First reported some 5,000 years ago, the medicinal use of cannabis has since been reported anecdotally in the treatment a variety of conditions.1 Over the last century, as many commonly prescribed modern pharmaceuticals were discovered by studying ethnobotanical traditions, 80 years of prohibition have sidelined clinical cannabis research.2 The phytocannabinoids with physiological effects isolated in the 1960s and 1970s ultimately led to the identification of the endogenous receptors, ligands, enzymes, and transporter proteins that comprise what has been called the Endocannabinoid System (ECS).3 In addition to pharmaceutical development and testing, 28 states and the District of Columbia (DC) have enacted medicinal cannabis access programs,4 with over 1.2 million patients enrolled nationally.5

Although the US government still lists cannabis as a Schedule I drug,6 compounds derived from cannabis (Cannabis sativa, Cannabis indica) have recently entered FDA clinical testing, and some are approved for use in the European Union. As these trends continue, it is useful for physicians to understand the fundamentals of the ECS and the emerging pharmaceuticals that target this system, as well as the impact of medical cannabis regulations on their patients and practice.

Historical Use and Prohibition

The earliest writings on the use of medical cannabis date back to a 15th century BC Chinese Pharmacopoeia called the RhYa.7 Indian Ayurvedic texts from 600 BC described cannabis use for both stimulating and calming the mind, and also as an anti-phlegmatic and an anesthetic.8 The 700 BC Persian text the Venidad included over 10,000 medicinal plants and cited cannabis among the most significant.

Greek and Roman doctors prescribed cannabis for a variety of ailments, a tradition that persisted through the Renaissance.9 Western civilization brought hemp, a common name for Cannabis sativa, across the Atlantic. Cannabis tincture was added to the US Pharmacopeia in 1850,10 and was widely prescribed for a number of ailments. By 1918, US pharmaceutical firms grew over 60,000 pounds to produce tincture from the flowering tops.

During the early 20th century, growing concerns over its abuse potential drove many states to pass laws prohibiting cannabis, along with opium and alcohol. In 1936, Harry J. Anslinger, Commissioner of the newly established Federal Bureau of Narcotics, characterized marijuana as a dangerous drug and advised federal action. The American Medical Association called for further research, however Anslinger’s efforts led to the 1937 Marijuana Tax Act, which greatly diminished its use. Further shaping public opinion were films such as Reefer Madness (1936) and a chain of anti-marijuana articles published in newspapers owned by William Randolph Hearst.11

With increasing associations to crime, cannabis was removed from the Pharmacopoeia in 1942. The next decades saw increasing enforcement and harsher punishment of cannabis related offenses, culminating in the Schedule I classification under the Controlled Substances Act in 1970. Since that time, the National Institute on Drug Abuse (NIDA) regulated all clinical research conducted in the US, using cannabis grown by the University of Mississippi. Recently, though, the DEA announced that it will certify additional institutions to provide medical cannabis for research.12

Phytocannabinoids and the ECS

Raphael Mechoulam and colleagues identified and synthesized the main psychoactive component of cannabis, delta-9-tetrahydrocannabinol (THC), along with cannabidiol (CBD) and several other constituents in 1964.13 Subsequently, at least 113 different phytocannabinoids unique to cannabis were identified along with numerous terpenes found in other plants.14 While some debate remains regarding the taxonomy of cannabis, plant morphology suggests that four species exist: Cannabis sativa, Cannabis indica, Cannabis rhudarelis, and Cannabis kafiristanica, with genetic confirmation of at least two original species lineages (Cannabis sativa and Cannabis indica).15,16

A frequent misconception within the lay literature is that Cannabis sativa derived strains offer more of a stimulating effect, thus are for daytime use, while Cannabis indica offers more of a relaxing, narcotic effect, thus reserved for nighttime use.17-19 This alludes to a variation in odor, texture, and physiological effect found in individual strains, which is thought to be derived from the combined effects of the various phytocannabinoids and terpenes present.20 Hybridization and breeding towards a higher THC content has diluted the genetics and diminished the presence of higher levels of the other cannabinoids in many strains used today for medical marijuana.21

Ben Shabat proposed that the multiple ligands and receptors of the ECS allowed an unprecedented level of orchestrated modulation he called the entourage effect.22,23 Some have proposed that the specific concentration of phytocannabinoids, terpenes, and other active compounds exert their activity via an analogous entourage effect upon both the ECS and non-ECS components, such as the combination of THC and CBD used in nabiximols.

The ECS is a ubiquitous signaling system present throughout human tissues. Its function has been summarized as playing a major role in our ability to, “relax, eat, sleep, forget, and protect.”24 In 1990, Herkenham and colleagues discovered endogenous receptors for a synthetic THC analog showed high densities in basal ganglia, hippocampus, and cerebellum, but with paucity in the brainstem respiratory centers, a pattern preserved within numerous mammalian species.25 These so-called CB1 (Cannabinoid 1) receptors proved to be the most numerous g-protein coupled receptors26 in the CNS.27

Soon thereafter, Devane, Hanus, and Mechoulam (who identified THC in 1964), discovered an endogenous arachidonic acid derivative with strong affinity for the newly isolated CB1 receptors. They called it N-arachidonoylethanolamine (AEA) or anandamide, named after “ananda,” a Sanskrit word for “bliss.”28 THC and AEA were found to additionally activate a second g-protein coupled receptor expressed in peripheral tissues, called CB2 (Cannabinoid 2). The principal expression of the CB2 receptor in peripheral tissues, such as immune cells and gastrointestinal cells, suggested roles far removed from the psychoactive effects of the plant that led to its discovery.29 An additional ligand known as 2-arachidonoylglycerol (2AG) was subsequently isolated from canine gut and showed affinities for both CB1 and CB2.30 These main putative ligands are postsynaptic, membrane bound, fatty acid precursors with complex and varied synthetic pathways, and are released in response to depolarization (AEA)31 and increased postsynaptic calcium (2AG).32

AEA has a rapid half-life due to the activity of fatty acid amide hydrolase (FAAH),33 whereas 2AG has a longer half-life and is terminated by monoacylglycerol lipase (MAGL).34 Multiple other ligands and receptors are thought to be involved in the ECS, in addition to transporter proteins that shuttle the lipophilic ligands to their presynaptic targets.35

The presence of presynaptic receptors co-localized with postsynaptic ligands suggested a homeostatic role. Preclinical and clinical studies further indicate ECS involvement in embryogenesis, driving suckling in neonates, learning and memory, emotional processing, hunger and satiety, inflammation, pain, and carcinogenesis.36

Ethnobotanical traditions, preclinical and pharmacological studies, and the increasingly available clinical data suggest that modulation of the ECS may be useful for the treatment of diverse disorders, such as painful peripheral neuropathy, pain associated with cancer, stimulation of appetite in AIDS wasting and chemotherapy treatment, irritable bowel syndrome, fibromyalgia, migraine, depression, epilepsy, heart disease, and many other diseases.37-40 AEA and 2AG, along with the putative modulatory constituents N-palmitoylethanolamide and N-oleoylethanolamide, have been found in decreased levels in the cerebrospinal fluid of MS patients.41-43 Additional interventions such as acupuncture, massage, and lifestyle modifications such as diet and exercise also play a role in balancing the ECS.44

While cannabis derived therapies may offer a great opportunity to modulate the ECS, understanding the risk obviously becomes prudent. Underreporting of adult use and research regulation frustrate attempts to quantify the health risks of acute and chronic cannabis use. Some of these potential risks may include addiction,45 driving impairment,46 cardiopulmonary complications associated with smoked cannabis,47,48 carcinogenesis,49 and complications during pregnancy.50 Adverse reactions are common, and may include cognitive dysfunction, paranoia, tachycardia, and orthostatic hypotension.51 A paradoxical cannabinoid hyperemesis syndrome, associated with chronic cannabis abuse, has been reported.52 Of note, drug-drug interactions may prove concerning, as cannabis use is associated with significant inactivation of cytochrome p450.53


Phase 3 studies of the botanical compound Epidiolex (cannabidiol) showed a reduction in frequency and severity of seizures in patients with Lennox Gastaut Syndrome and separately in Dravet syndrome with good tolerability and low incidence of adverse reactions.54-55 Multiple possible mechanisms including CBD affinity at non-cannabinoid receptor targets are proposed.56-58 A botanical compound of THC and CBD derived from cannabis known as Sativex (nabiximols) is approved in the EU for treatment of painful spasms associated with multiple sclerosis and FDA trials are ongoing for pain associated with cancer.59

Synthetic cannabimimetic compounds have shown mixed results. For example, Marinol (dronabinol) is synthetic THC indicated for cachexia and anorexia in patients with AIDS, as well as for nausea and vomiting associated with cancer chemotherapy.60

Cesamet (nabilone) is a synthetic cannabinoid that is chemically similar to naturally occurring THC and is approved for treatment of nausea and vomiting associated with cancer chemotherapy when other drugs have failed.61 Some have suggested that dronabinol and nabilone are not as effective as botanical extracts of cannabis due to removal of the active and inactive matrix of compounds found in whole plant extracts.62

Some of this is attributed to the increased psychoactive effects from orally ingested cannabis and cannabis-derived products, large in part to the conversion of Delta9THC to 11HydroxyTHC, a longer acting, more potent psychoactive derivative.63-64

Rimonabant (Acomplia, Zimulti), a selective CB1 antagonist, was approved in the EU for weight loss in obese patients with other complications such as dyslipidemia or diabetes. It was suspended due to severe psychiatric side effects, including increased risk of suicide, and thus was never approved by the FDA.65 Synthetic cannabinoids have side effects and risks that far exceed those of cannabis or cannabis extracts and there is great concern over the safety, unregulated proliferation, and abuse of these compounds.66

Medical-Legal Issues

Significant variations exist amongst medical cannabis programs in each of the 28 states and DC, as well as the 16 states with CBD-specific laws and three states that had medical marijuana on the ballot for 2016.67-69 Thus, physicians who certify patients within medical cannabis programs should familiarize themselves with the applicable state specific regulations, and confirm appropriate coverage with their malpractice insurance carrier. Proper documentation, including the specific indication(s) for certification, as well a discussion of potential risks is necessary.70

Unique liabilities present risk for certifying physicians. For example, despite provisions in the California legislation that called for protection for physicians who certified patients according to regulations, the Clinton administration in 1997 announced that any physicians who recommended or prescribed cannabis would face losing their DEA registration.71 However, a successful lawsuit raised by California physicians concerned their First Amendment rights to discuss the literature with their patients72 and the DEA did not proceed. Cases in Ohio,73 Massachusetts,74 and Colorado75 have shown that physicians who do not follow state guidelines face penalties, suspension, and even revocation of their licensure.


Emerging evidence suggests important roles for the ECS in central and peripheral tissues and diseases, thus it is beneficial to keep apprised of ongoing developments. The further identification of multiple ECS components heralds the potential for multiple new treatment options, including whole plant and molecular-based pharmaceutical products that will follow traditional FDA approval pipelines.

Concomitantly, a body of literature concerning the clinical use of whole plant cannabis and its derivatives for a large variety of medical conditions continues to expand. Given the increasing numbers of patients certified for cannabis use, it is important for physicians caring for patients utilizing medical cannabis to understand the common side effects, risks, and alternative methods of ingestion. n

Shawn Masia, MD is a board certified neurologist and clinical Neurophysiologist. He provides evidence-based, patient-centered care via telemedicine platforms at hospitals across the country.

Ryan D Zaklin, MD, MA is a board certified Internal Medicine physician practicing north of Boston. His focus on Integrative Medicine and Mind-Body Medicine has led to his interest in Endocannabinoid Medicine and Cannabis-based Therapeutics.

1. Deitch, Robert. Hemp: American history revisited : the plant with a divided history . Algora Publishing, 2003.

2. Veeresham, Ciddi. “Natural products derived from plants as a source of drugs.” Journal of advanced pharmaceutical technology & research 3.4 (2012): 200.

3. Mechoulam, Raphael et al. “Early phytocannabinoid chemistry to endocannabinoids and beyond.” Nature Reviews Neuroscience 15.11 (2014): 757-764.

4. “25 Legal Medical Marijuana States and DC Medical Marijuana ...” 2010. Accessed 1 Sep. 2016.

5. “Number of Legal Medical Marijuana Patients Medical Marijuana ...” 2014. Accessed 1 Sep. 2016.

6. Hoffmann, Diane E, and Ellen Weber. “Medical marijuana and the law.” New England Journal of Medicine. 362.16 (2010): 14531457.

7. “Marihuana Research Findings: 1976, 14 ARCHIVES National ...” 2014. Accessed 1 Sep. 2016.

8. “Cannabis: The Story of a Weed That Rocked the World: Jonathon ...” 2016. 3 Sep. 2016.

9. “Cannabis: A History: Martin Booth: 9780312424947: ...” 2016. Accessed 1 Sep. 2016.

10. “Medical Marijuana Law Richard Boire, Kevin Feeney Google Books.” 2015. Accessed 1 Sep. 2016.

11. Holland, Julie. “The Pot Book.” 2008. 1 Sep. 2016 .

12. “ / Headquarters News Releases, 08/11/16.” 13 Sep. 2016.

13. Gaoni, Y. “Isolation, Structure, and Partial Synthesis of an ... ACS Publications.” 1964. .

14. AizpuruaOlaizola, Oier et al. “Evolution of the Cannabinoid and Terpene Content during the Growth of Cannabis sativa Plants from Different Chemotypes.” Journal of natural products 79.2 (2016): 324331.

15. Hillig, KW. Genetic evidence for speciation in Cannabis (Cannabaceae). Genetic Resources and Crop Evolution 52.2 (2005): 161180.

16. Piomelli, Daniele, and Ethan B Russo. “The cannabis sativa versus cannabis indica debate: an interview with Ethan Russo, MD.” Cannabis and Cannabinoid Research 1.1 (2016): 4446.

17. Hillig, KW. Genetic evidence for speciation in Cannabis (Cannabaceae). Genetic Resources and Crop Evolution 52.2 (2005): 161180.

18. Backes, Michael, and Andrew Weil. Cannabis pharmacy: the practical guide to medical marijuana . Black Dog & Leventhal, 2014.

19. Piomelli, D. “The Cannabis sativa Versus Cannabis indica Debate: An Interview ...” 2016.

20. A Corral, VL. “Differential Effects of Medical Marijuana Based on Strain and Route of ...” 2001.

21. Backes, Michael, and Andrew Weil. Cannabis pharmacy: the practical guide to medical marijuana . Black Dog & Leventhal, 2014.

22. BenShabat, Shimon et al. “An entourage effect: inactive endogenous fatty acid glycerol esters enhance 2arachidonoylglycerol cannabinoid activity.” European journal of pharmacology 353.1 (1998): 2331.

23. Mechoulam, Raphael, and Shimon BenShabat. “From ganzigunnu to anandamide and 2arachidonoylglycerol: the ongoing story of cannabis.” Natural product reports 16.2 (1999): 131143.

24. Di Marzo, Vincenzo et al. “Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action.” Trends in neurosciences 21.12 (1998): 521528.

25. Herkenham, MABL et al. “Cannabinoid receptor localization in brain.” Proceedings of the national Academy of sciences 87.5 (1990): 19321936.

26. Herkenham, Miles et al. “Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study.” The Journal of neuroscience 11.2 (1991): 563583.

27. Glass, M, RLM Faull, and M Dragunow. “Cannabinoid receptors in the human brain: a detailed anatomical and quantitative autoradiographic study in the fetal, neonatal and adult human brain.” Neuroscience 77.2 (1997): 299318.

28. Devane, William A et al. “Isolation and structure of a brain constituent that binds to the cannabinoid receptor.” Science 258.5090 (1992): 19461949.

29. Munro, Sean, Kerrie L Thomas, and Muna AbuShaar. “Molecular characterization of a peripheral receptor for cannabinoids.” 365.6441 (1993): 6165.

30. Mechoulam, Raphael et al. “Identification of an endogenous 2monoglyceride, present in canine gut, that binds to cannabinoid receptors.” Biochemical pharmacology 50.1 (1995): 8390.

31. Walker, J Michael et al. “Pain modulation by release of the endogenous cannabinoid anandamide.” Proceedings of the National Academy of Sciences 96.21 (1999): 1219812203.

32. Shonesy, Brian C et al. “The initiation of synaptic 2AG mobilization requires both an increased supply of diacylglycerol precursor and increased postsynaptic calcium.” Neuropharmacology 91 (2015): 5762.

33. “Fatty acid amide hydrolase Wikipedia, the free encyclopedia.” 2015. 3 Sep. 2016.

34. Kano, Masanobu et al. “Endocannabinoidmediated control of synaptic transmission.” Physiological reviews 89.1 (2009): 309380.

35. McPartland, JM. “Care and Feeding of the Endocannabinoid System: A Systematic ...” 2014.

36. Di Marzo, Vincenzo. “‘Endocannabinoids’ and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance.” Biochimica et Biophysica Acta (BBA)Lipids and Lipid Metabolism 1392.2 (1998): 153175.

37. Di Marzo, Vincenzo. “‘Endocannabinoids’ and other fatty acid derivatives with cannabimimetic properties: biochemistry and possible physiopathological relevance.” Biochimica et Biophysica Acta (BBA)Lipids and Lipid Metabolism 1392.2 (1998): 153175.

38. Russo, Ethan B. “Clinical Endocannabinoid Deficiency (CECD).” Neuroendocrinology Letters 29.2 (2008).

39. Russo, Ethan B, Geoffrey W Guy, and Philip J Robson. “Cannabis, Pain, and Sleep: Lessons from Therapeutic Clinical Trials of Sativex®, a Cannabis‐ Based Medicine.” Chemistry & biodiversity 4.8 (2007): 17291743.

40. Smith, Steele Clarke, and Mark S Wagner. “Clinical endocannabinoid deficiency (CECD) revisited: can this concept explain the therapeutic benefits of cannabis in migraine, fibromyalgia, irritable bowel syndrome and other treatmentresistant conditions?.” Neuro endocrinology letters 35.3 (2013): 198201.

41. “GWPharma Sativex.” 2009. 21 Sep. 2016.

42. Collin, C. “A doubleblind, randomized, placebocontrolled, parallelgroup study ...” 2010.

43. Di Filippo, M. “Abnormalities in the cerebrospinal fluid levels of endocannabinoids in ...” 2008.

44. McPartland, JM. “Care and Feeding of the Endocannabinoid System: A Systematic ...” 2014.

45. Hasin, DS. “DSM5 Criteria for Substance Use Disorders ... NCBI.” 2013.

46. Asbridge, Mark, Jill A Hayden, and Jennifer L Cartwright. “Acute cannabis consumption and motor vehicle collision risk: systematic review of observational studies and metaanalysis.” Bmj 344 (2012): e536.

47. Fisher, BA. “Cardiovascular complications induced by cannabis smoking: a ... NCBI.” 2005.

48. Tetrault, JM. “Effects of Marijuana Smoking on Pulmonary Function and Respiratory ...” 2007.

49. Hall, W. “Adverse health effects of nonmedical cannabis use The Lancet.” 2009.

50. BROWN, HL. “Smoking and Marijuana Use in Pregnancy Wolters Kluwer Health.” 2013. < >

51. Hall, W. “Adverse effects of cannabis The UK Cannabis Internet Activists UKCIA.” 1998.

52. Sontineni, SP. “Cannabinoid hyperemesis syndrome: clinical diagnosis of an ... NCBI.” 2009.

53. Carter, Gregory T et al. “Medicinal cannabis: rational guidelines for dosing.” IDrugs 7.5 (2004): 464470.

54. Phase 3, GW Pharmaceuticals Announces Positive. “Pivotal Study Results for Epidiolex (Cannabidiol). March 2016.”

55. “GWPharma GW Pharmaceuticals plc Reports Third Quarter 2016 ...” 2016. 1 Sep. 2016.

56. Jones, NA. “Cannabidiol exerts anticonvulsant effects in animal models of ...” 2012.

57. Jones, Nicholas A et al. “Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo.” Journal of Pharmacology and Experimental Therapeutics 332.2 (2010): 569577.

58. Devinsky, Orrin et al. “Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other

neuropsychiatric disorders.” Epilepsia 55.6 (2014): 791802.

59. “GWPharma Sativex R&D.” 2012. 3 Sep. 2016.

60. “About MARINOL | MARINOL (dronabinol) Capsules.” 2015. 3 Sep. 2016.

61. “Full Prescribing Information Cesamet.” 2010. 13 Sep. 2016.

62. McPartland, John M, and Ethan B Russo. “Cannabis and cannabis extracts: greater than the sum of their parts?.” Journal of Cannabis Therapeutics 1.34 (2001): 103132.

63. Joy, JE. “Marijuana and Medicine Medical Marijuana” 2008.

64. Schwilke, Eugene W et al. “Δ9tetrahydrocannabinol (THC), 11hydroxyTHC, and 11nor9carboxyTHC plasma pharmacokinetics during and after continuous highdose oral THC.” Clinical chemistry 55.12 (2009): 21802189.

65. Sam, Amir H, Victoria Salem, and Mohammad A Ghatei. “Rimonabant: from RIO to ban.” Journal of obesity 2011 (2011).

66. Castaneto, MS. “Synthetic Cannabinoids: Epidemiology, Pharmacodynamics ... NCBI.” 2014.

67. “28 Legal Medical Marijuana States and DC Medical Marijuana ...” 2010. 28 Nov. 2016.

68. “16 States with Laws Specifically about Legal Cannabidiol (CBD ...” 2016. 22 Sep. 2016.

69. “Three States Considering Medical Marijuana Legalization Medical...” 2010. 22 Sep. 2016.

70. “the potential medical liability for physicians recommending.” 4 Sep. 2016.

71. Annas, George J. “Reefer madnessthe federal response to California’s medical marijuana law.” NEJM. 337 (1997): 435439.

72. No, DC. “CONANT v. WALTERS American Civil Liberties Union.” 2006.

73. “Doctor Could Lose His License After Approving Medical Marijuana ...” 2014. 4 Sep. 2016.

74. “Medical marijuana doctors loses license to practice The Boston Globe.” 2016. 4 Sep. 2016.

75. “Four Colorado doctors suspended over medical ... The Denver Post.” 2016. 4 Sep. 2016.