The pharmaceutical industry is showing not only increasing interest in synthetic modulators of the endogenous cannabinoid system, but also industry members are funding several clinical studies with cannabis whole plant extracts in Europe and Canada with the intention to develop approved cannabis based medicines. This indicates that therapeutic exploitation of natural cannabis will be economically sound. However the present Schedule I classification of cannabis and THC is an impediment to the pharmaceutical development of cannabinoid drugs becaused of the costly restrictions it places on research..
Large pharmaceutical companies such as Pfizer, GlaxoSmithKline and Novartis are demonstrating increasing interest in the therapeutic use of cannabinoids and their derivatives, according to a report of the Wall Street Journal on 28 February 2001. Other firms are already conducting research, such as the researchers at the Bayer AG who found that cannabinoid CB(1) receptors were upregulated in a rat model of chronic neuropathic pain (Siegling et al. 2001). Today, the only available cannabinoids are THC (dronabinol, Marinol) and the dronabinol derivative nabilone. Individual scientists, academic labs and small drug firms are currently the main promoters of pharmaceutical research, because large drug companies have traditionally been reserved with regard to the cost and the political problems associated with marketing marijuana as medicine. This situation appears to be changing. “We see them — Pfizer, GlaxoSmithKline, Novartis — all the time at the meetings of the society now,” says Roger Pertwee, professor at the University of Aberdeen in the U.K. and secretary of the International Cannabinoid Research Society (ICRS). “They never came in the past.”
Firms that are engaged in natural cannabis preparations are GW Pharmaceuticals in the UK and the phytopharmaceutical company Bionorica in Germany. Research and development costs of GW Pharmaceuticals increased to 5.1 million British Pounds in 2001 (PA News, June 13, 2001). Bionorica just started to manufacture dronabinol, and according to personal communication, intends to manufacture a cannabis extract and to start with clinical research shortly (Grotenhermen 2002). The Institute for Oncological and Immunological Research in Berlin (Germany) intends to licence their capsulated cannabis extract to a pharmaceuticals manufacturer, once research has demonstrated the extract’s effectiveness for treatment of severeal illnesses. Several million Euros have already been invested in research.
These activities demonstrate that the cannabinoid system is an increasingly interesting target for the devlopment of drugs by the pharmaceutical industry and that firms are investing millions of dollars into the research with natural cannabis. They appear to be confident that these investments are justified by the medicinal potential of the plant. However, according to the Institute of Medicine development of cannabinoid drugs is greately complicated by the Schedule I classification of both cannabis and tetrahydrocannabinols:
Under the CSA, marijuana and THC are in Schedule I, the most restrictive schedule. The scheduling of any other cannabinoid under this act first hinges on whether it is found in the plant. All cannabinoids in the plant are automatically in Schedule I because they fall under the act’s definition of marijuana (21 U.S.C. § 802 (16)). In addition, under DEA’s regulations, synthetic equivalents of the substances contained in the plant and “synthetic substances, derivatives, and their isomers” whose “chemical structure and pharmacological activity” are “similar” to THC also are automatically in Schedule I (21 CFR § 1308.11(d)(27). Based on the examples listed in the regulations, the word similar probably limits the applicability of the regulation to isomers of THC, but DEA’s interpretation of its own regulations would carry significant weight in any specific situation.
. . . . For the reasons noted above, any changes in scheduling of marijuana and THC would also affect other plant cannabinoids. For the present, however, any cannabinoid found in the plant is automatically controlled in Schedule I.
Investigators are affected by Schedule I requirements even if their research is being conducted in vitro or on animals. For example, researchers studying cannabinoids found in the plant are required under the CSA to submit their research protocol to DEA, which issues a registration that is contingent on FDA’s evaluation and approval of the protocol (21 CFR § 1301.18). DEA also inspects the researcher’s security arrangements. However, the regulatory implications are quite different for cannabinoids not found in the plant. Such cannabinoids appear to be unscheduled unless the FDA or DEA decides that they are sufficiently similar to THC to be placed automatically into Schedule I under the regulatory definition outlined above or the FDA or the manufacturer deems them to have potential for abuse, thereby triggering de novo the scheduling process noted above. Thus far, the cannabinoids most commonly used in preclinical research (Table 5.1) [not included here] appear to be sufficiently distinct from THC that they are not currently considered controlled substances by definition (F. Sapienza, DEA, personal communication, 1998). No new cannabinoids other than THC have yet been clinically tested in the United States, so scheduling experience is limited. The unscheduled status of some cannabinoids might change as research progresses. Results of early clinical research could lead a manufacturer to proceed with or lead the FDA to require abuse liability testing. Depending on the results of such studies, DHHS might or might not recommend scheduling de novo to DEA, which makes the final decision case by case.
Will newly discovered cannabinoids be subject to scheduling? That is a complex question that has no simple answer. The answer depends entirely on each new cannabinoid—whether it is found in the plant, its chemical and pharmacological relationship to THC, and its potential for abuse. Novel cannabinoids with strong similarity to THC are likely to be scheduled at some point before marketing, whereas those with weak similarity might not be. The manufacturer’s submission to FDA, which contains its own studies and its request for a particular schedule, can also shape the outcome. Cannabinoids found in the plant are automatically in Schedule I until the manufacturer requests and provides justification for rescheduling. The CSA does permit DEA to reschedule a substance (move it to a different schedule) and to deschedule a substance (remove it from control under the CSA) according to the scheduling criteria . . . and the process outlined above. (Joy JE, et al, 1999).
References
Grotenhermen F. The medical use of cannabis in Germany. J Drug Issues 2002, in press.
Joy JE, Watson SJ, Benson JA, editors. Marijuana and medicine: Assessing the science base. Washington DC: Institute of Medicine, National Academy Press, 1999
Siegling A, Hofmann HA, Denzer D, Mauler F, De Vry J. Cannabinoid CB(1) receptor upregulation in a rat model of chronic neuropathic pain. Eur J Pharmacol 2001; 415(1): R5-R7
