Curr Pain Headache Rep. 2017 (Apr); 21 (4): 19 ~ FULL TEXT
Philip S. Kim, Michael A. Fishman
Center for Interventional Pain Spine and Ageless MD, LLC,
931 East Haverford Road, Suite 202,
Bryn Mawr, PA, 19010, USA.
PURPOSE OF REVIEW: Marijuana has been used both medicinally and recreationally since ancient times and interest in its compounds for pain relief has increased in recent years. The identification of our own intrinsic, endocannabinoid system has laid the foundation for further research.
RECENT FINDINGS: Synthetic cannabinoids are being developed and synthesized from the marijuana plant such as dronabinol and nabilone. The US Food and Drug Administration approved the use of dronabinol and nabilone for chemotherapy-associated nausea and vomiting and HIV (Human Immunodeficiency Virus) wasting. Nabiximols is a cannabis extract that is approved for the treatment of spasticity and intractable pain in Canada and the UK. Further clinical trials are studying the effect of marijuana extracts for seizure disorders. Phytocannabinoids have been identified as key compounds involved in analgesia and anti-inflammatory effects. Other compounds found in cannabis such as flavonoids and terpenes are also being investigated as to their individual or synergistic effects. This article will review relevant literature regarding medical use of marijuana and cannabinoid pharmaceuticals with an emphasis on pain and headaches.
KEYWORDS: Cannabinoids; Cannabis; Headache; Marijuana; Nociception; Pain; Tetrahydrocannabinols
The medical use of cannabis has been documented in ancient
Greece and China.  The most commonly used species of the
plant are Cannabis sativa and Cannabis indica. Each variety
has varying composition and relative concentrations of active
compounds. In the last two centuries, Cannabis has been used
and recommended by various physicians. Dr. William B.
OShaughnessy, an Irish physician, introduced Indian hemp
to Europe with reports of high rates of success for rheumatism,
rabies, cholera, tetanus, cramps, and delirium. Dr. William
Osler reported benefits of cannabis for various conditions including
migraines and menstrual cramps. The Marihuana Tax
Act of 1937 began the government intervention that lead to the
downfall of cannabis for medical use. The removal of cannabis
in 1940 from the US Pharmacopeia further compromised
its medical use. In 1970, the Controlled Substance Act made
cannabis a schedule I drug. Recently, the USA has opened the
policies for medical marijuana by allowing the States to legislate
medical marijuana laws. Currently, there are 23 states
with medical marijuana laws. Interesting, the federal government
applied for and was granted a patent on cannabinoids for
antioxidant and neuroprotectant use in 2003.
Cannabinoids and medical marijuana research follows a similar
path to other plant-derived therapy. Opium poppy
(Papaver Somniferum) led to the development of the standard
narcotic analgesic morphine. The morphine alkaloid led to the
development of various synthetic derivatives and discovery of
the endogenous endorphin systems. Like morphine, the isolation
and identification of the first cannabinoid Δ9-
tetrahyrocannabinol (THC) in 1964 by Dr. Raphael
Mechoulam led to discovery of the endogenous cannabinoid
system. Endogenous cannabinoids are natural chemicals such
as anandamide (AEA) and 2-arachidonoylglycerol (2-AG).
The basic function of the endocannabinoid system acts to
modulate the sensitivity to many other neurotransmitters such
as dopamine and serotonin in the central nervous system
(Fig. 1). The human experience of pain and response to stress
involves the interaction of endocannabinoids through endorphins
and cortisol release. From a global perspective, the
endocannabinoid system functions are: relax, eat, sleep, forget,
and protect.  AEA is hydrolyzed by the enzyme fatty
acid amide hydrolase (FAAH) to arachidonic acid and ethanolamine;
2-AG is metabolized by monaoacylglycerol lipase
(MGL) into arachidonic acid and glycerol. 
FAAH and MGL, represent potential therapeutic targets to
modulate endogenous endocannabinoid levels or potential
mechanisms of dysfunction in the development of various
disease states. Currently, there are two well-defined
cannabinoid receptors CB1 (Cannabinoid receptor 1) and
CB2 (Cannabinoid receptor 2).  CB1 is a seventransmembrane
spanning G protein-coupled receptor
inhibiting cyclic AMP release.  CB1 is the primary
neuromodulatory receptor accounting for the psychopharmacological
effect of THC and most of its analgesic effects.
Presynaptic activation of CB1 acts as a synaptic circuit breaker
to inhibit neurotransmitters such as GABA (gamma-
Aminobutyric acid) or glutamate. CB2 works primarily as an
immunomodulatory receptor in the periphery. It is postulated
that CB2 modulates persistent inflammatory and neuropathic
pain conditions.  THC, the prototypical phytocannabinoid,
is a weak partial agonist of both CB1 and CB2 receptors. 
Cannabinoids can be broken down into three subgroups: endogenous
endocannabinoids, botanicals (phytocannabinoids), and
synthetic derivatives. Over 60 different phytocannabinoids have
been identified in the marijuana plant.  The principal cannabinoids
appear to be delta-9-tetrahydrocannabinol andcannabidiol (CBD). Other potential cannabinoids with medical
value include cannabigerol (CBG), Cannabinol (CBN),
cannabichromene (CBC) and tetrahydrocannabivarin (THCV).  CBG is a product of delta-9-THC oxidation and displays
potentGABA reuptake inhibition activity and phospholipaseA2
modulator. [9, 10] CBD lacks detectable psychoactivity and
does not appear to bind to either CB1 or CB2 receptors in high
concentrations. Rather, it displays activity at other targets such as
ion channels, receptors and enzymes. Pre-clinical studies support
anti-inflammatory, analgesic, anti-emetic, anti-psychotic, anti-ischemic,
anxiolytic and anti-epileptiform activity. THCVacts as a
CB1 receptor antagonist and CB2 receptor partial agonist with
pre-clinical studies suggesting ant-epileptiform/anti-convulsant
In the living plant, these phytocannabinoids exist as both inactivemonocarboxylic
acids and an active decarboxylated forms.
Heating above 120 ฐC promotes decarboxylation and results in
biological activation.  Other constituents in cannabis with potential
medical benefit include the following: terpenes, noncannabinoid
phenols, flavonoids and vitamins. Further differences
in the chemical constituents are noted in various cannabis
species and extraction techniques. The terpenes and flavonoids
are not yet well characterized, but they are believed to have a
broad spectrum of potential anti-inflammatory, anti-oxidant, antibacterial
and anti-neoplastic actions. An example is noted in
myrecene, a terpenoid, with anti-inflammatory activity via
PGE-2 and opioid type analgesic effect blocked by naloxone.
The scientific and pharmaceutical approach to identify single
ingredients and synthesize one compound, such as THC, for
use may not offer full effect of the polypharmaceutical cannabis
plant. The many constituentsmay work by multiple mechanisms
to improve therapeutic activity either an additive or synergistic
manner and mitigate the side effects if their predominant active
ingredients.  An example is the co-administration of CBD
and THC may result in attenuation or potentiation of some of the
effects of THC through a pharmacodynamics mechanisms. 
A ratio of CBD to THC of at least 8:1 attenuates THC induced
effects, where as CBD potentiates THC at a ratio 2:1.
Potentiation of THC may be caused by inhibition of THC metabolism
in the liver.
Synthetic cannabinoids have been developed to mimic THC.
Oral dronabinol (THC) has been available asMarinolฎ for nausea
associated with chemotherapy and appetite stimulation with
HIV/AIDS. In the USA, it is classified as a schedule III drug. A
new liquid dronabinol formulation called Syndrosฎ has recently
been approved for the same indication. Nabilone is another formulation
of synthetic THC marketed under the brand name
Cesametฎ and available as an anti-emetic for chemotherapyassociated
nausea and is a schedule II substance. It is ten times
more potent than dronabinol. Ajulemic acid (CT3) is a synthetic
THC currently being studied in phase II randomized clinical trial
in peripheral neuropathic pain.  Other synthetic cannabinoids
are in development.
Biochemical and Neurophysiological Basis of Pain Control by Cannabinoids
Thorough reviews of pre-clinical and clinical studies support
the therapeutic effects of cannabinoids in nociception. [14, 15]
The endocannabinoid system is active in the central and peripheral
nervous system at nociception centers such as the
periaqueductal gray matter, ventroposterolateral nucleus of the
thalamus and the spinal cord. In neuropathic pain states,
endocannabinoids are involved in stress-induced analgesia,
wind-up phenomena, and central sensitization. [16, 17] The
periaqueductal gray region has also been implicated in migraine
generation.  In the peripheral nervous system, the
endocannabinoid system is active in suppressing hyperalgesia
and allodynia.  Pathological pain states such Complex
Regional Pain Syndrome (CRPS) has been postulated to arise
and at least involve a dysregulation of the endocannabinoid
An endocannabinoid deficiency is theorized to underlie the
pathophysiology of migraine or headaches.  Clinical studies
suggest that the lower concentration of anandamide is
found in the cerebral spinal fluid of migraineurs and the calcitonin
gene-related peptide (CGRP) and nitric oxide (NO)
levels are increased. [21, 22] In addition, the activity of the
anandamide-degrading enzyme, FAAH, is significantly decreased
in chronic migraineurs compared to controls.  It
is also postulated that active migraines are aggravated by release
of serotonin during migraine attacks. In one study, THC
inhibited release of serotonin from platelets in a plasma sample
taken during an active migraine episode.  The
endocannabinoid system is active in the trigeminovascular
system, which has been implicated in migraine pathogenesis
at the vascular and neurochemical level. 
Other postulated endocannabinoid-deficiency conditions
include fibromyalgia, idiopathic bowl syndrome and endometriosis
. The endocannabinoid system is also very active in
modulating nociceptive response in gastrointestinal and visceral
sites . Endocannabinoid modulators may help restore
homeostasis and lead to normalization of function in
pathophysiological conditions. 
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