Medicinal use of cannabis in various cultures can be traced back for many hundreds, perhaps thousands, of years. During the late nineteenth and early twentieth centuries, crude cannabis extracts were accepted pharmaceuticals in Europe and the United States. Indeed, six different types of cannabis preparations were listed in an early edition of The Merck Index (1896) of pharmaceutical compounds. However, the medicinal use of cannabis gradually declined, in part because the available preparations tended to be unstable and had inconsistent potency.

Interest in the possible therapeutic benefits of cannabinoids was later revived following the discovery of THC and the subsequent manufacture and testing of various synthetic compounds. Current therapeutic use of cannabinoids takes three major forms: (1) medical marijuana, in which marijuana itself is prescribed by a physician and then usually smoked or inhaled through some other mechanism; (2) extracts from the cannabis plant that contain specific amounts of THC and CBD; and (3) pure synthetic THC or other cannabinoid agonists that are typically consumed orally. We will first cover all three current forms of cannabinoid administration, after which we will discuss emerging therapeutic applications of cannabinoid-based medications.

The arguments for and against medical marijuana are well known and are brought up every time the issue comes up for debate (Russo, 2016). One common argument favoring medical marijuana is a presumption of greater efficacy compared with synthetic THC. As there are few, if any, controlled clinical studies on this topic, the efficacy argument is based mainly on anecdotal testimony by patients who have compared the degree of symptom relief from smoked marijuana with that provided by dronabinol, a synthetic form of THC licensed and sold under the trade name Marinol. Even in the absence of clinical studies, however, the efficacy argument is plausible based on at least two considerations. First, as we saw earlier in the chapter, THC is subject to extensive first-pass hepatic metabolism when taken orally, thereby limiting its bioavailability. This problem is avoided when cannabis is smoked or inhaled in vapor form (i.e., “cannavaping”; see Varlet et al., 2016). The second consideration has been termed herbal synergism, meaning that other phytocannabinoids such as CBD may interact with THC and/or have their own biological activity that contributes to therapeutic benefit (Russo, 2016). An additional argument concerns price, as marijuana is inexpensive to produce and, therefore, may be more cost-effective than many alternative prescription medications. Arguments against medical marijuana are many, including the difficulty of standardizing dosage in an herbal preparation, health concerns that are particularly relevant for patients who use marijuana regularly for a long period of time, the possibility of developing cannabis dependence, and not least, the fact that cannabis possession is still illegal at the federal level because of its designation as a Schedule I substance by the DEA.

Despite concerns about the potential adverse consequences of legalizing marijuana for medical use, by late 2016, 25 states, the District of Columbia, Guam, and Puerto Rico had all enacted laws implementing public medical marijuana and cannabis programs (National Conference of State Legislatures, 2016). An additional 17 states permit limited medical access to cannabis preparations relatively low in THC but high in CBD. The aim of these limited-access programs is to minimize abuse potential of the medication while maintaining therapeutic efficacy. Future studies are clearly needed to ascertain whether marijuana does, in fact, confer greater therapeutic benefit than purified cannabinoid preparations. As well, the increasing availability of medical marijuana will provide the opportunity to determine whether the adverse outcomes predicted by its opponents come to pass over time.

Although the legalization of marijuana for medical use is a relatively recent phenomenon in most parts of the United States, purified cannabinoid preparations have been available for a longer period of time, thereby affording more opportunity for controlled studies testing their treatment efficacy. Such preparations include the previously mentioned dronabinol, the THC analog nabilone (trade name Cesamet), and a cannabis extract called nabiximols (trade name Sativex), which contains a mixture of THC and CBD. Dronabinol is an oral medication prescribed to treat appetite and weight loss in patients with AIDS and to suppress nausea and vomiting from cancer chemotherapy in patients who haven’t responded adequately to first-line antinausea medications. Nabilone is also taken orally and is licensed for the same uses as dronabinol; however, it is also commonly prescribed as an adjunct therapeutic agent for managing chronic, including neuropathic, pain. Nabiximols, which is formulated as an oral spray, is currently licensed in a number of countries for the treatment of neuropathic pain and spasticity in patients with multiple sclerosis. It has undergone clinical testing in the United States but had not been approved by the FDA at the time of this writing. Patients contemplating use of any cannabinoid drugs should be aware that they can produce various side effects such as sedation, dizziness, confusion, dry mouth, and mild euphoria. Alternatively, dysphoria may occur in people unfamiliar with the effects of smoked marijuana. Fortunately, such side effects tend to be greatest when the drug is first taken and generally diminish within a few days or weeks.

Whiting and colleagues (2015) recently performed a systematic review and meta-analysis of therapeutic efficacy of cannabinoid medications and, in a few cases, smoked THC. Using an approach termed GRADE to assess the overall quality of published reports on this topic (Guyatt et al., 2008), the authors concluded that there was moderate-quality evidence for a beneficial effect of nabiximols or smoked THC on chronic neuropathic or cancer pain. The same level of quality was determined for a wider range of cannabinoid medications (including dronabinol, nabilone, and nabiximols) in reducing spasticity associated with multiple sclerosis. Surprisingly, the review only reported low-quality evidence for therapeutic efficacy in treating chemotherapy-induced nausea and vomiting or weight loss in patients with AIDS. Other recent reviews similarly concluded that existing cannabinoid medications should only be prescribed in cases of “breakthrough” nausea and vomiting in which patients have failed to respond to first-line medications (May and Glode, 2016; Tafelski et al., 2016). Note, however, that this conclusion does not preclude the possibility that smoked or inhaled cannabis could be more efficacious than dronabinol or nabilone, as only the latter two drugs have been studied systematically in patients with cancer who are receiving chemotherapy.

Novel therapeutic approaches to cannabinoid pharmacotherapy are being tested because of the limitations of existing medications. Such approaches include selectively targeting CB₂ instead of CB₁ receptors, administering compounds that have poor blood–brain barrier penetrance and thus only affect peripheral cannabinoid receptors, and blocking fatty acid amide hydrolase (FAAH) or monoacyl-glycerol lipase (MAGL) to elevate endocannabinoid levels. An additional approach that has generated much excitement is the potential use of CBD to target mechanisms distinct from the classical CB₁ and CB₂ receptors. CBD has a complex pharmacology that includes blocking a G protein–coupled receptor called GPR55 and enhancing the activity of serotonin 5-HT_1A and glycine α₁ and α₃ receptors (Fasinu et al., 2016; Marichal-Cancino et al., 2016). CBD can also alter intracellular Ca²⁺ levels, and it exerts potent antioxidant and anti-inflammatory effects in various model systems.

Researchers also continue to search for new or expanded applications for cannabinoid-based medications. Some of the disorders for which cannabinoid medications may be applicable are migraine and cluster headaches (Baron, 2015), visceral pain (Sharkey and Wiley, 2016), and neurodegenerative disorders and stroke (Aso and Ferrer, 2014, 2016; Fernández-Ruiz et al., 2015; Kluger et al., 2015; Navarro et al., 2016). As CB₁ receptors are located in many parts of the neural circuitry that control mood and cognition, it is not surprising that cannabinoid-based medications might be developed to treat neuropsychiatric disorders such as depression, anxiety disorders, schizophrenia, and addiction (Blessing et al., 2015; Hurd et al., 2015; Iseger and Bossong, 2015; Korem et al., 2016; Ogawa and Kunugi, 2015; Zlebnik and Cheer, 2016). With respect to anxiety, it is worth noting that at least eight states currently permit marijuana to be prescribed for post-traumatic stress disorder (PTSD) (Yarnell, 2015). On the other hand, although proponents of medical marijuana have long argued for its use in treating glaucoma, the effect of marijuana in reducing intraocular pressure is relatively short-lived, making it an unattractive option for most patients when compared with standard glaucoma medications (Novack, 2016; Sun et al., 2015).

Finally, we discuss a particularly exciting initiative in cannabinoid pharmacotherapy, namely the use of CBD to treat pediatric epileptic disorders. The ability of cannabis to suppress epileptic seizures has been known for hundreds, if not thousands, of years (Friedman and Devinsky, 2015). For this reason, significant numbers of patients with epilepsy self-medicate with marijuana, either illegally or legally under applicable medical marijuana laws. However, the efficacy of cannabis to treat seizure disorders has not been established using properly controlled clinical studies, and moreover there are substantial risks associated with long-term cannabis use (see the Cannabis Abuse and the Effects of Chronic Cannabis Exposure section below). Among the patients most in need of new medications are children with rare, genetic, and drug-resistant forms of epilepsy such as Dravet syndrome and Lennox-Gastaut syndrome. One such patient was Charlotte Figi, who was born in 2006 and seemed like a healthy baby until she experienced her first seizure at 3 months of age. Over the next few years, Charlotte’s symptoms progressively worsened until she was having 300 grand mal seizures a week. She was finally diagnosed with Dravet syndrome, also known as severe myoclonic epilepsy in infancy, which is a severe seizure disorder that responds poorly to standard antiepileptic medications and if left unchecked, may cause severe neurological problems and developmental delays. Once it became clear that Charlotte’s life was in danger from her illness, her parents began to consider nontraditional avenues for treatment, including cannabis. Finally, a breakthrough occurred when Charlotte began to receive daily oral doses of a cannabis oil extract that was low in THC but high in CBD. CBD was known to have antiseizure activity from animal studies (Jones et al., 2010; see Figure 1), but human clinical testing had not yet been performed. The strain of cannabis from which the CBD-rich oil was derived was supplied by a small firm (now associated with a nonprofit foundation) in Colorado, one of the approved medical marijuana states. This cannabis strain was subsequently named Charlotte’s Web in recognition of its most famous patient. Widespread publicity about Charlotte’s success story (see, for example, Young, 2013) led to the treatment of other children suffering from intractable epilepsy with the same or similar formulations high in CBD. In most cases, parents reported significant improvement in their children’s symptoms; however, again these are not controlled clinical trials, and it is important to be concerned about bias, since families are desperate for the treatment to work (Porter and Jacobson, 2013). Fortunately, several pharmaceutical companies are now developing and testing CBD medications that, if shown to be efficacious in clinical trials, are likely to be approved for licensure (Rosenberg et al., 2015). Most far along in development is Epidiolex, an oil-based formulation containing 99% CBD extracted from cannabis plants. Over the past several years, Epidiolex has been granted orphan drug status for both Dravet and Lennox-Gastaut syndromes, and in 2016 the manufacturer announced positive results from phase 3 clinical trials involving both disorders. These results suggest that Epidiolex, perhaps followed by other CBD-based medications, will be approved for treatment of pediatric epilepsies before too long.

 

Figure 1 Antiseizure activity of CBD in rats. Effects of CBD were tested in adult male laboratory rats injected with 80 mg/kg pentylenetetrazol, a proconvulsant drug commonly used in animal studies to assess anticonvulsant activity of a test compound. The figure shows a cannabidiol dose-dependent reduction in percentage of animals exhibiting tonic–clonic seizures, which is the most serious type of seizure observed. (After Jones et al., 2010.)

In summary, marijuana is available by prescription in many states, and still others allow medical use of cannabis-derived preparations low in THC but high in CBD. The potential advantages of smoked or inhaled cannabis compared with oral THC include greater bioavailability and possible herbal synergy due to the interactions of multiple bioactive cannabinoids present in the whole plant. However, long-term use of marijuana poses significant health concerns, which has spurred great interest in the development of pure cannabinoid medications designed to minimize these concerns. The unique properties of CBD are particularly intriguing, with application of this molecule to the treatment of refractory pediatric epileptic disorders leading the way to acceptability of new cannabinoid-based medications. On the flip side, caution is always warranted when developing novel medications, and drugs targeting the endocannabinoid system are no exception to this dictum. We mentioned earlier that pharmaceutical companies have begun to assess the potential therapeutic benefits of compounds that block FAAH, the enzyme that breaks down anandamide. One such compound, BIA 10-2474 (synthesized by the Portuguese pharmaceutical company Bial), was administered to 90 volunteers in a phase 1 clinical trial in France. You will recall from Chapter 4 that phase 1 trials are used to test a new drug for toxicity and pharmacokinetic properties in a small cohort of healthy people. Tragically, one of the drug-treated study participants died, four suffered from brain damage (i.e., cerebral hemorrhage and necrosis) that may be irreversible, and an additional person was hospitalized for other reasons (Kaur et al., 2016). These serious consequences occurred in people who received multiple doses of the compound. We don’t yet know why such unexpected effects occurred. Proposed theories center around (1) that BIA 10-2474 was an irreversible inhibitor of FAAH, thereby causing an immune reaction in the affected individuals; (2) that BIA 10-2474 may have caused the brain damage by affecting other molecular targets besides FAAH (so-called “off-target” effects); or (3) that impurities were present in the material administered to the individuals. While some risk always exists for people who are the first to receive a newly developed drug, it is, of course, imperative that the manufacturer take every precaution to mitigate such risk. It is not clear that such precautions were taken by Bial in its clinical trial of BIA 10-2474 (Kaur et al., 2016; Kroll, 2016a).

References

Aso, E., and Ferrer, I. (2014). Cannabinoids for treatment of Alzheimer’s disease: Moving toward the clinic. Front. Pharmacol., 5, 37. doi: 10.3389/fphar.2014.00037.

Aso, E., and Ferrer, I. (2016). CB₂ cannabinoid receptor as potential target against Alzheimer’s disease. Front. Neurosci., 10, 243. doi: 10.3389/fnins.2016.00243.

Baron, E. P. (2015). Comprehensive review of medicinal marijuana, cannabinoids, and therapeutic implications in medicine and headache: What a long strange trip it’s been …. Headache, 55, 885–916.

Blessing, E. M., Steenkamp, M. M., Manzanares, J., and Marmar, C. R. (2015). Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics, 12, 825–836.

Fasinu, P. S., Phillips, S., ElSohly, M. A., and Walker, L. A. (2016). Current status and prospects for cannabidiol preparations as new therapeutic agents. Pharmacotherapy, 36, 781–796.

Fernández-Ruiz, J., Moro, M. A., and Martinez-Orgado, J. (2015). Cannabinoids in neurodegenerative disorders and stroke/brain trauma: From preclinical models to clinical applications. Neurotherapeutics, 12, 795–806.

Friedman, D., and Devinsky, O. (2015). Cannabinoids in the treatment of epilepsy. New Engl. J. Med., 373, 1048–1058.

Guyatt, G. H., Oxman, A. D., Vist, G. E., Kunz, R., Falck-Ytter, Y., Alonso-Coello, P., et al. (2008). GRADE: An emerging consensus on rating quality of evidence and strength of recommendations. BMJ, 336, 924. doi: 10.1136/bmj.39489.470347. AD.

Hurd, Y. L., Yoon, M., Manini, A. F., Hernandez, S., Olmedo, R., Ostman, M., et al. (2015). Early phase in the development of cannabidiol as a treatment for addiction: Opioid relapse takes initial center stage. Neurotherapeutics, 12, 807–815.

Iseger, T. A., and Bossong, M. G. (2015). A systematic review of the antipsychotic properties of cannabidiol in humans. Schizophr. Res., 182, 153–161.

Jones, N. A., Hill, A. J., Smith, I., Bevan, S. A., Williams, C. M., Whalley, B. J., et al. (2010). Cannabidiol displays antiepileptiform and antiseizure properties in vitro and in vivo. J. Pharmacol. Exp. Ther., 332, 569–577.

Kaur, R., Sidhu, P., and Singh, S. (2016). What failed BIA 10–2474 Phase I clinical trial? Global speculations and recommendations for future Phase I trials. J. Pharmacol. Pharmacother., 7, 120–126.

Kluger, B., Triolo, P., Jones, W., and Jankovic, J. (2015). The therapeutic potential of cannabinoids for movement disorders. Mov. Dis., 30, 313–327.

Korem, N., Zer-Aviv, T. M., Ganon-Elazar, E., Abush, H., and Akirav, I. (2016). Targeting the endocannabinoid system to treat anxiety-related disorders. J. Basic Clin. Physiol. Pharmacol., 27, 193–202.

Kroll, D. (2016a). Scientists speculate on what caused the Bial drug testing tragedy in France. Forbes. Available at www.forbes.com/sites/davidkroll/2016/01/18/scientists-speculateon-what-caused-the-bial-drug-testingtragedy-in-france/#274bd8d25404.

Marichal-Cancino, B. A., Fajardo-Valdez, A., Ruiz-Contreras, A. E., Méndez-Diaz, M., and Prospéro-García, O. (2016). Advances in the physiology of GPR55 in the central nervous system. Curr. Neuropharmacol., 15, 771–778.

May, M. B., and Glode, A. E. (2016). Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics. Cancer Manag. Res., 8, 49–55.

National Conference of State Legislatures. (2016). State Medical Marijuana Laws. Available at www.ncsl.org/research/health/state-medical-marijuana-laws.aspx.

Navarro, G., Morales, P., Rodriguez-Cueto, C., Fernández-Ruiz, J., Jagerovic, N., and Franco, R. (2016). Targeting cannabinoid CB₂ receptors in the central nervous system: Medicinal chemistry approaches with focus on neurodegenerative disorders. Front. Neurosci., 10, 406. doi: 10.3389/fnins.2016.00406.

Novack, G. D. (2016). Cannabinoids for treatment of glaucoma. Curr. Opin. Ophthalmol., 27, 146–150.

Ogawa, S., and Kunugi, H. (2015). Inhibitors of fatty acid amide hydrolase and monoacylglycerol lipase: New targets for future antidepressants. Curr. Neuropharmacol., 13, 760–775.

Porter, B. E., and Jacobson, C. (2013). Report of a parent survey of cannabidiol-enriched cannabis in pediatric treatment-resistant epilepsy. Epilepsy Behav., 29, 574–577.

Rosenberg, E. C., Tsien, R. W., Whalley, B. J., and Devinsky, O. (2015). Cannabinoids and epilepsy. Neurotherapeutics, 12, 747–768.

Russo, E. B. (2016). Current therapeutic cannabis controversies and clinical trial design issues. Front. Pharmacol., 7, 309. doi: 10.3389/fphar.2016.00309.

Sharkey, K. A., and Wiley, J. W. (2016). The role of the endocannabinoid system in the brain–gut axis. Gastroenterology, 151, 252–266.

Sun, X., Xu, C. S., Chadha, N., Chen, A., and Liu, J. (2015). Marijuana for glaucoma: A recipe for disaster or treatment? Yale J. Biol. Med., 88, 265–269.

Tafelski, S., Häuser, W., and Schäfer, M. (2016). Efficacy, tolerability, and safety of cannabinoids for chemotherapyinduced nausea and vomiting: A systematic review of systematic reviews. Schmerz, 30, 14–24.

Varlet, V., Concha-Lozano, N., Berthet, A., Plateel, G., Favrat, B., De Cesare, M., et al. (2016). Drug vaping applied to cannabis: Is “cannavaping” a therapeutic alternative to marijuana? Sci. Rep., 6, 25599. doi: 10.1038/srep25599.

Whiting, P. F., Wolff, R. F., Deshpande, S., Di Nisio, M., Duffy, S., Hernandez, A. V., et al. (2015). Cannabinoids for medical use: A systematic review and metaanalysis. JAMA, 313, 2456–2473.

Yarnell, S. (2015). The use of medicinal marijuana for posttraumatic stress disorder: A review of the current literature. Prim. Care Companion CNS Disord., 17, 3. doi: 10.4088/PCC.15r01786.

Young, S. (2013). Marijuana Stops Child’s Severe Seizures. CNN. Available at www. cnn.com/2013/08/07/health/charlotte-child-medical-marijuana/.

Zlebnik, N. E., and Cheer, J. F. (2016). Beyond the CB₁ receptor: Is cannabidiol the answer for disorders of motivation? Annu. Rev. Neurosci., 39, 1–17.