide hydrolase is targeted for reducing pain, anxiety and post-traumatic stress disorder)
  • NAAA (N-acylethanolamine acid amidase is involved in insulin sensitivity and fatty liver disease)
  • MGL (monoacylglycerol lipase is target for anti-emetic and anti-inflammatory medications)
  • ABHD6 and 12 (serine hydrolases) and many more.

All this data suggests that endocannabinoid system is more complex than we know so far and there could be many different mechanisms involved.

But what is the therapeutic potential of cannabinoids? What do we know so far?

Pain

Cannabinoids have shown to be effective in pain relief in animal models and more specifically in inflammatory and neuropathic pain. It is documented that pain relief effect is result of CB1 and CB2 modulation, however there is data that inhibition of FAAH or MGL enzymes could also be part of the mechanism of pain relief. Interestingly some of the non-steroid anti-inflammatory drugs, which are already on the market, are also involved in FAAH inhibition.

Nausea and vomiting

Similar mechanism of inhibition of FAAH and MGL enzymes is described in suppressing nausea and vomiting. Synthetic analogues of THC are used for cancer patients in chemotherapy to prevent nausea and vomiting.

Eating disorders

Increased levels of endocannabinoids anandamide and 2AG have shown to increase appetite. Animal models have demonstarted that inhibition of CB1 cannabinoid receptor leads to reduced appetite.

Glaucoma

Activation of CB1 receptor was shown to lead to rapid reduction in intraocular pressure.

Neurodegeneration / Neuroprotection

It was observed that patients with Huntington disease have reduced expression of CB1 cannabinoid receptor in the brain – in the region associated with locomotor function – while microglial cells express CB2 receptor. Similar case was observed in patients with Parkinson’s disease. The data about Alzheimer seems to be contradictory.

Also CB1 cannabinoid receptors are activated in cerebral ischaemia / stroke.

Multiple sclerosis

It is studied that CBD and THC benefit multiple sclerosis patients by modulating CB1 and CB2 via PPARs.

Schizophrenia

There is no conclusive data on CBD and THC effect in schizophrenia, although THC and CBD have shown anti-psychotic effect.

Cancer

Cannabinoids have shown anti-tumor activity, for example THC induces apoptosis (cell death) via CB1 and CB2 receptors modulation.

Epilepsy

CBD has shown very promising results in treating epilepsy.

Stress and anxiety

Anti-anxiety effect is observed when the levels of anandamide are reduced. Stress relief is also observed when FAAH enzyme is inhibited and this process is mediated by CB1 receptor.

Although some mechanisms are already known there is still a lot to be explored in relation to endocannabinod system and its involvement in different processes of the human body.

Sources

 

Read more at Cannabis Research section 

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