June 2010


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By Dr Farid F. Youssef

Quote: “I am in no form or fashion advocating the smoking of cannabis, a practice that is associated with numerous well documented severe health risks. Neither do I support its legalization. However the effects of cannabis are the result of the body, and the brain in particular, possessing its own endogenous cannabinoid system. We are seeking to understand this system, how its works, how it can be modified and how targeted drug delivery systems can be developed that maximize clinical benefits and minimize unwanted side effects.”

The Cannabis sativa plant has had a long, colourful and often controversial association with mankind. Originally cultivated to make hemp, a soft and durable fibre that was used extensively in the pre-industrial era for the production of rope, textiles and paper, it is also one of the oldest herbal remedies known to man, with texts from ancient China and India detailing its use as a treatment for a variety of illnesses. Even Queen Victoria of Britain is reported to have used it as a preparation for the treatment of menstrual cramps. Despite this wide variety of uses and its extensive commercial production (up to today over 40,000 hectares of hemp are under cultivation worldwide) cannabis is best known for its psychoactive properties and its association with recreational drug use (marijuana).

The Caribbean region, rightly or wrongly, has anecdotally been associated with the use of cannabis for such hedonistic purposes. The stereotypical image of a Rastafarian resplendent with ‘joint,’ as often personified by Bob Marley, is an iconic image of supposed Caribbean life. Those of us who live and work in the region know this demographic grouping actually represents the minority and best estimates of regular cannabis use are less than ten per cent.

The smoking of cannabis can produce a number of effects on the human body including disordered perception relating to sights, sounds, touch and even time, short-term memory loss and disruption of learning, a sense of mild euphoria and a feeling of tranquillity, anxiety, loss of motor skills, increased heart rate, pain relief, dry throat and mouth. This list is by no means exhaustive, and for decades, scientists have been intrigued by how this plant could have such a wide and varied response on so many different physiological systems. Research over the last 40 years has begun to answer this question and in particular, discoveries since 1990 have exponentially increased our knowledge and understanding of cannabis, how it works and what effects it has on the human body.

This new era of understanding began in 1964 when the primary active ingredient of cannabis, delta-9-tetrahydrocannabinol (THC) was identified. Advances in cannabinoid physiology proceeded slowly over the next two decades but of note during this period was the contribution made by two Caribbean scientists, Manley West and Albert Lockhart. West and Lockhart started their journey in cannabinoid research when they noted (i) a reduction in glaucoma among Rastafarians who traditionally used cannabis and (ii) persons from rural communities who used eyewash purportedly derived from cannabis claimed improved eyesight. This triggered ten years of pioneering research that culminated with the development and patent of a drug, Canasol, for the treatment for glaucoma.

In 1990, cannabinoid research really took off when the first THC receptor in the brain was discovered. Very soon afterwards another receptor was identified and scientists believe there are at least two more cannabinoid receptors still waiting to be fully characterized. Perhaps more fascinating though was the discovery two years later that the brain produces neurotransmitters itself that do the same thing as THC. In other words the brain produces its own ‘cannabis-like substances’. The most common and first discovered was named anandamide, derived from the Sanskrit word ananda meaning bliss. These naturally occurring substances produced by the body are called endocannabinoids. Together with their receptors they form the framework of a complex endocannabinoid signalling system which is found in many regions within the central nervous system and in a number of important peripheral tissues.

Given the widespread and complex nature of this cannabinoid system it is not surprising that it has been implicated in a number of physiological processes including learning and memory, regulation of appetite, immune function, regulation of pain and activation of neuroprotective pathways. Knowledge of these processes and how they can be manipulated is important as they offer novel forms of intervention in diverse clinical scenarios. At this point it should again be noted that researchers do not advocate the imbibing of cannabis, via smoking or otherwise, as an effective clinical intervention. What is being considered though, is targeted drug delivery systems through the development of specific compounds that minimize unwanted side effects and maximize clinical benefits. Some of the more interesting and relevant findings to date are detailed below.

Modulation of Pain
Cannabis, controversially, has long been used to treat intractable pain. In fact cannabinoids have been shown to be ten times more potent than morphine in some models of pain. Emerging evidence from clinical trials suggest there is much potential in the use of these compounds although not all studies show a clear benefit. Indeed in 2005 the drug Sativex was approved in Canada as a prescription medicine for the treatment of pain associated with cancer and neuropathic conditions. Sativex contains both THC and its inactive counterpart cannabidiol and is currently available in over twenty countries worldwide. While results are promising, it should be appreciated that effective therapeutic doses in humans still result in too many side effects, mandating more targeted application of cannabinoids be achieved.

Appetite
One of the more remarkable effects of cannabinoids is their ability to influence appetite by regulating a number of important brain regions linked to food intake. These include the hypothalamus (regulates the consumption of food) and the reward centres of the brain (when activated these give us the sense of pleasure associated with eating). This data has resulted in a number of clinical trials with a compound that blocks cannabinoid receptors called rimonabant. Rimonabant was tested as an anti-obesity medication, initially found to be highly successful and eventually licensed within the European Union. Due to the number of side effects, the medication was never approved in the United States and was eventually removed from use among European Union countries. Yet the evidence is such that several drug companies continue to invest heavily in this aspect of research.

Learning and Memory
The adverse effects of smoking cannabis on memory have been repeatedly seen in chronic users. It is now generally agreed that cannabinoids can modulate short-term memory but have minimal impact on long-term memory. Impairment of memory represents one of the side effects that must be avoided when utilizing cannabinoids. However, there may be a potential role for cannabinoids in Alzheimer’s disease and this is emerging as a new and promising area of research.

Immunological Function and multiple sclerosis
One of the very earliest accounts of the activity of cannabis from ancient China highlights its ability to attenuate rheumatism and thus its anti-inflammatory properties. These effects on the immune system have perhaps been best harnessed in the treatment of multiple sclerosis (MS). MS is a chronic autoimmune disease in which there is inflammation within the central nervous system. In particular there is an attack upon the fatty sheath that insulates brain cells leading to progressive motor and sensory deficits often accompanied by pain of varying severity. To date results have been mixed but encouraging enough to suggest that cannabinoids do have a role to play in the management of the symptoms of MS. Beyond managing symptomology efforts are underway to determine whether or not cannabinoids can actually slow disease progression.

Endocannabinoids and neuroprotection
Given the ubiquitous nature of cannabinoid receptors in the brain they have widely been viewed as a fine-tuner of neuronal function. Connected to this has been the suggestion that the endocannabinoid system offers a means of neuroprotection against a variety of different insults and pathological processes. This is a vast area of research including efforts to modulate damage due to strokes, Alzheimer’s disease, Parkinson’s disease, head injury and trauma.

In conclusion, our understanding of cannabinoids has dramatically increased within the past 20 years. This understanding has shed new light on the numerous processes in which endocannabinoids are involved and offered new vistas for modulation of these same processes. Despite the tremendous advances that have been made, successful interventions have yet to be fully elucidated. This is the ‘holy grail’ of cannabinoid research, the ability to develop compounds that disentangle the benefits of cannabinoids from their pitfalls and psychotropic side effects. Until this is done, the full potential of harnessing this system remains locked away, though results to date provide ample incentive for those currently working in the field.

-Dr. Farid F. Youssef is a lecturer, Department of Pre-Clinical Sciences, Faculty of Medical Sciences, UWI, St. Augustine Campus.