Over the years, research has been conducted on the medical applications of extracts of Cannabis sativa in all parts of the world. Although it is a controversial subject in the medical establishment, Cannabis is used for therapeutic applications by millions of people. In the USA eleven states have legalized the medical use of marijuana, despite the Supreme Court ruling that drug possession is unconstitutional. Recent reports have also indicated that cannabinoid’s extract, δ-9-tetrahydracannabinol ( 1) have been used to lower the intraocular pressure in the eye and has shown other neuroprotective actions potentially useful for treatment of glaucoma. In addition, another cannabis extract, drabinol, is approved by the Federal Drug Authority for use as an appetite stimulant for patients with AIDS ( 2). In this research report, the chemistry of Cannabis sativa will be examined and scientific evidence to substantiate its therapeutic efficacy will be reviewed.
Marijuana is derived from the plant Cannabis sativa which is grown in many tropical areas in the world. Most researchers agree that there is only one specie (sativa) with many variants, while others believe that there are only three different species ( 5). In continents such as Asia and Africa, Cannabis sativa has great medicinal significance. In India and other parts of Africa where Cannabis sativa is prevalent, there have more than 400 different chemicals present as certain primary extracts- Dronabinol (δ-9-tetrahydrocannabinol), (THC), Cannabinol and Cannabidiol. In this paper, three extracts of cannabinoids will be discussed. More importantly, these primary extracts of Cannabis are known to be widely used for their therapeutic uses.
According to the American Academy of Ophthalmology (1992), cannabinoids are not generally accepted as a safe and effective treatment for glaucoma. Although there is evidence that inhaling marijuana can lower intraocular pressure, cannabinoids do not (10). Other medical uses of cannabinoids include the treatment of depression, stimulation of appetite in AIDS patients, control of seizures in epileptic patients and the relief of nausea associated with cancer treatments (3). The strongest evidence relates to the effectiveness of THC (Dronabinol) and the synthetic cannabinoid - Nabilone in relieving nausea and vomiting secondary to cancer chemotherapy. Today in Britain, Nabilone is a licensed drug. While known in Canada as Cesamet, Nabilone is used mostly as an anathematic in the treatment of cancer and AIDS sufferers (6).
The general effects of these extracts are used as a sedative, analgesic, antispasmodic, anathematic and appetite stimulant, and to dull short term memory. Among recreational users, its mood elevating effect makes smoked marijuana quite popular (8).
Extracts, Uses and Evidences of Cannabis sativa
Scientific research carried out over the years has proved beyond doubt that several extracts of Cannabis sativa have been of potent therapeutic uses. Moreover, these uses have been sustained with concrete evidences in the field of medicine today. Besides, different research results have shown that several extracts of cannabis have improved the quality of life for many individuals (9). In this research, the following three extracts of Cannabis will be discussed:
1. Dronabinol (Tetrahydrocannabinol )
The structure of this compound is shown on figure 1. It is the main psychoactive substance found in the hemp plant Cannabis sativa. It was first isolated by Raphael Mechoulan and Yechiel Gaoni from the Weitzman institute in Relovot, Israel in 1964 (1) and assigned the chemical name:
(-)(-)(6aR, 10aR)-6, 6, 9-trimethyl-3-pentyl-6a, 7, 8,10a-tetrahydro-6H- benzo[C]chromen-1-ol.
Solvent extraction, thin-layer (TLC) and gas chromatography (GLC) techniques have been used for the separation and quantitative determination of cannabis plant constituents. THC has a chemical formula C 2H 30O 2 and a molecular mass of 314.46g/mol. In its pure form, it is a glassy solid when cold it becomes viscous, and sticky if warmed. THC has a very low solubility in water - 2.8g/L (water, 23C), but a good solubility in most organic solvents such as pure ethanol or hexane (1).
The pharmacological actions of THC are as a result of its binding to the cannabinoid receptor, CBI, located in the brain. Some effects of THC include relaxation, euphoria, altered space-time perception, alteration of visual, auditory and olfactory senses, fatigue and appetite stimulation shows more evidences of this extract. THC dissolved in sesame oil has an LD 50 value of 270 mg/kg when orally administered to male rats and 730 mg/kg to female rats dissolving it in sesame oil (1). If this were scaled up to human adult, the lethal dose would be 2.8 ounces for a person weighing 140 pounds. This is a low LD 50 for a large compound (13).
For some years the principal psychoactive ingredient of marijuana, THC has been available to healthcare providers in an oral form as dronabinol (trade name Marinol) for the treatment of emesis associated with cancer chemotherapy and for appetite stimulation in the treatment of AIDS wasting syndrome (13) . However, two studies of oral THC were conducted in patients with cancer pain. Both of these studies used the same standard single-dose analgesic study methodology and met the criteria for well controlled clinical trials of analgesic efficacy, but with small sample sizes. The first study in 10 cancer patients compared placebo and 5, 10, 15 and 20 mg doses of THC over a 6-hour observation period. The slope of the dose-response curve for pain relief was significant, as was a pair wise comparison of pain relief. In the second study, 36 cancer patients compared placebo, 10 and 20 mg of THC and 60 and 120 mg of codeine over a 7-hour observation period. Codeine-120 mg and THC 20 mg showed similar results and were significantly superior to placebo for the sum of the pain intensity differences and total pain relief. Hence, these studies do indicate that THC has some analgesic activity in humans. They also indicate that there is a, at best, a very narrow therapeutic window between doses that produce useful analgesia and those that produce unacceptable adverse CNS effects.
In another form, cannabis when used by a number of multiple sclerosis patients help in relieving spasm (1). Formal studies conducted on this subject have proved the possibility of therapeutic uses of cannabinoids.
Although other disputed studies indicate a variety of negative effects associated with constant long-term use, including memory loss, depression and loss of motivation, a more recent study indicates that high quantities of THC can improve memory. The long-term effects of THC on humans have been disputed because its status as an illegal drug prevents free research into this subject (7). Recently in April 2005, Canadian authorities approved the marketing of Sativex, a mouth spray for multiple sclerosis to alleviate pain. Sativex contains THC together with cannabiodiol (6). Currently in the United States, dronabinol is also marketed for the control of nausea and vomiting associated with cancer chemotherapy who have failed to respond adequately to conventional antiematic treatments.
2. Cannabidiol ( CBD )
Cannabinol, also known as CBD, is a non-psychoactive cannabinoid in the hemp plant Cannabis sativa. CBD has a chemical name 2-(1, S, 6S) -3-methyl-6-(prop-1-en-2-yl) cyclohex-2-enyl)-5-pentylbenzene -1, 3-diol and a chemical formula C 12H 30O 2. It has a molecular mass 314.46 g/mol and its melting point is between 66-67 ◦C. The mechanism of extracting cannabidiol from Cannabis is quite similar to THC, as explained earlier. Other procedures involve the harvest of cannabis in its crude form, then passing the extract over a chromatographic column and fractionating. (2)
Evidences have so far proved that CBD is not psychoactive but it appears to reduce the euphoric effect of THC- an isomer of cannabidiol. Besides, studies have shown that it may decrease the rate of THC clearance from the body perhaps by interfering with the biochemistry of THC in the liver. CBD has been proven medically to relieve convulsion, inflammation, anxiety and nausea. More studies show CBD, a non-psychoactive cannabinoid of Marijuana, was given to 5 patients with dystopia disorders and a 20-50% improvement occurred in all 5 patients. (12)
3. Cannabinol (CBN )
This is an active component of Cannabis and is also the primary product of THC degradation. Cannabinol content increases as THC degrades in storage and with exposure to light and air. CBN is mildly psychoactive and is perceived to be a sedative. Cannabinol extraction from its crude form - cannabis is quite similar to extraction mechanisms discussed earlier in this paper.
Evidences of cannabinol are quite similar to other extracts earlier mentioned in this paper. On its medical applications, CBN is believed to produce a depressant effect, “fuzzy” forehead
In the world of science today, the science of cannabinoids has generated a lot of momentum. Besides, medical evidences have indicated that these substances are helpful through its numerous medical applications. Furthermore, in-depth studies and research have actually proved the effects of cannabinoids (through its administration to mouse/rats) but no limited studies have been administered to humans (11). Although questions do arise on its limitation and whether or not there are side effects using cannabinoids extracts, there has not been any concrete conviction that such side effects would be life threatening.
Recent developments have justified that research results over the years have been able to substantiate different therapeutic uses of cannabis. Synthetic THC- dronabinol, is usedin several countries including the USA, Netherlands and Germany (6). In the United States, Marinol is a phase III drug which is available by prescription. Considered to be a non-narcotic, it has a low risk of physical or mental dependence. An analog of drabinol, nabilone is classified as a schedule II FDA controlled substance. Marinol has been approved by the FDA in the treatment of anorexia of AIDS patients as well as for refractory nausea and vomiting of patients undergoing chemotherapy (9).
Furthermore, there have been several reasons why researches on cannabis are not pursued with so much vigor. These reasons are due to the illegality of Marijuana, its limitations and the use of marijuana (smoked) for recreational purposes. Also, the use of marijuana is not yet fully accepted in the medical establishment. Although, there have been no comprehensive surveys of the demographics and medical conditions of medical marijuana users, a few reports provide some indication. In each case, survey results should be understood to reflect the situation in which they were conducted, and are not necessarily characteristic of medical marijuana users as a whole (12).
John Mendelson, an internist and pharmacologist at the University of California, San Francisco (UCSF) Pain Management Center, surveyed 100 members of the San Francisco Cannabis Cultivation Club who were using marijuana at least weekly. Most of the respondents were unemployed men in their forties. Subjects were paid $50 to participate in the survey; this might have encouraged a greater representation of unemployed subjects. All subjects were tested for drug use. About half tested positive for marijuana only; the other half tested positive for drugs in addition to marijuana (23% for cocaine and 13% for amphetamines). The predominant disorder was AIDS, followed by roughly equal numbers of members who reported chronic pain, mood disorders, and musculoskeletal disorders (12).
Marijuana is not legally marketed in the United States but as cannabinoids, it is administered as a drug- Marinol which is approved by the FDA here in the United States. The 1992 approval of Marinol for the treatment of anorexia in AIDS patients marked a major transformation in the composition of the patient population. Marinol's use had been restricted to oncology patients (12). The oncology market for Marinol gradually receded as a result of the introduction of newer medications. Much of the recent growth of the market for Marinol (which is about 10% per year) is attributed to its increasing use by HIV patients being treated with combination antiretroviral therapy. Marinol appears to have a dual effect, not only stimulating appetite but also combating the nausea and vomiting associated with combination therapy (12).
However, the way marijuana is used in the United States does not commonly lead to such profound mental effects. Despite potent psycho activity and pharmacologic actions on multiple organ systems, cannabinoids have remarkably low lethal toxicity. Lethal doses in humans are not known. Given THC's potency on some brain functions, the clinical pharmacology of marijuana containing high concentrations of THC, for example greater than 10%, may well differ from plant material containing only 1or 2% THC simply because of the greater dose delivered.(13)
THC and other cannabinoids in marijuana have immunosuppressant properties producing impaired cell-mediated and humoral immune system responses. THC and other cannabinoids suppress antibody formation, cytokine production, leukocyte migration and natural killer-cell activities. Cannabinoids decrease host resistance to infection from bacterial and viral infection in animals. (15)
Furthermore, cannabinoids have been characterized as immunomodulators because although they generally suppress, they occasionally enhance some immune responses. Reviews of marijuana immune system effects have characterized the effects as complicated or conflicting or controversial. The clinical significance or relevance of these studies remains uncertain. (15)
Despite the medical benefits of cannabinoids, there are also side effects attributed to it. Marinol's most common adverse events are associated with the central nervous system (CNS): anxiety, confusion, depersonalization, dizziness, euphoria, dysphoria, somnolence, and thinking abnormality (11). In two recent clinical trials, CNS adverse events occurred in about one-third of patients, but only a small percentage discontinued the drug because of adverse effects. Lowering the dose of dronabinol can minimize side effects, especially dysphoria (12).
In summary, cannabinoids are an interesting group of compounds with potentially far-reaching therapeutic applications but also do have certain limitations in its clinical use .Besides, there have been numerous studies both in animals and in various clinical states on the use of cannabinoids on neurological and various movement disorders. These results range from anecdotal reports to surveys and clinical trials. Marijuana or tetrahydrocannabinol (THC) is reported to have some antispastic, analgesic, antitremor and antiataxia actions as well as some activity in multiple sclerosis and in spinal cord injury patients
There is a surge of scientific interest in their development as new drugs, but the road to market for any new drug is expensive, long, risky, and studded with scientific, regulatory, and commercial obstacles. Experience with the only approved cannabinoid, - dronabinol, might not illuminate the pathway because of the government's heavy contribution to research and development, dronabinol's scheduling history, and its small market. There appear to be only two novel cannabinoids actively being developed for human use, but they have yet to be tested in humans in the United States. Their experience is likely to be more predictive of the marketing prospects for other cannabinoids. It is too early to forecast the prospects for cannabinoids, other than to note that their development at this point is considered to be especially risky, to judge by the paucity of products in development and the small size of the pharmaceutical firms sponsoring them.
The market outlook in the United States is distinctly unfavorable for the marijuana plant and for cannabinoids found in the plant. Commercial interest in bringing them to market appears nonexistent. Cannabinoids in the plant are automatically placed in the most restrictive schedule of the Controlled Substances Act, and this is a substantial deterrent to development. Not only is the plant itself subject to the same scheduling strictures as are individual plant cannabinoids, but development of marijuana also is encumbered by a constellation of scientific, regulatory, and commercial impediments to availability.
There is however, the need for further research , particularly in circumstances where long -term administration of marijuana might be considered for therapeutic purposes; for example in individuals who are HIV-positive who have tumors, malignancies, or diseases where immune system function may be important in the genesis of the disease. However, the health relevance of these findings to human marijuana use remains uncertain. Conclusive evidence for increased malignancy, or enhanced acquisition of HIV or the development of AIDS, has not been associated with marijuana use. (15)
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