Alice P. Mead†
Modern medicine increasingly seeks to provide treatment approaches that are “evidence based.” Specifically, the Food, Drug, and Cosmetic Act (FDCA) has been developed over the last 100 years to implement cutting-edge scientific knowledge, with the goal of ensuring that new medications are carefully tested for quality, safety, and efficacy. The Food and Drug Administration (FDA), the agency charged with enforcing the FDCA, closely scrutinizes all aspects of medication development.
This system of medication development also enhances and supports the effectiveness of the physician-patient relationship. Medications that successfully pass through this process are accompanied upon marketing by extensive preclinical and clinical testing which provide a robust body of risk/benefit and pharmacological data. Physicians rely upon these data to inform their prescribing decisions and to facilitate informed consent discussions with their patients.
Furthermore, the FDA process has additional aspects that further protect patient welfare. Medications are approved for marketing only for use in a particular medical condition and by a specified patient population. The FDA requires that manufacturers’ promotional claims be limited to those supported by clinical trial data. Manufacturing facilities are registered with, and inspected by, the FDA to ensure that the manufacturing process is conducted in accordance with validated quality control tools. Medications must be prescribed and dispensed under the supervision of physicians and pharmacists, labeled with instructions for use, and accompanied by information about side effects. While not without its flaws, the FDA process assures the purity, identity, and potency/standardization of products and it is resoundingly supported by all major medical organizations.
How does “medical marijuana” comport with this FDA paradigm? Cannabis products available in dispensaries vary significantly in composition, particularly in their THC content. Since North American cannabis has been bred primarily for recreational use, its THC content has increased in recent decades, as sinsemilla has been in greater demand and sophisticated indoor cultivation practices have become more common. Dispensaries offer a wide range of dosage forms—smoked, vaporized, baked goods, candies, beverages, etc.—but none of these ensures a standardized dose. Furthermore, smoking unquestionably delivers harmful combustion products to the lungs and causes lung damage consisting of persistent cough and bronchitis, particularly with chronic use. Vaporizers—of which there are many different types—have not been shown adequately (by the FDA’s strict standards) to eliminate such toxins. Finally, contamination with dangerous microbes, heavy metals, and pesticides is unfortunately a serious risk of cannabis from various sources.
The dispensary “system” does not take place within the regulated supply chain for pharmaceuticals. Once a “member,” anyone can purchase cannabis, even from multiple dispensaries. Importantly, dispensaries do not collect either efficacy or adverse event data; therefore, it is impossible to know in any reliable way which patients and conditions are being benefitted and to what extent, and who is being harmed and how; yet such post-marketing data are routinely collected for all other prescription medications. In these dispensaries, medical advice is often offered by untrained and unlicensed individuals, who make broad efficacy claims for their products—or offer no information at all. There is often no meaningful physician supervision. A cash payment is all that is required in many cases to obtain a physician’s “recommendation.” Products have no assurance of quality control and are not labeled with instructions for use. Health insurance is not available, since the products are not FDA-approved.
What about the cost of FDA-approved products? The average “medical marijuana” patient uses 1.8 – 3.0 grams per day, although many patients use significantly more. The average price in dispensaries is eleven to fifteen dollars per gram, but prices of twenty-three dollars per gram (or even more) have been advertised. Therefore, an average daily use of 2.2 grams, multiplied by the lowest price of eleven dollars per gram, equals a cost of $726 per thirty-day month. If a patient uses more than 2.2 grams per day or pays more than eleven dollars per gram, the monthly cost is huge, with no reliable quality control or health insurance coverage. It would appear that this controversy is not really about cost.
Securing FDA approval for a cannabis product is certainly possible. The FDA has issued a document entitled “Guidance for Industry: Botanical Drug Products,” which sets forth the requirements for developing medications derived from botanical materials. This Guidance permits some leniency in early research, but, by the state of advanced clinical trials or New Drug Application (NDA), all conventional standards for a new medication must be met. This would likely require that herbal material should be cultivated under highly controlled conditions in order to produce standardized starting materials. Furthermore, the active ingredients should, in all probability, be extracted from the herbal materials and formulated into an appropriate dosage form. There is no precedent in the FDA process for administering any herbal material directly in crude form, since, as noted above, it would be extremely challenging to achieve a reproducible dose and/or to avoid carcinogenic toxins.
FDA approval is only one regulatory requirement that a cannabis-derived product must obtain in order to be marketed. The other element is rescheduling under the Controlled Substances Act (CSA). Cannabis is classified under Schedule I of the CSA, the strictest schedule. Substances in Schedule I can only be used within federally-licensed research programs. The question therefore arises as to whether cannabis/marijuana must be rescheduled in order for a cannabis-derived product to be marketed? The answer to this question would seem to be negative. The Drug Enforcement Administration (DEA) has demonstrated that it will register (license) individual research sites conducting research under FDA-approved Investigational New Drug (IND) applications. Once the FDA approves a specific product for marketing, such approval constitutes “accepted medical use in the U.S.,” thereby allowing that particular medication to be rescheduled to Schedule II or lower, making it available to patients by prescription. The current scheduling of cannabis/marijuana—the substance—would not necessarily be affected.
Contrary to popular opinion, even if cannabis as a substance were to be reclassified into Schedule II, this would not make herbal cannabis (or all cannabis products) available directly to patients. Even cannabis advocates recognize this fact. Physicians can prescribe, and pharmacists can dispense, only those medications that have been approved by the FDA. Therefore, even if cannabis were rescheduled, only a specific cannabis-containing product, one that had completed the FDA approval process, could be prescribed. Nor could pharmacists compound cannabis-containing products for large numbers of patients without very likely running afoul of the FDCA.
Anecdotal reports relating to cannabis suggest that this will be a field in which significant research will take place in the coming years. There is much more to the cannabis plant than the pharmacology of THC. Cannabis contains over sixty cannabinoids; each has its own pharmacology and, in all probability, its own separate therapeutic potential. In earlier times, the harvest from a field of wild cannabis from certain areas such as Morocco and Afghanistan would have comprised approximately half THC and half CBD (cannabidiol) as the predominant cannabinoids. CBD has been determined to have anti-inflammatory, anti-oxidant, and neuroprotective effects, amongst others. It lacks THC-like psychoactivity and, indeed, is believed to mitigate some of the negative effects of THC, including intoxicating effects. As a result, it has essentially been bred out of modern cannabis.
The research community has become quite intrigued by the potential therapeutic applications of CBD and other non-THC cannabinoids, as well as molecules that modulate or otherwise affect the cannabinoid receptor system that exists in the human body. Formulations of cannabinoids, such as Sativex® (CBD: THC 1:1) or Cannador® (CBD: THC approximately 1:2) are being actively investigated in clinical trials. These and other cannabinoids are under study for a variety of medical conditions, such as diabetes/metabolic syndrome, cancer/tumor progression, mental disorders, epilepsy, etc.
Research is also progressing on different delivery systems for cannabinoids. Cannabinoid formulations containing a significant proportion of THC have a narrow therapeutic window. That is, patients may have difficulty finding a dose that achieves sufficient symptom relief without producing unacceptable side effects, especially those involving the central nervous system. The smoked/inhaled route causes THC blood levels to rise dramatically and then to drop off rapidly. Such rapid off/on effect tends to produce psychoactivity, maximize intoxication and possible reinforcement, and, as a result, higher drug abuse liability. Such onset is probably neither desirable nor necessary for patients with chronic medical conditions, who generally prefer a longer-acting medication. On the other hand, the oral route for THC-containing preparations has been shown to have poor bioavailability, a prolonged and unpredictable onset of action, and to produce a psychoactive metabolite that is possibly more potent than THC, often leading to dysphoria. Finally, cannabinoids, unlike opioids, are also insoluble in water and sensitive to degradation by heat and light. Only recently has modern technology permitted the development of dosage forms and delivery systems that address these challenges. It is for these reasons that the development of modern cannabis-derived or cannabinoid medications has lagged far behind that of modern opioids. However, scientists are now investigating various novel delivery systems and formulations.
Sativex® (nabiximols) is one of many products that may appear on pharmacy shelves in the coming years. It comprises highly consistent extracts from two unique cannabis strains, one of which is extremely high in CBD. A formulation of 1:1 CBD:THC is achieved through quantitative addition of the extracts . The preparation is administered as an oromucosal spray (absorbed by the lining of the patient’s mouth). This dosage form has an intermediate onset of action that allows patients to titrate (adjust) their individual dose. Sativex® has been approved in the U.K. as an adjunctive (add-on) treatment for spasticity in multiple sclerosis (MS) and in Canada for pain unrelieved by opioids in advanced cancer and for neuropathic pain in MS. It is undergoing advanced clinical trials in the U.S. for pain in advanced cancer. Sativex® is the first complex plant extract in modern times to receive regulatory approval as a prescription medication, and it has been produced by means of an extremely rigorous pharmaceutical development program.
The mainstream media and the general public are generally not aware of the enormous amount of rigorous scientific research that is taking place with cannabinoids. Improved research technologies and a rapidly-expanding understanding of the endocannabinoid receptor system have resulted in a huge body of preclinical data. These data, in turn, have identified many promising avenues for further clinical (human) research. We are moving rapidly into an era when numerous cannabis-derived and cannabinoid medications will take their place in the physician’s armamentarium. Respecting the mandates of “evidence based” medicine—including adherence to the FDA approval process—offers patients (and their physicians) the best opportunity to identify medications that will meet their medical needs.
† consultant, specializing in regulatory law governing new drug and device development; patient confidentiality and informed consent; and domestic and international treaty issues relating to controlled drugs and drug treatment policy. Ms. Meads clients include members of the pharmaceutical industry and other health-related organizations. Ms. Mead served for eleven years as staff counsel to the California Medical Association (CMA), focusing on bioethics, including informed consent, confidentiality, end-of-life care, discrimination, and drug abuse treatment/control issues. Prior to that time, Ms. Mead was a litigation associate at the firm of Morrison & Forester and an Assistant Professor of Law at Arizona State University College of Law (now Sandra Day O’Connor College of Law), specializing in constitutional law issues.
 The word “marijuana” is a slang term. The proper scientific term is “cannabis.”
 Cannabis dispensaries, sometimes known as “collectives” or “cooperatives,” are generally free-standing establishments that dispense (for a fee, often called a “donation”) cannabis and cannabis products to individuals possessing a recommendation from a physician stating that the individual may benefit from the use of cannabis for medical purposes.
 This is the bud of the unfertilized female cannabis plant, where cannabinoid concentrations are highest.
 Roger N. Bloor, Tianshu S. Wang, Patrick Spanel & David Smith, Ammonia Release from Heated ‘Street’ Cannabis Leaf and Its Potential Toxic Effects on Cannabis Users, 103 Addiction 1671 (2008).
 John M. McPartland, Contaminants and Adulterants in Herbal Cannabis, in Cannabis and Cannabinoids Pharmacology, Toxicology, and Therapeutic Potential 337 (Franjo Grotenhermen & Ethan Russo eds., 2002); Arno Hazekamp, An Evaluation of the Quality of Medicinal Grade Cannabis in the Netherlands, 1 Cannabinoids 1 (2006), http://www.cannabis-med.org/english/journal/en_2006_01_1.pdf.
 The herbal material for the products needs not be cultivated in the U.S. under international agreements established over the past 85 years; the U.S. does not cultivate narcotic raw material domestically, but rather imports such material from selected countries. Authorized Sources of Narcotic Raw Materials, 73 Fed. Reg. 6843-01 (Feb. 6, 2008).
 Center for Medicinal Cannabis Research, Report to the California Legislature (2010), available at www.cmcr.ucsd.edu (describing clinical and preclinical studies registered by the DEA); Positive Data in Sativex Phase IIb Trial Support Advancing into Phase III Development in Cancer Pain, GW Pharmaceuticals (March 23, 2010), www.gwpharm.com (describing the study results from research sites in the U.S. and other countries).
 Compare 21 C.F.R. § 1308.13(g)(1) (2006) (THC in an FDA-approved formulation in Schedule III), with 21 C.F.R. § 1308.11(d)(27) (2010) (all other tetrahydrocannabinols in Schedule I).
 Institute of Medicine, Marijuana and Medicine: Assessing the Science Base 201-03 (Janet E. Joy, Stanley J. Watson, Jr. & John A. Benson, Jr. eds., 1999).