Cannabis for Pain and Headaches: Primer

This section is compiled by Frank M. Painter, D.C.
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FROM:   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. [1] 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. O’Shaughnessy, 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.

      Endocannabinoid System

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. [3]

These enzymes, 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). [4] CB1 is a seventransmembrane spanning G protein-coupled receptor inhibiting cyclic AMP release. [4] 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. [5] THC, the prototypical phytocannabinoid, is a weak partial agonist of both CB1 and CB2 receptors. [6••]


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. [7] 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). [8••] 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 properties.

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. [7] 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. [11] 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. [12] 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. [13] 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. [18] In the peripheral nervous system, the endocannabinoid system is active in suppressing hyperalgesia and allodynia. [19] Pathological pain states such Complex Regional Pain Syndrome (CRPS) has been postulated to arise and at least involve a dysregulation of the endocannabinoid system.

An endocannabinoid deficiency is theorized to underlie the pathophysiology of migraine or headaches. [20] 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. [23] 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. [24] The endocannabinoid system is active in the trigeminovascular system, which has been implicated in migraine pathogenesis at the vascular and neurochemical level. [25] Other postulated endocannabinoid-deficiency conditions include fibromyalgia, idiopathic bowl syndrome and endometriosis [20]. The endocannabinoid system is also very active in modulating nociceptive response in gastrointestinal and visceral sites [26••]. Endocannabinoid modulators may help restore homeostasis and lead to normalization of function in pathophysiological conditions. [20]


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