Dispense MagazineThe Biochemical System Controlling the Effects of Cannabis
by Jahan Marcu,
Chief Scientific Officer, Americans for Safe Access (safeaccessnow.org) Follow @SafeAccessNow and @PatientFocused on Twitter for more information.
In every one of us there is a complex biological system working to keep our brains and body in order. When this biochemical system is functioning optimally it is keeping you happy, calm, and helping you to fight infection, digest food properly, maintain regular sleep, and brain function. The housekeeping properties of this system are vital to a healthy existence. The system is built out of proteins called CB1 and CB2 “receptors” and the “endocannabinoids” that bind to them. The endocannabinoid system keeps our brain and body healthy1.
Studies with genetically modified mice, which are created without CB1 or CB2 receptors, has shown that without this biochemical system we would probably die at birth2-5. Studies in both humans and animals demonstrate that blocking this biochemical system can result in dreadful consequences, including but not limited to depression, stress, nausea, vomiting, diarrhea, anxiety and increased suicidality6-9. The only antagonist drug ever to be marketed to humans that blocked our cannabinoid receptors – Acomplia® (rimonabant, Sanofi-Aventis) – was quickly withdrawn from the market due to its negative health consequences10.
Human and animal studies show that stimulating this biochemical system can have both highly beneficial health effects and few negative side-effects11,12. The scientific evidence supporting the benefits related to stimulating the endocannabinoid system is overwhelming.
HOW MEDICAL CANNABIS WORKS
Cannabis has been used for centuries to treat neurological and neurodegenerative disorders, such as epilepsy or spastic disorders. The medieval Arab writer Ibn al-Badri documented the use of hashish or a cannabis concentrate to cure a neurodegenerative disorder (probably epilepsy) afflicting the son of the chamberlain of the Caliphate Council in Baghdad11. Centuries later western physicians including W.B. O’Shaughnessy and other British neurologists of the 19th century confirmed the benefits of cannabis concentrates (hashish, hash oil, and tinctures) in the treatment of spasticity, convulsions and related neurodegenerative disorders.
The progression of diseases such as multiple sclerosis, Parkinson’s Diseases, Lou Gehrig’s, and other neurodegenerative diseases are affected by neuro- inflammation and neuro-degeneration (brain cell death)13. Cannabis can have a positive effect on these and related disorders in a number of ways. The active ingredients on the cannabis plant can decrease neuro-inflammation by inhibiting the movement, growth, and activity of immune cells. Basically, when the endocannabinoid system is stimulated by the mixture of compounds from the cannabis plant, it results in decreasing the migration and activation of the immune cells that maintain the environment of neurodegenerative disorders, disrupting the signals sustaining inflammation and cell death14.
Another important aspect of neurodegenerative disorders is the irreversible death of neurons leading to progressive dysfunction. Excessive glutamate receptor activity is known to cause neuronal cell death by damaging cells and creating reactive oxygen species. The CB1 receptor proteins found in the brain have a direct affect on neurons by limiting glutamate release when they are stimulated on presynaptic nerve terminals. Cannabis compounds are also wonderful anti-oxidants, reduce oxidative damage, and block the activities of inflammatory signaling molecules like TNFα. Stimulation of the endocannabinoid system also has pro- survival effects on brain cells15,16.
At the present time, the evidence of the endocannabinoid system as an appropriate target to treat disease does not solely come from the limited-approved studies on marijuana from the National Institute of Drug Abuse (NIDA). The information comes from a wealth of new information about stimulating this biological system and the mechanisms explaining the central role of this system in health. No physiological system has ever been studied that hasn’t been found to be, at least, positively modulated by the endocannabinoid system—it is inherent to our proper functioning. Recent reports provide convincing evidence that cannabis, cannabis extracts, and mixtures of the plants active ingredients are useful for treating epilepsy (i.e., Dravet’s), traumatic brain injury, cancers, post- traumatic stress disorder, HIV, wasting, glaucoma, Crohn’s disease, multiple sclerosis, autism, and other diseases and symptoms18.
Since the isolation of tetrahydrocannabinol (THC) in the 1960’s, several groups have explored THC for its therapeutic effects (i.e., anti-epileptic effects) in adults and children19,20. THC is the superior anti-convulsant compound found on the plant. Its efficacy is increased with other plant components, such as cannabidiol (CBD). In mammals, the receptors for THC, CB1 and CB2 are up-regulated during disease, such as during an epileptic episode or inflammation. During disease state or injury the endocannabinoid system up-regulates it’s activity. This up-regulation in certain disorders is documented to increase both the release of endocannabinoids and the levels of these receptors. Up-regulation appears as an attempt to reduce or abolish unwanted effects or to slow the progression of various disorders. The body is asking for a compound to activate these receptors to decrease inflammation, repair damaged cells, and ultimately slow the progression of degenerative disorders. The evidence supporting this biochemical system being up-regulated in diseases is established in a number of disease models.
The evidence demonstrates that this biological system is intimately involved in the regulation of many important aspects of health. There are anectodotal, basic scientific evidence, and clinical trials of cannabis and cannabis-based medicines affecting symptom relief and increasing the quality of life in many neurodegenerative disorders. Many of these diseases are characterized by changes in as the endocannabinoid system comprised of the cannabinoid receptors (i.e.,CB1 and CB2) the endocannabinoids. Their activity and expression levels are altered in disease states. This endocannabinoid system is altered in diseases and conditions. For example, this system is altered in epileptic patients, during epileptic seizures and the evidence shows that modulation of this biological system can alter seizure activity.
Over 30 controlled human studies have looked at the effect of a variety of cannabis-based medicines (including whole-plant inhaled, oral capsules, and oral extracts) for the treatment of neurodegenerative disorders. The data generated from these clinical trials suggest that cannabis can result in improvements in spasticity, muscle spasms, pain, sleep quality, tremors and the patient’s general condition12,21.
The summation of these clinical trials suggests THC as the primary therapeutic ingredient. However, the presence of CBD may reduce unwanted side effects of THC. Animal and basic research also demonstrates a potential for synergizing or enhancing certain therapeutic effects when THC and CBD are applied in an appropriate combination for a specific condition. The therapeutic rationale for combining THC and CBD, and other cannabis plant components in fixed ratios, can result in a decrease in unwanted side effects and an enhancement of benefits.
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23. Novotna, A. et al. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols* (Sativex®), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. European Journal of Neurology 18, 1122–1131 (2011).
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