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Summer 2007, Vol. 25, No. 2
Feature
Cannabinoids: A Secret History
By Tom Geller
The history of cannabinoids starts with the use of cannabis as a fiber plant over 12,000 years ago. The plant was first specified in a medical context by the Chinese emperor Shen-Nung in 2700 BCE to treat “beri-beri, constipation, female weakness, gout, malaria, rheumatism and absentmindedness.' Wide-ranging recommendations for cannabis use continued in to appear in ancient sources until around the 2nd century CE, when Western-world documentation on its uses—as on many other scientific matters—disappeared. Even so, cannabis (also called hemp) continued to be cultivated in Europe and Asia as a fiber plant and ultimately became a central non-food crop of colonial and post-revolutionary America. Cannabis almost certainly found use as a drug everywhere that it grew with sufficient potency. George Washington, among others, is believed to have smoked hemp for entertainment and to relieve tooth pain.
In 1799 Napoleon Bonaparte’s army returned to France from an unsuccessful Egyptian military campaign, bringing with it three science-minded soldiers who carried new knowledge of the plant. Napoleon’s scientists were perhaps the first Western Europeans to study cannabinoids’ effects methodically; two of them, Silvestre de Sacy and P. C. Rouyer, published papers on cannabinoids in a French medical journal in 1809, touching off a new round of medical inquiry. The drug began to enjoy moderate popularity as an intoxicant and home remedy used in alcohol-based tinctures, poultices, and other forms.
Interest in cannabinoids surged in 1841 when the Irish doctor William Brooke O’Shaughnessy published a seminal article in the obscure journal Transactions of the Medical and Physical Society of Bengal. Although O’Shaughnessy’s choice of publication would seem to have limited his audience, his 49-page treatise nevertheless became an important reference for 19th-century scientists interested in cannabinoids’ effects. His report summarized cannabis use as both an intoxicant and a medical drug in Europe and around the world. Most important, he noted, “The extraordinary symptoms [found in the hemp of Turkey and India] depend on a resinous secretion with which it abounds and which seems totally absent in the European kind.' This resinous secretion is, of course, the plant part richest in cannabinoids.
From Cure-all to Social Ill
Sir William’s work (O’Shaughnessy was knighted in 1856) sparked interest in cannabinoids throughout the scientific community and the public at large. Two years later in Great Britain, John Clendenning studied cannabinoids as a clinical tool for treating chronic pain and alcohol withdrawal; in France, psychiatrist Jacques-Joseph Moreau’s 1845 book Du haschich et de l’aliénation mentale (Hashish and Mental Alienation) described mental effects of the drug; the British Medical Association’s president, Sir Robert Christison, recommended it for treating (among other things) tetanus and pain relief; and Sir John Russell Reynolds, personal physician to Queen Victoria, prescribed it for “female problems.”
Soon after it appeared in the U.S. Pharmacopoeia in 1850, cannabis was marketed in patent medicines, with some packages eventually carrying the Good Housekeeping Seal of Approval. As was typical of patent medicines, manufacturers claimed the drug could cure practically everything and included it in products as diverse as aphrodisiacs and foot powder. Many of these advertising claims were supported by mainstream medical studies such as the 1860 Report of the Ohio State Medical Committee on Cannabis Indica. Cannabis was also a standard ingredient in tinctures and generic compound drugs. Among the companies that produced cannabis-containing compounds were Abbott Laboratories; E. R. Squibb and Sons (now Bristol-Myers Squibb); Smith, Kline and Company (now GlaxoSmithKline); Eli Lilly; Sharp and Dohme (now Merck); and Parke, Davis.
But even in the mid-19th century the drug had its critics. Personal accounts described such uncomfortable side effects such as nausea, reduced productivity and concentration, and exhaustion. Cannabis’s image came under further attack in the 1880s when burgeoning temperance movements expanded their mandate from alcohol to other substances, encompassing all with warnings against intoxication in general. Media outlets reacted to this popular movement with sensational stories of alcohol, marijuana, and opium excess. A substantial number of these reports played on fears that cannabis use encouraged a foreign threat put forth by immigrants and racial and ethnic minorities. One sign of this change appeared in the 1910s, as the Spanish term marihuana started to supplant cannabis in reports of drug-related crime, while cannabis continued to be the term used for medical applications.
Growing suspicions regarding patent medicines added to the public’s doubts about cannabis’s medical legitimacy. The Pure Food and Drugs Act of 1906 did not target cannabis specifically but laid the path for future anticannabis regulations (see “How Chemists Pushed for Consumer Protection,” CH, Summer 2006, pp. 6–11). Next came the Harrison Narcotics Tax Act of 1914, which regulated and taxed opiates and cocaine—but, again, not cannabis. In 1920 sales of alcohol were prohibited by the 18th Amendment. Cannabis remained unregulated federally until 1937, ironically only four years after the 21st Amendment acknowledged the failure of alcohol prohibition.
The regulation that felled cannabis—the 1937 Marihuana Tax Act—effectively prohibited it by imposing regulations that were difficult or impossible to meet. On its face the act only required purchase of a $1 tax stamp by all who possessed, traded, or prescribed cannabis. But the devil was in its associated 60 pages of regulations, which detailed the application and maintenance process for obtaining the stamp. Doctors who wished to prescribe it had to give the Federal Bureau of Narcotics extensive information, including the names and addresses of patients, circumstances surrounding the prescriptions, and so on. Frequent reports and Treasury Department inspections were required, and errors were punishable by a fine of $2,000 (about $25,000 in today’s dollars), a five-year imprisonment, or both. As with the Harrison Act, the power to tax conveyed the power to destroy, and the Marihuana Tax Act’s restrictions—together with widely publicized arrests of doctors who failed to meet tax act requirements—effectively closed off legal channels for provision of the substance.
The chill affected researchers as well as clinicians. Medical journals published dozens of studies before the tax act but few after its enactment. As researcher Lester Grinspoon noted, “virtually no medical investigation of cannabis was conducted for many years” as a string of additional laws, including the 1951 Boggs Act and the 1970 Controlled Substances Act, further deterred research.
Today, American researchers who wish to obtain legal cannabis for scientific study must apply to the National Institute on Drug Abuse (NIDA), which maintains a government-funded, 1.5-acre marijuana farm in Oxford, Mississippi. Compared with street marijuana, however, the government’s plants are low in cannabinoid content, and some researchers have also complained of the institute’s slow and seemingly arbitrary decisions. In 1994 Donald Abrams, a professor of medicine at the University of California, San Francisco, proposed to study the effects of smoking cannabis on HIV-related weight loss, but his application was rejected by NIDA, even though it had been approved by the U.S. Food and Drug Administration. When he then resubmitted his proposal, this time emphasizing the drug’s potential negative effects, NIDA not only approved the study but also provided him with nearly a million dollars in funding. Another researcher, Lyle Craker of the University of Massachusetts–Amherst, applied to the Drug Enforcement Administration in 2001 for the right to grow cannabis for research purposes as a way of sidestepping these potency and access issues. For three years he heard nothing, until a federal court ordered the Drug Enforcement Administration to respond. They said no, so he sued them. That case is still under way.
Cannabinoid Chemistry
The Cannabis genus arguably includes three distinct plants: c. sativa (classified by Carl Linnaeus in 1753), c. indica (Jean Baptiste Lamarck, 1783), and c. ruderalis (Dmitri Erastovich Janischewsky, 1924). Because they can interbreed, researchers disagree as to whether the three should be classified as separate species. Adding to the confusion, Cannabis is only one of several genera sometimes called hemp. One 16th-century account, for example, refers to wood nettle (Laportea canadensis) as “wild hemp” and dogbane (Apocynum cannabinum) as “Indian hemp.” Generally, only c. sativa, which is high in euphoric delta-9-tetrahydrocannabinol (THC), and c. indica, which is high in analgesic cannabidiol (CBD) and sedative cannabinol (CBN), are cultivated for their cannabinoid content.
Natural cannabinoids are a family of over 60 chemicals that occur in cannabis plants; several synthetic cannabinoids have been produced in the laboratory. The phenolic cannabinoids are insoluble in water but dissolve well in such nonpolar organic solvents as lipids and alcohols. They vaporize between 150°C and 200°C. Taken together, these properties help to explain some of the popular means of delivering the drug: water pipes remove particulates and water-soluble components while concentrating cannabinoids; alcohol tinctures and fatty baked goods provide a medium for the desired compounds; and vaporizers allow users to inhale cannabinoids without burning plant matter.
By far the best-known cannabinoid is THC, first isolated by Israeli researchers Raphael Mechoulam and Yechiel Gaoni in 1964. CBD is a commonly known, non-psychoactive substance that alters THC’s effects through a still-unknown mechanism and acts as an analgesic. (Some sources believe it also adds a sedative effect; others disagree.) Finally, CBN, which is absent in the fresh plant but develops as it dries, is an oxidation product of THC also considered to have a mildly sedative quality. Other natural cannabinoids include cannabigerol (CBG), cannabichromene (CBC), cannabivarol (CBV), tetrahydrocannabivarin, and cannabidivarin. Studies on some of these have hinted at potential medical applications: CBC, for example, has been shown to have anti-inflammatory properties, while CBG apparently acts as an antimicrobial agent.
Starting with O’Shaughnessy, several scientists attempted to identify cannabis’s active components, giving such names as cannabin (1846), cannabene (1870s), cannabinine (1881), and cannabindon (1894) to the mixtures they found. But credit for isolating and describing the first true cannabinoids goes to two parties: Scot tish biochemist Alexander Robertus Todd (later Sir Todd, then Baron Todd) in 1939 and the American Roger Adams, whose extensive 1940 series in the Journal of the American Chemical Society served as the primary base of cannabinoid knowledge for decades. On commission from the Federal Bureau of Narcotics in the late 1930s, Adams produced moderately pure cannabidiol and cannabinol from Minnesotan wild hemp using a petroleum ether extraction process devised in 1896. A generous researcher, Adams gave credit to one of his predecessors, Robert Cahn, for isolating cannabinol nearly ten years earlier but noted that Cahn’s structure was “dubious.”
Adams was a remarkable scientist, graduating from Harvard at 20 and founding that school’s first elementary organic chemistry laboratory. He eventually became head of the Chemistry Department at the University of Illinois at Urbana-Champaign and developed the eponymous “Adams catalyst.” Nevertheless, something— presumably either his government-sponsored work on cannabinoids or errors in his Federal Bureau of Investigation file—led J. Edgar Hoover’s agency to classify him as a “suspect American citizen” and prevented him from accepting an invitation from Vannevar Bush to join the National Defense Research Committee during World War II. Ultimately his security clearance was approved, and he worked to develop synthetic rubber as the war drew to a close.
From the Body to the Laboratory
The human body has two primary types of cannabinoid receptors: CB1, found mostly in the brain, and CB2, found primarily in the immune system, particularly the spleen. Nature tends to be spare in its construction, so the question naturally arises: why are humans equipped with cannabinoid receptors? Do our bodies produce some sort of “endocannabinoid”? If not, what role might the cannabis plant have played in human evolution?
One answer came from the various efforts of William Devane, Allyn Howlett, Lumír Hanus, and Aviva Breuer, with much of the work done in Mechoulam’s Hebrew University laboratory. Together they discovered and described the brain chemical arachidonyl ethanolamine, a CB1 neurotransmitter that they named “anandamide.” The second endocannabinoid, named 2-arachidonoyl glycerol (2-AG), was isolated from the spleen and was identified in Mechoulam’s laboratory by doctoral student Shimon Ben-Shabat in 1995, with biological work later completed by Daniele Piomelli and Nephi Stella at the University of California, Irvine.
These developments provided insight on drug function, and—most important—provided direction for future study. For example, studies showed that cannabinoids’ interaction with these receptors appears to inhibit the release of harmful substances and incites neuroprotective activity, and may therefore be useful in treating tumors and brain injuries. (2-AG levels increase by nearly 10 times after head injuries.) Over the past 20 years researchers have been digging ever more deeply into cannabinoids’ biochemistry to apply these lessons to medicine.
As we come to understand cannabinoids’ effects, medical professionals are trying to isolate them. While recreational marijuana users might enjoy the natural plant’s mind-altering qualities, potential patients would likely see these as side effects. And so a great deal of institutionally based research on cannabinoids has been focused on synthesis. Synthetic cannabinoids fall broadly into two categories: those developed as drugs and those used solely in research.
Research synthetics came first, starting with CP 55,940, a 1974 Pfizer development that aided in the 1988 discovery of cannabinoid receptors and is still used for cannabinoid research. Levonantradol, an analog of THC, started appearing in studies in 1981. According to Mechoulam, who synthesized research cannabinoid HU210 in 1988, most research cannabinoids including HU210, CP 55,940, and levonantradol all “act as THC but are more potent.”
Several synthetics have been tested as drugs. Nabilone was created in 1985 by Eli Lilly and is now owned by Valeant Pharmaceuticals. Nabilone is available in Canada as Cesamet and acts similarly to THC. Dronabinol is a synthetic THC produced by Unimed Pharmaceuticals in 1986 and marketed under the trademark Marinol. Dronabinol is currently the only synthetic cannabinoid approved for medical use in the United States. Ajulemic acid, owned by Sumner Burstein and Atlantic Technology Ventures, was first synthesized in 1992. It has been in development and trials since 2000, including testing in humans for pain relief. HU-211, or Dexanabinol, is a follow-up to HU-210 and was licensed to the Pharmos Corporation for development. In 2004 HU-211 failed human trials as an antitrauma drug. Cannabinor, another Pharmos Corporation product, is currently in Phase II of trials as a CB2-specific agonist.
Other products in development are based on naturally derived products or indirect effects of cannabinoid chemistry. Sativex, an oral spray made from normalized extracts of marijuana rather than synthesized cannabinoids, was approved for use to treat multiple sclerosis patients in Canada in 2005. Each spritz contains approximately 2.5 mg each of THC and CBD. The product is currently entering the third phase of clinical trials in the United States. The pharmaceutical company SanofiAventis has applied to the U.S. Food and Drug Administration for approval of rimonabant, a drug that affects lipid metabolism and seems to be important in diabetes treatment. Currently marketed in Europe as Acomplia, rimonabant is based on SR-144528, a synthetic antagonist that prevents other cannabinoids from binding with the CB1 receptor. The most intriguing of its results is that it blocks the snacking urge well known to recreational marijuana users. Rimonabant has received considerable attention as a potential diet drug wherever it has become available, and counterfeit versions are already advertised for sale.
A Surge in Research
Today cannabinoid use and research are tangled in a web of contradictions. Consider natural cannabis: the United States government considers it illegal, but 11 states permit and regulate its use for medical purposes. Researchers are encouraged to examine only synthetic cannabinoids by their greater ease of access and medical demand for pinpoint-accurate applications. Drugs such as Acomplia may completely change the popular image of cannabinoids.
It appears that cannabinoid research has reached a critical mass. To quote Mechoulam, “We are learning a lot almost every week. I am almost certain that various cannabinoids will become important drugs. Almost all major pharmaceutical companies have groups working on cannabinoids.” Regardless of the chemicals’ rocky past, it seems researchers are at a point of no return. In the past 200 years cannabinoids have ricocheted in the public mind between being a miracle cure and an obsession of the dissolute. Now we’ve gained basic knowledge of what cannabinoids are, how they work, and how to synthesize them. We are at the same time knowledgeable and naive, cracking the chemical code while the applications remain elusive—and sometimes forbidden. The next decade should be especially exciting for anyone in this field.
For Further Reading
Abel, Earnest L. Marihuana: The First Twelve Thousand Years. New York: Phenum Press, 1980.
Adams, R. "Marihuana." Science 92:115 (9 August 1940), 115-119.
Mandavilli, A. "Marijuana Researchers Reach for Pot of Gold." Nature Medicine 9:10 (October 2003), 1227.
Mechoulam, R. "Marihuana Chemistry." Science 168:3936 (5 June 1970), 1159-1166.
Mikuriya, Tod H., ed. Marijuana Medical Papers: 1839-1972. Berkeley, CA: MediComp Press, 1972.
Nicoll, Roger A.; Bradley N. Alger. "The Brain's Own Marijuana." Scientific American 21:6 (December 2004), 45-51.
Tom Geller is a San Francisco–based freelance science and technology writer. He wishes to thank Raphael Mechoulam for his assistance with this article.
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