Developing Cannabis-Based Medicines
This article has been re-posted from the April – May 2003 Cannabis Health Journal.
By Matt Elrod
In November 1998, a year before the Institute of Medicine [1] rekindled North American interest in cannabinoid research and the development of cannabis-based Pharmaceuticals, the UK House of Lords Select Committee on Science and Technology published its report “Cannabis: The Scientific and Medical Evidence” [2], which recommended that clinical trials of cannabis “should be mounted as a matter of urgency”. The committee recognized the deficiencies of existing orally administered cannabis derivatives, such as ronabinol.
“Research should be promoted into alternative modes of administration (e.g. inhalation, sub-lingual, rectal), which would retain the benefit of rapid absorption offered by smoking, without the adverse effects”. One expert who provided testimony to the Committee, Dr. Geoffrey W. Guy, was uniquely positioned to fulfill the parliamentary mandate. Dubbed “the man most likely to succeed at going to pot” by the Financial Times, [3] Dr. Guy is an entrepreneur and physician who specializes in phytopharmaceuticals, plant-based medicines and their delivery systems.
Having founded Phytopharm [4] in 1989 to develop botanical extracts and shepherd them to market, Dr. Guy is adept at navigating the cumbersome regulations governing both natural health products and controlled substances. Perhaps more significantly, unlike most medicinal cannabis enthusiasts, Dr. Guy has a reputation within Europe’s conservative medical community for playing and winning by their rules. Dr. Guy’s background made him distinctly qualified to overcome the clinical, social and bureaucratic hurdles that have thus far prevented cannabis from regaining its place in the pharmacopoeia.
Dr. Guy founded GW Pharmaceuticals [5], still the only company dedicated to developing cannabis-based medicines, in early 1998. A collaboration with HortaPharm BV of the Netherlands gave GW a commanding “first mover” advantage.
HortaPharm’s medicinal cannabis varieties, known as “chemovars”, had been standardized and stabilized for over 20 years to consistently express specific cannabinoids, however, HortaPharm lacked the ability to develop pharmaceuticals and sought drug company partners to take the next step. GW was the only company with the vision to take the HortaPharm research through the development and approval process.
Botanists initially chose 10 Dutch chemovars bred to express high quantities of either THC (delta-9 tetrahydrocannabinol) or CBD (cannabidiol) for their first crop of 5,000 plants grown organically in secretive and exceedingly secure glasshouses in the south of England. The computer-controlled glasshouses are among of the most sophisticated in Europe. No chemicals are used and all pest control is biological.
A GW contractor uses supercritical fluid extraction (SFE), a fairly new technique for extracting lipophilic and volatile com- pounds. [6] SFE utilizes carbon dioxide, which is Generally Regarded As Safe (GRAS), making the extraction process free of organic solvents. Liquid CO2 is forced into supercritical state (SC-CO2) by regulating its temperature and pressure. Supercritical fluid is heavy like a liquid but has the penetrating properties of a gas. SC-CO2 is inert and does not interact chemically with the botanical material or the extraction apparatus.
GW is developing 3 delivery technologies; an oral spray, a tablet which dissolves under the tongue, and a compact inhaler containing miniature heating elements that vapourize cannabis extracts. The spray technology is being utilized for the Group’s lead product, the CBD/THC mixture. Active compounds in the “oro-mucosal” spray are primarily absorbed by the lining of the mouth and the tongue and begin to take effect within about 15- 20 minutes. Some of the extract may also be swallowed, providing symptomatic relief for 4 to 6 hours. The inhaler’s effects are felt almost immediately and do not last as long.
Depending on government requirements, both the spray and the inhaler may be equipped with the company’s “Advanced Dispensing System (ADS)”,a solid-state device resembling a portable phone, which measures and monitors use to help ensure optimal dosages and prevent diversion to the black market. The tamper-resistant device can also be connected to the internet, so doctors and clinicians can remotely monitor their patients’ consumption. As Orwellian as digital drug dispensing systems that phone home might appear, currently many controlled subtances must be consumed under close medical supervision. The ADS promises to grant patients who need such drugs more freedom and autonomy. For example, GW, encouraged by the Home Office, is currently collaborating with the National Addiction Centre (NAC) to trial the ADS for the administration of methadone and diamorphine (heroin) in the treatment of drug addiction. If successful, the program will extend to other countries in Europe and North America.
The ADS was originally developed to make cannabis-based products more palatable to U.S. regulatory authorities, who still classify cannabis at the highest (most restrictive) level as a Schedule I substance. [7] Attempts by various petitioners to have cannabis rescheduled have been unsuccessful. [8] Despite over- whelming evidence to the contrary, U.S. authorities maintain that cannabis has not recognized medicinal value and a high potential for abuse, a position they have not seriously reconsidered since before the discovery of cannabinoid receptors over a decade ago.
GW’s clinical trials have demonstrated that, once patients are no longer “cannabis naive“ and have become accustomed to the psychoactive effects, they are both able and inclined to titrate and personally individualize their dose to achieve improvement in their symptoms with- out experiencing unwanted effects that might interfere with their day-to-day activities. GW consultant Dr. Ethan Russo expects precautionary labeling will be similar to that found on synthetic cannabinoid packaging, advising patients to avoid driving or operating heavy machinery until they have become accustomed to the drug.
Based on their experiences and the remarkable safety profile of cannabis and cannabis-based products, GW does not anticipate a need for the ADS outside of the USA. GW currently has 3 extracts under investigation; one derived from CBD-rich chemovars, one from THC-rich varieties and one with an even mixture of these two most promising cannabinoids.
Proportions of terpenoids, flavonoids and other therapeutically active cannabinoids, such as CBC, CBG and THC-V, are consistent and monitored but left unaltered. Dr. Russo explains “Flavonoids are antioxidants and anti-inflammatory components with anti-aging and cell protective responses. Terpenoids are the essential oils that give cannabis its aroma. There are many with important medical benefits that include anti-inflammatory, analgesic, bronchodilating and memory-enhancing effects. The patient receives the full complement of synergistic phytochemicals. Only the cough is removed. Together this herbal mixture produces effects and medical benefits unobtainable with synthetic THC such as Marinol”. Plant varieties bred to express these less understood compounds are already being cultivated and clinical trials designed to explore their pharmacological properties are on the drawing board or underway.
One of the significant medical benefits of using whole-cannabis extracts appears to be some attenuation of the sometimes unpleasant psychoactive effects of pure THC. CBD in particular seems to “soften” the effect of THC and is known to have anti-psychotic properties. Another bene- fit is the unusual breadth of effect.“These medicines have unique effectiveness for a wide range of conditions, and within the same condition, can often target multiple symptoms. For example, GW research has found that “patients with multiple sclerosis have experienced substantial relief from spasticity, poor sleep, bladder dysfunction and pain,” says David Hadorn, M.D., a GW consultant.
Currently, MS sufferers must orchestrate the carefully timed and measured administration of several distinct, interacting, chemical entities to achieve this broad “shot gun” effect.
Another advantage of GW’s pharmaceutical grade extracts is that they are likely to reach many people who would otherwise miss out on the benefits of cannabis- based medicines. This is perhaps especially true for elderly patients, many of whom have chronic pain and other symptoms, for which cannabis-based medicines would likely provide substantial relief. Most elderly patients are cannabis-naive, however, and would have great difficulty accepting the idea of “toking up”. A prescription oral spray would be perfectly acceptable to many such patients – literally “just what the doctor ordered”.
In previous Phase II trials, there was a 50% average reduction in the participant’s use of opiates. The reduction in
opiate use suggests future analgesics may combine opiates and cannabinoids for their very different but complementary effects. In fact, animal studies have found that opiate/cannabinoid mixtures do not cause the severe withdrawal symptoms associated with long-term opiate use. [9] Perhaps cannabinoids will eventually be integrated into GW’s methadone and diamorphine products.
Try as they might to divorce their company and its research from the politically charged debate over cannabis law reform, research on whole plant extracts, more than research on synthetic analogs, is applicable to the forbidden herb. When reporting GW progress, the media tend to equate their cannabis-based medicine extracts with cannabis, often exploiting the “snicker factor” with pot puns and allusions to stoner stereotypes.
Interpretations also seem linked to geopolitical preconceptions. Most British papers herald GW’s encouraging findings as further evidence of the medicinal benefits of cannabis – more reason to reform medicinal cannabis laws – while U.S. papers tend to characterize cannabis- based medicines as a socially acceptable, non-psychoactive alternative to smoked cannabis. A magic prohibitionist bullet that will render herbal cannabis, and therefore efforts to reform cannabis laws, obsolete.
Cannabis law reforms are also changing the environment for cannabis-based pharmaceuticals. Some British papers have attributed gains in GW stock value to last year’s indications Parliament may reclassify cannabis from Class B to the less restrictive Class C this summer.
Others cited plans for cannabis reclassification as having the opposite, negative effect on GW’s financial outlook. Some activists, such as Richard Cowan, the former national director of the National Organization for the Reform of Marijuana Laws, expect cannabis law reforms to reduce the market viability of cannabis- based pharmaceuticals.
“GW Pharmaceuticals is making excellent progress and I wish them well, but I think that their business will suffer when marijuana is legalized,” wrote Cowan in his online magazine. [10] Dr. Russo thinks the tent is big enough,“the decriminalization or legalization of cannabis will likely occur in many nations, but represents no real threat to this company’s viability or ultimate profitability.”
GW is walking a fine line between alarming cannabis prohibitionists, who see medicinal cannabis as a “stalking horse” for broader liberalization, and whole cannabis advocates, who suspect GW of trying to “monopolize” cannabis therapeutics and introduce products that would replace, rather than offer alternatives to, herbal cannabis. Writing for Cannabis Culture Magazine, Canadian activist David Malmo-Levine went so far as to accuse GW of conspiring to corner the world-wide market for both cannabis pharmaceuticals and cannabis plants. [11] Others believe GW’s ultimate goal is to create, on behalf of vested interests, medicinal cannabis products that do not produce the illicitly sought “side-effect” of euphoria.
“This is simply untrue,” insists Dr. Russo,“GW Pharmaceuticals extracts contain predominantly THC, predominantly CBD or a 1:1 THC/CBD mix, as well as the essential oil terpenoids and flavonoids of the natural herb. If someone used a sufficient dose of the extracts containing THC, they would become ‘high’.” “GW does not expect cannabis as a plant to disappear,” continued Russo,“However, cannabis the plant can never be accepted by the FDA as a smoked prescription medicine as the rules stand. Standardized cannabis-based medicine extracts can.
For the person who wishes HMO reimbursement or coverage under a national health service policy for a defined prescription medicine that will help with their condition, it is the ticket. Not every- one grows grapes when there is Cabernet Sauvignon on the shelf. Similarly, some will toke on ‘homegrown’, while others will reach for the vapourizer, and others for the standardized prescription product. Nothing will advance the acceptance of cannabis faster than good quality research of this type.”
Noted cannabis expert Dr. Lester Grinspoon has a similar vision “… we are going to have two distribution systems for medical cannabis. One will be the conventional model of pharmacy-filled prescriptions for FDA-approved medicines derived from cannabis as isolated or synthetic cannabinoids and cannabinoid analogs. The other will have more in common with some of the means of distribution and use of alternative and herbal medicines. The only difference, an enormous one, will be the continued illegality of whole smoked or ingested cannabis. In any case, increasing medical use by either distribution pathway will inevitably make growing numbers of people familiar with cannabis and its derivatives. As they learn that its harmfulness has been greatly exaggerated and its usefulness underestimated, the pressure will increase for drastic change in the way we as a society deal with this drug.”[12]
GW is now capable of producing medicine for 20,000 patients per annum. They expect to have their first product, for treating multiple sclerosis and neuropathic pain, on the UK market by the end of 2003. The company plans to price its products competitively with other medicines used for similar conditions and at levels that allow provision under govern- mental health insurance plans.
Based on discussions with national regulatory authorities, GW anticipates gaining approval for their first line of extracts in Western Europe, Australia, New Zealand and Canada within months of UK approval. The timing of approval of GW products in the United States is less certain because the company has yet to receive final guidance from the FDA concerning how much additional research, if any, will be required for approval in the US. They will also need a development partner to handle promotion and distribution in North America. Dr. Hadorn predicts that it will probably be “at least two years following UK approval” before GW’s medicines are available in the United States.
END NOTES
1) Janet E. Joy, Stanley J. Watson, Jr., and John A Benson Jr., “Marijuana and Medicine: Assessing the Science Base,” <http://www.nap.edu/html /marimed/> Division of Neuroscience and Behavioral Research, Institute of Medicine
(Washington, DC: National Academy Press, 1999), http://www.nap.edu/readingroom/books/marimed>
2) House of Lords Select Committee on Science and Technology, “Ninth Report,” London: United Kingdom (1998): Cannabis: The Scientific and Medical Evidence.
<http://www.publications.parliament.uk/pa/ld1 99798/ldselect/ldsctech/151/15101.htm>
3) The Man Most Likely To Succeed At Going To Pot, Nicholas Timmins, The Financial Times, June 15, 1998, <http://www.mapinc.org/drugnews /v98/n461/a06.html>
4) Phytopharm plc. <http://www.phytopharm.co.uk>
5) GW Pharmaceuticals plc, <http://gwpharm.com>
6) Supercritical fluid extraction (SFE), M <http://elchem.kaist.ac.kr/vt/chemed/sep/sf/sfe.htm>
7) High Court Upholds Marijuana As Dangerous Drug, Drug Enforcement Administration, June 6, 2002, <http://www.usdoj.gov/dea/pubs/pressrel/pr060602.html>
8) Petitions to reschedule marijuana in the United States, <http://www.druglibrary.org/ olsen/NORML/PETITIONS/petitions.html>
9) Notes on the International Cannabinoid Research Society 1998 Symposium on Cannabinoids, La Grande Motte, France, 23-25 July 1998, Professor Leslie Iversen FRS, Specialist Adviser, <http://www.publications.parliament.uk/pa/ld199 798/ldselect/ldsctech/151/151a05.htm>
10) UK Firm hopes to have “a cannabis-based medicine ready to be prescribed by doctors with- in three to four years.” How Time Flies When You Are Not In Pain!,1999. <http://www.marijuananews.com/marijuananews/cowan/uk_firm_ hopes_to_have_.htm>
11) Will Pot Be Patented?, David Malmo-Levine, Cannabis Culture Magazine #41, Mar 2003,
<http://www.cannabisculture.com/articles/2780.html>
12) On the Pharmaceuticalization of Marijuana, Lester Grinspoon, MD, International Journal of Drug Policy, 12 (5-6) (2001) pp. 377 – 383., <http://rxmarijuana.com/Pharmaceuticalization.htm>
Links
Cannabis from the Chemist, BBC Panorama, November 2001
http://news.bbc.co.uk/1/hi/programmes/panora- ma/1625124.stm
http://www.pottv.net/archive/shows/pottvshows e-1628.html