CHAPTER 2

THE MEDICAL-SCIENTIFIC LITERATURE


INTRODUCTION AND BACKGROUND

Cannabis sativa plant is called `ganja' in India and Jamaica, `marijuana' in North America, 'hif' in North Africa and `dagga' in South Africa. The plant produces a resin often referred to as `hashish'.

As early as 2737 BC the Chinese Emperor Sheng Nun described cannabis as a superior herb and for centuries it was embraced unreservedly (Cole 2000). There are records of its use in Arabic medicine dating back to the 8th century. Cannabis sativa was used for over a thousand years as a textile and medicine in Arabia, Mesopotamia, Persia, Egypt, China, India and extensive areas of Europe (Lozano 2001). In 1901 a United Kingdom Royal Commission concluded that cannabis was relatively harmless and not worth banning (Cole 2000).

Cannabis sativa was classified in the 18th century by Carl von Linne. It was first admitted to western pharmacopoeias in the 1800s. In 1839 W.B. O'Shaghnessy at the Medical School of Calcutta observed its use in the indigenous treatment of various disorders and found that tincture of hemp was an effective analgesic, anticonvulsant and muscle relaxant (Grinspoon 2000). It was included in the British, United States and Indian Pharmacopoeias up to 1932, 1941 and 1966, respectively.

Ganja was brought to the West Indies in the middle 19th century by East Indian labourers who came primarily to Guyana, Trinidad and Jamaica. Up until the early years of the 20th century it was widely used as a folk medicine and did not appear to constitute a major social problem.

Beginning in the 1920s, interest in cannabis as a recreational drug grew. During the 1960s and 1970s there was a large increase in the use of smoked cannabis as an intoxicant in the USA and Europe. Starting in the 1980s there has been renewed interest in the potential medicinal uses of cannabis and its derivatives.


RESEARCH

There have been many commissions over the years looking at the effect of cannabis. Some of these are:

Indian Hemp Drug Commission 1894
Panama Canal Zone Report 1925
LaGuardia Commission Report 1944
The British Wooten Report 1969
The Canadian La Dain Commission Report 1970
National Commission on Marihuana and Drug Abuse (USA) 1972
The Dutch Baan Commission 1972
Commission of the Australian Government 1977
National Academy of Science Report (USA) 1982
Report by the Dutch Government 1995
Report to the House of Lords (Britain) mid 1990s

There is also extensive research at a number of levels. The use of cannabis engenders strong feelings and many of the research reports reflect this. There is a strong body of opinion that sees cannabis as harmful and advances 'scientific evidence' to prove this. On the other hand there is an equally strong body of opinion that feels that cannabis has been unnecessarily vilified and that it has relatively minor harmful effects and great potential for medicinal use. This group also advances `scientific evidence' to prove its point. It is therefore necessary to analyse the `scientific evidence' bearing in mind the source and especially to note those items agreed on by both groups and done by independent groups such as the World Health Organization (WHO).

EPIDEMIOLOGY OF GANJA USE IN JAMAICA

Ganja is widely used for recreational, medicinal (folk medicine) and religious purposes in Jamaica. The 1990 Carl Stone study among respondents age 15 and over island wide showed 47% in the Metropolitan areas and 43% in the rural areas who had ever used ganja. The usage was higher among males than females but cut across all social, educational and economic groups. In the upper income group 46% of males and 25% of females had tried ganja, the figures for the middle income group were 33% of males and 10% of females, and for the lower income group 52% of males and 18% of females.

A national lifestyle survey carried out by the Ministry of Health in 1993 reported that among Jamaicans 15 - 49 years old 37% of the men and 10% of the women had ever used ganja.

A 1997 survey by Ken Douglas among 8,000 in-school adolescents, grades 9 to 13, found 27% had had lifetime ever-use of smoked ganja, a significant increase from the 20% reported in a 1986 school study. In the 1997 study 20% reported ever use of ganja tea. Turning to current use over the preceding 30 days, the study showed 8% had smoked ganja and 6% had had ganja tea.

Recent data coming out of Treatment and Rehabilitation Centres published in the National Council on Drug Abuse Infosum for October 2000 shows that some of the clients admitted with a history of smoking ganja had their first use as early as between 5 and 9 years old.

Of 282 clients who went into treatment for a ganja habit in 1999-2000, 4% started using the drug from age 5 to age 9, 26% from age 10 to age 14 and 3% from age 15 to age 19, that is one-third of them started smoking ganja at the age of 19 or below. These figures show the widespread use of ganja in Jamaica and the early age of initiation.

Other studies have sought to look at any link between traffic accidents, trauma and drug use. The role of alcohol is well recognised but the possible causative role of ganja is less clear. Francis et al. (1995), in a pilot study of alcohol and drug-related traffic accidents and deaths in two Jamaican parishes, found evidence of alcohol intake in 77.5% of fatalities and 35.5% had alcohol levels above the legal acceptable limits; 22.5% of road traffic fatalities tested positive for cannabis and 3.2% for cocaine.

McDonald et al. (1999) took sera and urine samples from 111 trauma patients seen at the Accident and Emergency Department of the University Hospital of the West Indies, Jamaica, over a three-month period. Alcohol levels were tested in the blood and the urine was tested for metabolites of cannabis and cocaine. Results showed 38% of patients negative for any drug, 62% positive for one or more drugs; 15% for alcohol only, 15% for alcohol and cannabis, 25% for cannabis only, 5% for cannabis and cocaine, 1% for cocaine only, and 1% for all three.

Many patients admitted to the psychiatric services on the island report ganja use. For example, approximately 60-80 % of males admitted to the Cornwall Regional Hospital Acute Psychiatric Unit in 1999 gave a history of ganja use, although this was not necessarily the reason for their admission (Abel 2001).

PHARMACOLOGY

Cannabis sativa contains 400 known chemicals. The family of chemically related 21-carbon alkaloids found uniquely in the cannabis plant are known as cannabinoids. There are sixty different cannabinoids. One of these, delta-9- tetrahydrocannabinol (THC), is the most abundant and accounts for the intoxicating properties of cannabis. THC dissolves readily in fat but not in water. When smoked, THC is rapidly absorbed into the blood stream, giving perceptible effects within minutes. When taken by mouth peak effect may not occur for hours but last much longer. The THC also persists in the brain longer than in the blood, so that psychological effects persist for some time after the level of THC in the blood begins to fall.

THC is widely distributed in fatty tissue of the body, whence there is slow release, thus producing low levels of THC in the blood for several days after a single dose, although there is no evidence that any significant pharmacological effects persist for more than 4-6 hours after smoking and 6-8 hours after ingestion.

It is now recognised that THC interacts with a naturally occurring system in the body, known as the cannabinoid system. THC takes effect by acting upon cannabinoid receptors. Two types of cannabinoid receptors have been identified, namely the CB1 receptors and the CB2 receptors. CB1 receptors are present on nerve cells, in the brain and spinal cord as well as in some peripheral tissues; CB2 receptors are found mainly in the immune system and are not present in the brain (NCDA1998).

The CB1 receptors are distributed differentially in the various regions of the brain, in a pattern that is similar throughout a variety of mammalian species, including humans. Most of the receptors are in the basal ganglia, cerebellum, cerebral cortex and hippocampus. A rough correlation appears to exist between the distribution and some of the effects of cannabis. For example, binding sites in the hippocampus and cortex are linked to the subtle effects of cannabis on cognitive function, while those in the basal ganglia and cerebellum may be associated with cannabis-produced ataxia (WHO 1997).

From animal experiments, CB1 receptors seem to mediate pain relief, memory impairment, control of movements, lowering of body temperature and to reduce gut activity. It is also assumed that they mediate the intoxicant effects of THC (NCDA 1998).

Little is known about the physiological role of the more recently discovered CB2 receptors, found in macrophages (white blood cells) in the spleen, but they seem to be involved in the modulation of the function of the immune system.

The presence of this cannabinoid system has implications for further research into the effects of cannabis on the body and the potential beneficial uses of cannabis.

EFFECTS OF CANNABIS

Acute effects

A state of euphoric intoxication is induced. There is mild intoxication, relaxation, increased sociability, heightened sensory perception and increased appetite. In higher doses acute effects can include perceptual changes, depersonalisation and panic (WHO 1997).

Other behavioural changes associated with cannabis intoxication include loss of time sense, sensation of `high', anxiety, tension and confusion (Matthew et al. 1993).

Intoxication with cannabis leads to slight impairment of psychomotor and cognitive function, which is important for those driving a vehicle, flying an aircraft or operating machinery. Subtle impairment of cognitive function may persist for twenty-four hours.

There is sufficient consistency and coherence in the evidence from experimental studies and studies of cannabinoid levels among accident victims to conclude that there is an increased risk of motor vehicle accidents among persons who drive when intoxicated with cannabis (WHO, 1997). Cannabis can impair various components of driving behaviour, such as braking time, starting time, and reaction to red lights or other danger signals. However, persons under the influence of cannabis may perceive that they are impaired and where they can compensate, they do so.

Such compensation may not be possible when they are presented with unexpected events and hence the risk of accidents remains higher following cannabis use (WHO 1997).

A study carried out on the effects of cannabis on aircraft pilot performance showed that cannabis use impaired flight performance at 0.25, 4, 8, and 24 hours after smoking. These results suggest that human performance while using complex machinery can be impaired as long as 24 hours after smoking as little as 20mg of THC, and that the user may be unaware of the drug's influence (Leirer et al. 1991).

There is a short-term effect on the cardiovascular system. There can be an increase in the heart rate and lowering of the blood pressure. This would be of concern in persons with ischaemic heart disease (angina).

A single dose of cannabis for an inexperienced user, or an over-dose for a habitual user, can sometimes induce a variety of intensely psychic effects, including anxiety, panic, paranoia and feelings of impending doom. These effects usually persist for only a few hours.

Signs of intoxication include blood-shot eyes, lack of coordination, enhanced sensations and perceptions, increased appetite, dry mouth, possible dizziness and nausea.

Effects on the Brain-Psychiatric/Psychological

Cannabis (THC) is said to affect the neurons (brain cells) in the information processing section of the hippocampus, the part of the brain that is responsible for memory and the integration of sensory experiences with emotion and motivation.

Literature on both sides recognise that short-term memory can be affected in the acute phase of ganja intoxication. This does not seem to affect recall of previously learned items but does appear to interfere with the learning of new material. Researchers note great variation in results to cognitive testing and point out that individual response to marijuana varies considerably (Zimmer and Morgan 1997).

Marijuana's effect on cognition in the real world seems to depend on the time and place people choose to use marijuana and the tasks they are performing. In the laboratory, marijuana temporarily impairs short-term memory and learning. In real world structured settings, such as the classroom, it is likely to have similar effects (Zimmer and Morgan 1997).

Several studies have shown that cannabis appears to increase the perceived rate of the passage of time. Cannabis is also known to impair psychomotor performance in a wide variety of tasks, such as handwriting and tests of motor coordination.

There is less agreement about the long-term effects of ganja on the brain. Some authorities state that chronic marijuana use interferes with the interplay of chemical and electrical impulses between brain cells, causes shrinkage and death of brain cells. However, other authorities point out that the experiments showing death of brain cells were carried out in animal models exposed to concentration of THC about 100-fold higher than even a heavy marijuana user would be exposed to. It is stated that in other studies exposing monkeys to amounts equivalent to 4-5 marijuana cigarettes a day for a year these findings could not be replicated (Zimmer and Morgan 1997). The early claims of gross anatomical changes in the brains of chronic cannabis users have not been substantiated by later studies with high-resolution computerized tomography, in either humans or primates (Rimbaugh et al.1980; Hannerz and Hindmarsh 1983).

It is felt that learned behaviours, which are dependent on the hippocampus, deteriorate after chronic exposure to THC and that chronic abuse of cannabis is associated with impaired attention and memory. It is also reported that prenatal exposure is associated with impaired verbal reasoning and memory in pre-school children (Abel 2001).

Zimmer and Morgan point out that during the past thirty years, researchers have found, at most, minor cognitive differences between chronic marijuana users and non users, and the results differ substantially from one study to another. Based on this evidence, it does not appear that long-term marijuana use causes any significant permanent harm to intellectual ability. Even animal studies, which show short-term memory and learning impairment with high doses of THC, have not produced evidence of permanent damage.

Studies (Fletcher et al. 1996) have shown that the long-term use of cannabis leads to subtle and selective impairment of cognitive functioning. Prolonged use may lead to progressively greater impairment, which may not recover with cessation of use for at least 24 hours (Pope and Yurgelum-Todd 1995) or 6 weeks (Solowij et al. 1991), and which could potentially affect functioning in daily life.

Not all individuals are equally affected. The basis for individual differences needs to be identified and examined. There has also been insufficient research to address the impact of long-term cannabis use on cognitive functioning in adolescents and young adults, and on different age groups and genders (WHO 1997).

The Diagnostic Statistical Manual IV for classification of disorders and diseases recognises the following conditions:

Cannabis Dependence
Cannabis Abuse
Cannabis Intoxication
Cannabis Induced Psychotic Disorder
Amotivational Syndrome
Cannabis Induced Anxiety Disorder
Cannabis Induced Mood Disorder.

Cannabis dependence is seen as compulsive, habitual use and not a physiological dependence or addiction. Tolerance to most of the effects of cannabis has been reported in individuals who use cannabis chronically (Abel 2001). Studies conducted over many decades in a variety of settings have found that when high-dose marijuana users stop using the drug, withdrawal symptoms rarely occur and when they do, they tend to be mild and transitory (Zimmer and Morgan 1997). The presence of withdrawal symptoms is one of the markers for addiction. It is therefore felt that cannabis is a weakly addictive drug but does induce dependence in a significant minority.

However, in the WHO report, Cannabis: a health perspective and research agenda, it is stated that clinical and epidemiological research has clarified the status of the cannabis dependence syndrome. A reduced emphasis on the importance formerly attached to tolerance and withdrawal symptoms in diagnostic criteria for dependence has removed a major reason for scepticism about the existence of a cannabis dependence syndrome.

Research using standardised diagnostic criteria has produced good evidence of a cannabis dependence syndrome that is characterized by impairment, or loss of control over use of the substance, cognitive and motivational handicaps which interfere with occupational performance and are due to cannabis use, and other related problems such as lowered self-esteem and depression, particularly in long-term heavy users. As with other psychoactive substances, the risk of developing dependence is highest among those with a history of daily cannabis use. It is estimated that about half of those who use cannabis daily will become dependent (Anthony and Helzer 1991).

Since tolerance and withdrawal symptoms are still widely regarded as diagnostic criteria of substance dependence, it is worth noting that there is abundant experimental evidence of tolerance to many of the effects of cannabis. There is not yet universal agreement about the production of a withdrawal syndrome (WHO 1997).

Apart from the acute psychic effects noted previously, cannabis intoxication in some instances may lead to a longer lasting toxic psychosis involving delusions and hallucinations that can be misdiagnosed as schizophrenic illness. This is transient and clears up within a few days of termination of cannabis use.

It is well established that cannabis can exacerbate the symptoms of those already suffering from schizophrenic illness and may worsen the course of the illness (NCDA 1998; WHO 1997).

The occurrence of an "amotivational state" in long term heavy cannabis users with loss of energy and the will to work has been postulated. However some feel that this represents nothing more than an ongoing intoxication (NCDA 1998).

Studies of high school students show that heavy marijuana use is associated with academic failure. Heavy marijuana users have lower grades and lower career aspirations than occasional users or nonusers. Heavy marijuana users are also more likely than occasional users or nonusers to drop out of school before graduation. However, most high school students who use marijuana heavily were performing poorly in school before they began using marijuana. Most have a number of emotional, psychological, and behavioural problems, often dating back to early childhood (Zimmer and Morgan 1997). It is therefore possible that the underlying problems lead to the marijuana use rather than the marijuana being the cause of all the problems. When studies control for other factors marijuana use makes no significant contribution to high school student's academic performance (Zimmer and Morgan 1997).

It is noted that there are a number of factors that influence the effects cannabis may have on an individual. These include:

Potency of the cannabis (the THC content of marijuana is said to have increased from the 1960s to the present time and varies among different plants)
The route of administration
The smoking technique
The dose
The setting
The user's past experience
The user's unique biological vulnerability to the effects of cannabis.

Effects on other organ systems

Respiratory System

Tobacco smoking causes a number of lung diseases, including chronic bronchitis, emphysema and cancer. Except for their active ingredients-nicotine and cannabinoids-bacco smoke and marijuana smoke are similar with a greater concentration of the carcinogenic benzathracenes and benzpyrenes in marijuana smoke.

In the United States, marijuana smokers typically inhale more deeply and retain smoke in their lungs longer than tobacco smokers. As a result, marijuana smokers deposit more dangerous material in the lungs each time they smoke. However it is said to be the total volume of inhaled toxic material over time that matters and not the amount inhaled per cigarette. It is further postulated that even heavy marijuana smokers never reach the smoke consumption levels of heavy tobacco smokers (Zimmer and Morgan 1997).

Theoretically, the risks to the respiratory tract of smoking marijuana are similar to those of tobacco smoking. In human studies, it has been shown that the principal respiratory damage caused by long-term cannabis smoking is an epithelial injury of the trachea and major bronchi (WHO 1997). The alveolar macrophage, the key cell in the lung's defence against infection, has been shown to be impaired by cannabis smoke in both animal and human studies (WHO 1997). Studies suggest that regular cannabis consumption reduces the respiratory immune response to invading organisms. Further, serious invasive fungal infections as a result of cannabis contamination have been reported among individuals who are immuno-compromised, including a series of patients who were affected by AIDS (Denning et al. 1991).

These findings suggest that persistent cannabis consumption over prolonged periods can cause airway injury, lung inflammation, and impaired pulmonary defence against infection. Epidemiological studies that have adjusted for sex, age, race, education, and alcohol consumption, suggest that daily cannabis smokers have a slightly elevated risk of respiratory illness compared to non-smokers.

Reproductive System

Studies, including a Jamaican study, have shown lowered sperm count and motility in ganja smokers compared to non-smokers (NCDA 2001). There is no demonstrable difference in testosterone level or levels of female sex hormones. In neither male nor female have researchers produced evidence of permanent harm to reproductive function from either acute or chronic marijuana administration. There is no convincing evidence of infertility related to marijuana consumption in humans (Zimmer and Morgan 1997).

Results from research looking at effects of cannabis smoking in pregnancy vary. Some reports point to an increased risk of early foetal death, decreased foetal weight and premature birth. In animal studies, THC has been shown to produce spontaneous abortion, low birth weight and physical deformity-but only with extremely high doses, only in some species of rodents, and only when the THC is given at specific times during pregnancy. Studies with primates show little evidence of foetal harm from THC (Zimmer and Morgan 1997).

There is reasonable evidence that cannabis use during pregnancy impairs foetal development, leading to a reduction in birth weight, perhaps as a consequence of shorter gestation, and probably by the same mechanism as cigarette smoking, namely, foetal hypoxia (WHO, 1997).

There is ongoing research, for example the Ottawa Prenatal Prospective Study, looking for possible effects of prenatal exposure to cannabis on later development. So far there is no consistent evidence of any significant difference in the development of children exposed to prenatal cannabis as against those not so exposed. The study suggests that any long-term consequences of prenatal exposure to the child are very subtle. (Fried 1980; Fried 1995).

Another study suggests that in utero exposure to cannabis can affect to some degree the mental development of the growing child (Day et al. 1994).

MEDICINAL USES OF CANNABIS

The medicinal uses of cannabis are well documented in the modern scientific literature. Using either smoked cannabis or extract preparations from the cannabis, researchers have conducted controlled studies.

The broad range of potential therapeutic applications of cannabinoids reflects the wide distribution of cannabinoid receptors throughout the brain and other parts of the body. The possibility of distinct subtypes of cannabinoid receptors and the probable development of new compounds to bind selectively to these receptors, as either agonists or blockers, may well open the door to the selective treatment of a number of disorders.

Areas in which cannabis has been shown to have therapeutic use are:

Reducing nausea and vomiting
Stimulating appetite
Promoting weight gain
Diminishing high intraocular pressure from glaucoma

There are also reports of use of cannabis for:

Reduction of muscle spasticity from spinal cord injuries
Reduction of muscle spasticity and tremors in multiple sclerosis
Relief of migraine headaches
Depression
Seizures
Insomnia
Chronic pain

Although an anti-emetic effect of THC had been suggested as early as 1972, the first report of a placebo-controlled trial came in 1975 from one of the top oncology centres in the USA (Hollister 2001). An oral preparation, dronabinol, has been used especially in cancer chemotherapy patients for control of the side effects of nausea and vomiting. Although smoked marijuana is often preferred by the patients, whether it is superior to orally administered THC has not been tested in controlled comparisons (Hollister 2001). Smoked cannabis is more immediate in its effects than oral THC. Cannervert is also available for use in motion sickness.

The use as an appetite stimulant is of particular use in cancer and AIDS patients. In the USA, approximately 16 per cent of the total AIDS population suffer from the progressive anorexia and weight loss known as AIDS wasting syndrome. An open pilot study of dronabinol in patients with AIDS-associated wasting syndrome showed it effective in increasing weight as well as being well tolerated (Hollister 2001).

The international literature recognises the role cannabis can have in reducing intraocular pressure in glaucoma. Local researchers, Professor Hon. Manley West and Dr. George Lockhart developed the extract Cannasol, which is now registered and used in the treatment of glaucoma. Another product, Asmasol, was developed based on the Cannasol research, for the treatment of cough, cold and bronchial asthma. There was also work done by the late Professor Sir John Golding and Professor West towards developing a protocol for use of a cannabis preparation in the control of pain in terminally ill patients (NCDA 1998).

In Europe, cannabis has been anecdotically reported to help in the symptoms associated with multiple sclerosis. Published trials have shown some positive results especially for spasticity, the pain associated with spasticity, tremor and urinary bladder control (NCDA 1998). An antispasmodic action of THC was confirmed by the first clinical study (Petro and Ellenberger 1989).

There is undoubtedly need for much further research into the potential of the medicinal use of cannabis and its extracts.

CONCLUSION

Information on the effects of cannabis on physical and psychological functioning has increased greatly, as has knowledge of the extent and patterns of use. However, there is still a need for further research in several important areas, including clinical and epidemiological research on human health effects, chemistry and pharmacology, and research into the therapeutic use of cannabinoids. Moreover, there are important gaps in knowledge about the health consequences of cannabis use (WHO, 1997).

There needs to be continued objective research and ongoing public education about all aspects of Cannabis sativa use.