CANNABIS FOR PAIN AND HEADACHES: PRIMER
 
   

Cannabis for Pain and Headaches: Primer

This section is compiled by Frank M. Painter, D.C.
Send all comments or additions to:
   Frankp@chiro.org
 
   

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.
phshkim@yahoo.com


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



Introduction

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

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]



References:

  1. Lamarine RJ. Marijuana: modern medical chimaera. J Drug Educ. 2012;42(1):1–11.

  2. Di Marzo V, Melck D, Bisogno T, De Petrocellis L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 1998;21(12):521–8. Good review of cannabinoid system and landmark.

  3. Cravatt BF, Giang DK, Mayfield SP, Boger DL, Lerner RA, Gilula NB. Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides. Nature. 1996;384(6604):83–7.

  4. Howlett AC, Johnson MR, Melvin LS, Milne GM. Nonclassical cannabinoid analgetics inhibit adenylate cyclase: development of a cannabinoid receptor model. Mol Pharmacol. 1988;33(3):297–302.

  5. Ibrahim MM, Porreca F, Lai J, Albrecht PJ, Rice FL, Khodorova A, et al. CB2 cannabinoid receptor activation produces antinociception by stimulating peripheral release of endogenous opioids. Proc Natl Acad Sci U S A. 2005;102(8):3093–8.

  6. Guindon J, Hohmann AG. The endocannabinoid system and pain. CNS Neurol Disord Drug Targets. 2009;8(6):403–21. Updated review of endocannabinoid system.

  7. Elsohly MA, Slade D. Chemical constituents of marijuana: the complex mixture of natural cannabinoids. Life Sci. 2005;78(5):539–48.

  8. Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci. 2009;30(10):515–27. Review of cannabis plant benefits from scientists.

  9. Banerjee SP, Snyder SH, Mechoulam R. Cannabinoids: influence on neurotransmitter uptake in rat brain synaptosomes. J Pharmacol Exp Ther. 1975;194(1):74–81.

  10. Evans AT, Formukong E, Evans FJ. Activation of phospholipase A2 by cannabinoids. Lack of correlation with CNS effects. FEBS Lett. 1987;211(2):119–22.

  11. McPartland JM, Pruitt PL. Side effects of pharmaceuticals not elicited by comparable herbal medicines: the case of tetrahydrocannabinol and marijuana. Altern Ther Health Med. 1999;5(4):57–62.

  12. Zuardi AW, Hallak JE, Crippa JA. Interaction between cannabidiol (CBD) and (9)-tetrahydrocannabinol (THC): influence of administration interval and dose ratio between the cannabinoids. Psychopharmacology (Berlin). 2012;219(1):247–9.

  13. Karst M, Salim K, Burstein S, Conrad I, Hoy L, Schneider U. Analgesic effect of the synthetic cannabinoid CT-3 on chronic neuropathic pain: a randomized controlled trial. JAMA. 2003;290(13):1757–62.

  14. Rahn EJ, Hohmann AG. Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. Neurotherapeutics. 2009;6(4):713–37. Updated review of basic clinical and scientific view of cannabinoids.

  15. Walker JM, Hohmann AG, Martin WJ, Strangman NM, Huang SM, Tsou K. The neurobiology of cannabinoid analgesia. Life Sci. 1999;65(6–7):665–73.

  16. Rahn EJ, Makriyannis A, Hohmann AG. Activation of cannabinoid CB1 and CB2 receptors suppresses neuropathic nociception evoked by the chemotherapeutic agent vincristine in rats. Br J Pharmacol. 2007;152(5):765–77.

  17. Strangman NM, Walker JM. Cannabinoid WIN 55,212-2 inhibits the activity-dependent facilitation of spinal nociceptive responses. J Neurophysiol. 1999;82(1):472–7.

  18. Lichtman AH, Cook SA, Martin BR. Investigation of brain sites mediating cannabinoid-induced antinociception in rats: evidence supporting periaqueductal gray involvement. J Pharmacol Exp Ther. 1996;276(2):585–93.

  19. Richardson JD, Kilo S, Hargreaves KM. Cannabinoids reduce hyperalgesia and inflammation via interaction with peripheral CB1 receptors. Pain. 1998;75(1):111–9.

  20. Russo EB. Clinical endocannabinoid deficiency (CECD): can this concept explain therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatment-resistant conditions? Neuro Endocrinol Lett. 2004;25(1–2):31–9.

  21. Sarchielli P, Pini LA, Coppola F, Rossi C, Baldi A, Mancini ML, et al. Endocannabinoids in chronic migraine: CSF findings suggest a system failure. Neuropsychopharmacology. 2007;32(6):1384–90. Understanding the endocannabinoid system role in migraines.

  22. Villalon CM, Olesen J. The role of CGRP in the pathophysiology of migraine and efficacy of CGRP receptor antagonists as acute antimigraine drugs. Pharmacol Ther. 2009;124(3):309–23.

  23. Cupini LM, Costa C, Sarchielli P, Bari M, Battista N, Eusebi P, et al. Degradation of endocannabinoids in chronic migraine and medication overuse headache. Neurobiol Dis. 2008;30(2):186–9.

  24. Volfe Z, Dvilansky A, Nathan I. Cannabinoids block release of serotonin from platelets induced by plasma from migraine patients. Int J Clin Pharmacol Res. 1985;5(4):243–6.

  25. Akerman S, Holland PR, Goadsby PJ. Cannabinoid (CB1) receptor activation inhibits trigeminovascular neurons. J Pharmacol Exp Ther. 2007;320(1):64–71.

  26. Izzo AA, Sharkey KA. Cannabinoids and the gut: new developments and emerging concepts. Pharmacol Ther. 2010;126(1):21–38. New concepts in the role of cannabinoids in gastrointestinal diseases.

  27. Watson SJ, Benson Jr JA, Joy JE. Marijuana and medicine: assessing the science base: a summary of the 1999 Institute of Medicine report. Arch Gen Psychiatry. 2000;57(6):547–52.

  28. Buggy DJ, Toogood L, Maric S, Sharpe P, Lambert DG, Rowbotham DJ. Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain. 2003;106(1–2):169–72.

  29. Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anaesth. 2006;53(8):769–75.

  30. Svendsen KB, Jensen TS, Bach FW. Does the cannabinoid dronabinol reduce central pain in multiple sclerosis? Randomised double blind placebo controlled crossover trial. BMJ. 2004;329(7460):253.

  31. Narang S, Gibson D, Wasan AD, Ross EL, Michna E, Nedeljkovic SS, et al. Efficacy of dronabinol as an adjuvant treatment for chronic pain patients on opioid therapy. J Pain. 2008;9(3):254–64.

  32. Wissel J, Haydn T, Muller J, Brenneis C, Berger T, Poewe W, et al. Low dose treatment with the synthetic cannabinoid Nabilone significantly reduces spasticity-related pain : a double-blind placebo-controlled cross-over trial. J Neurol. 2006;253(10):1337–41.

  33. Frank B, Serpell MG, Hughes J, Matthews JN, Kapur D. Comparison of analgesic effects and patient tolerability of nabilone and dihydrocodeine for chronic neuropathic pain: randomised, crossover, double blind study. BMJ. 2008;336(7637):199–201.

  34. Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the treatment of pain in fibromyalgia. J Pain. 2008;9(2):164–73.

  35. Ware MA, Fitzcharles MA, Joseph L, Shir Y. The effects of nabilone on sleep in fibromyalgia: results of a randomized controlled trial. Anesth Analg. 2010;110(2):604–10.

  36. Milstein SL, MacCannell K, Karr G, Clark S. Marijuana-produced changes in pain tolerance. Experienced and non-experienced subjects. Int Pharmacopsychiatry. 1975;10(3):177–82.

  37. Cooper ZD, Comer SD, Haney M. Comparison of the analgesic effects of dronabinol and smoked marijuana in daily marijuana smokers. Neuropsychopharmacology. 2013;38(10):1984–92.

  38. Greenwald MK, Stitzer ML. Antinociceptive, subjective and behavioral effects of smoked marijuana in humans. Drug Alcohol Depend. 2000;59(3):261–75.

  39. Wallace M, Schulteis G, Atkinson JH, Wolfson T, Lazzaretto D, Bentley H, et al. Dose-dependent effects of smoked cannabis on capsaicin-induced pain and hyperalgesia in healthy volunteers. Anesthesiology. 2007;107(5):785–96.

  40. Abrams DI, Jay CA, Shade SB, Vizoso H, Reda H, Press S, et al. Cannabis in painful HIVassociated sensory neuropathy: a randomized placebo-controlled trial. Neurology. 2007;68(7):515–21.

  41. Ellis RJ, Toperoff W, Vaida F, van den Brande G, Gonzales J, Gouaux B, et al. Smoked medicinal cannabis for neuropathic pain in HIV: a randomized, crossover clinical trial. Neuropsychopharmacology. 2009;34(3):672–80.

  42. Ware MA, Wang T, Shapiro S, Robinson A, Ducruet T, Huynh T, et al. Smoked cannabis for chronic neuropathic pain: a randomized controlled trial. CMAJ. 2010;182(14):E694–701.

  43. Wilsey B, Marcotte T, Tsodikov A, Millman J, Bentley H, Gouaux B, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain. 2008;9(6):506–21. One many studies support cannabis for neuropathic pain.

  44. Wilsey B, Marcotte TD, Deutsch R, Zhao H, Prasad H, Phan A. An exploratory human laboratory experiment evaluating vaporized cannabis in the treatment of neuropathic pain from spinal cord injury and disease. J Pain. 2016;17(9):982–1000.

  45. Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain. 2013;14(2):136–48.

  46. Zajicek JP, Sanders HP, Wright DE, Vickery PJ, Ingram WM, Reilly SM, et al. Cannabinoids in multiple sclerosis (CAMS) study: safety and efficacy data for 12 months follow up. J Neurol Neurosurg Psychiatry. 2005;76(12):1664–9. One of many studies supporting cannabis for multiple sclerosis.

  47. Ernst G, Denke C, Reif M, Schnelle M, Hagmeister H. Standarized cannabis extract in the treatment of postherpetic neuralgia: a randomized, double blind, placebo-controlled cross-over study. Leiden: International Associatin for Cannabis as Medicine; 2005.

  48. Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler. 2004;10(4):434–41.

  49. Notcutt W, Price M, Miller R, Newport S, Phillips C, Simmons S, et al. Initial experiences with medicinal extracts of cannabis for chronic pain: results from 34 “‘N of 1” studies. Anaesthesia. 2004;59(5):440–52.

  50. Berman JS, Symonds C, Birch R. Efficacy of two cannabis based medicinal extracts for relief of central neuropathic pain from brachial plexus avulsion: results of a randomised controlled trial. Pain. 2004;112(3):299–306.

  51. Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005;65(6):812–9.

  52. Blake DR, Robson P, Ho M, Jubb RW, McCabe CS. Preliminary assessment of the efficacy, tolerability and safety of a cannabis-based medicine (Sativex) in the treatment of pain caused by rheumatoid arthritis. Rheumatology (Oxford). 2006;45(1):50–2.

  53. Johnson JR, Burnell-Nugent M, Lossignol D, Ganae-Motan ED, Potts R, Fallon MT. Multicenter, double-blind, randomized, placebo-controlled, parallel-group study of the efficacy, safety, and tolerability of THC:CBD extract and THC extract in patients with intractable cancer-related pain. J Pain Symptom Manag. 2010;39(2):167–79. Support cannabis for cancer related pain.

  54. Portenoy RK, Ganae-Motan ED, Allende S, Yanagihara R, Shaiova L, Weinstein S, et al. Nabiximols for opioid-treated cancer patients with poorly-controlled chronic pain: a randomized, placebo-controlled, graded-dose trial. J Pain. 2012;13(5):438–49.

  55. Kavia RB, De Ridder D, Constantinescu CS, Stott CG, Fowler CJ. Randomized controlled trial of Sativex to treat detrusor overactivity in multiple sclerosis. Mult Scler. 2010;16(11):1349–59.

  56. Russo EB, Guy GW, Robson PJ. Cannabis, pain, and sleep: lessons from therapeutic clinical trials of Sativex, a cannabis-based medicine. Chem Biodivers. 2007;4(8):1729–43.

  57. Carter GT, Weydt P, Kyashna-Tocha M, Abrams DI. Medicinal cannabis: rational guidelines for dosing. IDrugs. 2004;7(5):464–70. Background on developing dosing for cannabis in many routes.

  58. Zuurman L, Ippel AE, Moin E, van Gerven JM. Biomarkers for the effects of cannabis and THC in healthy volunteers. Br J Clin Pharmacol. 2009;67(1):5–21.

  59. Huestis MA. Human cannabinoid pharmacokinetics. Chem Biodivers. 2007;4(8):1770–804.

  60. Agurell S, Halldin M, Lindgren JE, Ohlsson A, Widman M, Gillespie H, et al. Pharmacokinetics and metabolism of delta 1-tetrahydrocannabinol and other cannabinoids with emphasis on man. Pharmacol Rev. 1986;38(1):21–43.

  61. Tashkin DP. Smoked marijuana as a cause of lung injury. Monaldi Arch Chest Dis. 2005;63(2):93–100.

  62. Hashibe M, Morgenstern H, Cui Y, Tashkin DP, Zhang ZF, Cozen W, et al. Marijuana use and the risk of lung and upper aerodigestive tract cancers: results of a population-based case–control study. Cancer Epidemiol Biomarkers Prev. 2006;15(10):1829–34.

  63. Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. 2011;90(6):844–51. Good explanation on where opioids and cannabinoids interact in a close relationship.

  64. Ohlsson A, Lindgren JE, Wahlen A, Agurell S, Hollister LE, Gillespie HK. Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin Pharmacol Ther. 1980;28(3):409–16.

  65. Borgelt LM, Franson KL, Nussbaum AM, Wang GS. The pharmacologic and clinical effects of medical cannabis. Pharmacotherapy. 2013;33(2):195–209. Good review on cannabis side effects and complications.

  66. Cone EJ, Johnson RE, Paul BD, Mell LD, Mitchell J. Marijuana-laced brownies: behavioral effects, physiologic effects, and urinalysis in humans following ingestion. J Anal Toxicol. 1988;12(4):169–75.

  67. Merrick J, Lane B, Sebree T, Yaksh T, O’Neill C, Banks S. Identification of psychoactive degradants of cannabidiol in simulated gastric and physiological fluid. Cannabis Cannabinoid Res. 2016;1(1):102–12.

  68. Cooper ZD, Haney M. Sex-dependent effects of cannabis-induced analgesia. Drug Alcohol Depend. 2016;167:112–20.

  69. Volkow ND, Compton WM, Weiss SR. Adverse health effects of marijuana use. N Engl J Med. 2014;371(9):879. Up to date review of side effects and complication of cannabis.

  70. Zullino DF, Delessert D, Eap CB, Preisig M, Baumann P. Tobacco and cannabis smoking cessation can lead to intoxication with clozapine or olanzapine. Int Clin Psychopharmacol. 2002;17(3):141–3.

  71. Grotenhermen F. Pharmacokinetics and pharmacodynamics of cannabinoids. Clin Pharmacokinet. 2003;42(4):327–60.

  72. Solowij N, Battisti R. The chronic effects of cannabis on memory in humans: a review. Curr Drug Abuse Rev. 2008;1(1):81–98.

  73. Rossato M, Pagano C, Vettor R. The cannabinoid system and male reproductive functions. J Neuroendocrinol. 2008;20 Suppl 1:90–3.

  74. Tetrault JM, Crothers K, Moore BA, Mehra R, Concato J, Fiellin DA. Effects of marijuana smoking on pulmonary function and respiratory complications: a systematic review. Arch Intern Med. 2007;167(3):221–8. Review on impact of cannabis on the pulmonary systems.

  75. Mehra R, Moore BA, Crothers K, Tetrault J, Fiellin DA. The association between marijuana smoking and lung cancer: a systematic review. Arch Intern Med. 2006;166(13):1359–67.

  76. Meier MH, Caspi A, Cerda M, Hancox RJ, Harrington H, Houts R, et al. Associations between cannabis use and physical health problems in early midlife: a longitudinal comparison of persistent cannabis vs tobacco users. JAMA Psychiat. 2016;73(7):731–40.

  77. Anthony J, Warner L, Kessler R. Comparative epidemiology of dependence of tobacco, alcohol, controlled substances, and inhalants: basic finding from the national comorbidity survey. Exp Clin Psychopharmacol. 1994;2(3):244–68.

  78. Manzanares J, Corchero J, Romero J, Fernandez-Ruiz JJ, Ramos JA, Fuentes JA. Chronic administration of cannabinoids regulates proenkephalin mRNA levels in selected regions of the rat brain. Brain Res Mol Brain Res. 1998;55(1):126–32.

  79. Cichewicz DL, Martin ZL, Smith FL, Welch SP. Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose–response analysis and receptor identification. J Pharmacol Exp Ther. 1999;289(2):859–67.

  80. Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999–2010. JAMA Intern Med. 2014;174(10):1668–73. Report of the impact on cannabis on the opioid epidemic.

  81. Boehnke KF, Litinas E, Clauw DJ. Medical cannabis use is associated with decreased opiate medication use in a retrospective cross-sectional survey of patients with chronic pain. J Pain. 2016;17(6):739–44.



Return to the HEADACHE Page

Since 3-27-2017

         © 1995–2018 ~ The Chiropractic Resource Organization ~ All Rights Reserved