In every human there are complex
biological systems working to keep physiological functions in order. When these
biochemical systems are functioning optimally, they maintain optimal mood, help
maintain appropriate levels of immunity, proper digestion, regular sleep, brain
function, etc. The housekeeping properties of these systems have an important
role in modulating health and disease. One of these systems is the
endocannabinoid system (ECS). The system is built out of G protein-coupled receptors
called (CB1 and CB2 “receptors”) and the “endocannabinoids”
that bind to them. The ECS maintains normal cerebral and physiological
function.1
Human clinical trials and animal
studies show that stimulating this biochemical system can have both highly
beneficial health effects and few negative side effects.2,3 Basic
research experiments with genetically modified mice, which are created without
CB1 or CB2 receptors, have shown that without this
biochemical system, the animals (and presumably, humans) would probably die at
birth.4-7 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 even increased tendency for suicide.8-11 The only
antagonist drug ever to be marketed to humans that blocked the cannabinoid
receptors — Acomplia® (rimonabant; Sanofi-Aventis; Paris, France) —
was quickly withdrawn from the market due to its negative health consequences.12
How Medical Cannabis Works Cannabis (Cannabis sativa, Cannabaceae; common name marijuana,
among others) 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 Baghdad.2 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.13,14 However, it was not until the discovery of
the ECS in 1994 that scientists could explain these observations.
The progression of diseases such as
multiple sclerosis, Parkinson’s disease, amyotrophic lateral sclerosis (ALS; Lou
Gehrig’s disease), and other neurodegenerative diseases is affected by
neuroinflammation and neurodegeneration (brain cell death).15 Cannabis
can have a positive effect on these and related disorders in a number of ways.
Tetrahydrocannabinol (THC) from the cannabis plant stimulates CB2
receptors, which decreases neuroinflammation by inhibiting the movement,
growth, and activity of immune cells. Basically, the stimulation of the ECS by constituents
from the cannabis plant results in decreasing the migration and activation of
the immune cells that maintain the environment of neurodegenerative disorders, thereby
disrupting the signals that sustain inflammation and cell death.16
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 (ROS). The CB1 receptors found in the brain have a direct effect
on neurons by limiting glutamate release when stimulated at the presynaptic
nerve terminals. (Glutamate is a key neurotransmitter, derived from glutamic
acid, an amino acid.) Cannabis compounds are also potent antioxidants, reducing
oxidative damage and blocking the activities of inflammatory signaling
molecules like TNFα (tumor necrosis factor-alpha).
Stimulation of the ECS also has pro-survival effects on brain cells.17,18
At the present time, the evidence of
the ECS as an appropriate target to treat neurodegenerative and other diseases
does not come solely from the limited approved studies on marijuana from the U.S.
National Institute on
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. The ECS is inherent to proper human functioning;
in fact, every physiological system that has ever been studied is positively
modulated by it.19 Recent
reports suggest that cannabis, cannabis extracts, and mixtures of the plant’s
active ingredients are useful for treating epilepsy (i.e., Dravet syndrome), traumatic
brain injury, cancers, post-traumatic stress disorder (PTSD), human immunodeficiency
virus (HIV), wasting, glaucoma, Crohn’s disease, multiple sclerosis, autism,
and other diseases and symptoms.20
Since the isolation and structure elucidation
of the main ingredient found in cannabis (THC) in the 1960s, several research groups
have explored THC and other cannabinoids for therapeutic effects (e.g.,
anti-epileptic effects, palliative care) in adults and children.21-23 Also since
the elucidation of THC’s structure, over 100 other plant cannabinoids have been
documented.24-29 The
efficacy of THC can be increased with other phytocannabinoids and plant
compounds such as cannabidiol (CBD) and various terpenes, respectively.30-34 THC and CBD
are both psychoactive but have very different therapeutic mechanisms of action;
THC directly stimulates CB1 and CB2 receptors, while CBD
appears to interact with receptors of other important neurotransmitters, serotonin
and adenosine.33,35 When the
distinct mechanisms of THC and CBD are combined, they can trigger an
enhancement of activity. For example, experimentally derived combinations of
THC and CBD have been documented to synergistically inhibit cancer cell growth
in Petri dish experiments on human grade IV glioma cells by increasing activity
in a specific molecular pathway when co-applied.34 When a 1:1
combination is used clinically, it proves effective at treating multiple
sclerosis without causing intoxication.36-38
In mammals, the ECS is modulated during
disease or injury; for example, CB2 receptor density is increased
during inflammation or bone injury.39-42 This
upregulation or modulation during disease or injury is associated with increases
in both levels of endocannabinoids and the expression of the cannabinoid receptors
on the cell membrane.1,43,44 Modulation
of the ECS may be an attempt by the body to reduce or abolish unwanted effects
or to slow the progression of various disorders. There is evidence supporting a
modulation of this biochemical system in a number of disease models.2 Additionally,
a number of genetic mutations and polymorphisms of the ECS (e.g., CB1
and/or CB2 receptor mutations) in the human genome are associated
with diseases in human populations, such as anorexia, bulimia, migraines,
chronic pain, gastrointestinal disorders, mental disorders, alcoholism, and
other treatment-resistant conditions.45-50 A mutation
or fault in the ECS that may underlie a disease or condition has been coined as
the Clinical Endocannabinoid Deficiency Syndrome.47
Conclusion In addition to anecdotal reports and more than 30,000 basic scientific studies
with cannabinoids, there are also over 100 published clinical studies that have
looked at the effect of a variety of cannabis-based medicines (including
inhaled whole-plant material, oral THC capsules, and cannabis extracts) on the
treatment of a wide range of disorders.3,36,51
The data generated from these clinical
trials suggest that cannabis and its various preparations interact with the ECS
to result in improvements in spasticity, muscle spasms, pain, sleep quality,
tremors, appetite, and the patient’s general condition.3,51 Most of
these clinical trials have focused on either THC as the primary therapeutic
ingredient or a 1:1 ratio of THC to CBD, but there is a paucity of clinical
studies examining pure CBD for a therapeutic outcome.
Animal and human research also
demonstrates a potential for synergizing or enhancing certain therapeutic
effects when cannabinoids and/or terpenes are applied in an appropriate
combination. 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 therapeutic benefits.33,37
Jahan Marcu, PhD, is currently
the senior scientist at Americans for Safe Access and chief auditor for Patient
Focused Certification, an oversight program that audits cannabis operations.
Dr. Marcu is the director of research and development at Green Standard
Diagnostics, Inc. He is also on the board of directors of the International
Association for Cannabinoid Medicines. He received his PhD for significant
contributions to the study of the structure and function of the cannabinoid
receptors. He is also an author of the American Herbal Pharmacopoeia's cannabis
monograph. Dr. Marcu is a recipient of the Billy Martin research award from the
International Cannabinoid Research Society.
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