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The cannabis plant, of which there are a few different species, was first reportedly used in medicine over 5000 years ago. Cannabis Sativa and Cannabis Indica are the most popular species, while Cannabis Ruderalis is not as common.1 Cannabis is mostly used as a recreational drug which goes by many other names such as marijuana, weed, skunk, hashish, hemp, pot and ganga.
Cannabis Sativa is the most popular source of the drug, which is commonly used for medical and social purposes. The compounds responsible for the medical effects of cannabis are found in the sticky golden resin, which emanates from flowers in female plants. Over 460 compounds have been discovered in the cannabis plant, of which more than 60 possess a structure typical of cannabinoids.2
Cannabinoids (or phytocannabinoids) are a group of compounds which are only found naturally in cannabis plants, hence the similarity in names. The most common cannabinoid is delta-9-tetrahydrocannbinol (THC), a highly psychoactive compound present in large amounts in cannabis, and responsible for many of its effects. Other cannabinoids include cannabidiol (CBD), cannabinol (CBN), cannabigerol (CBG) and cannabichromene (CBC). Plants first produce cannabidiol, which is converted to THC and this is finally degraded to cannabinol. The extra carbon double-bonds in cannabinol make it 90% less psychoactive than THC, while cannabidiol is not psychoactive at all due to the extra hydroxyl group (Figure 1).3
Figure 1. Structure of the 3 main cannabinoids present in cannabis.3
The first recorded use of cannabis in medicine was during the reign of the Chinese emperor Chen Nung, over 5000 years ago for the treatment of rheumatic pains, constipation, malaria, and female disorders.4 It was also used as analgesic in surgery. In the subcontinent it was prescribed to quicken the mind, lower fevers, induce sleep, stimulate appetite and relieve headaches. Africa wasn't exempt from acknowledging its medical use either, where it was given to treat malaria, dysentery and fevers.
Irish doctor William O'Shaughnessy, serving in India when it was part of the British Empire, introduced cannabis to the western world. He tested preparations on animals and then gave it to patients to treat muscle spasms and pain (analgesia).5
However, the invention of the hypodermic syringe meant research on analgesic properties declined by the 1890's. Opiates were now being used as soluble drugs could be injected for fast relief of pain.1 The problem with cannabis was its insolubility so it could not be administered by injection.
Rumour has it that Queen Victoria's physician prescribed cannabis to her, for her premenstrual symptoms and menstrual cramps.6
In 1942 cannabis was removed from the USA Pharmacopoeia as it was believed to be harmful and addictive.7 In February 1994, the US District Court of Appeals in Washington DC issued that cannabis has no medical value. It is therefore classified as a Schedule 1 drug in the USA, with no current medical use.8 In the UK cannabis is currently categorised as a Class B substance.9
The sites at which cannabinoids act in the body are known as cannabinoid receptors, of which there are 2 types; CB1 and CB2.
Cannabinoid receptors are G-protein-coupled receptors, negatively coupled to adenylate cyclase and positively coupled to mitogen-activated protein (MAP) kinase. They have a specific function, which is to regulate the activity of calcium and potassium channels.10
CB1 receptors are greatly abundant in the brain, while CB2 receptors are plentiful in the immune system. The effect of THC when bound to CB1 receptors on nerves is to slow down their conduction. This could lead to a greater reaction time but it could also dull pain signals. The effect of THC when bound to CB2 receptors on white blood cells, may result in a lower resistance to disease but may also reduce painful inflammation.7
CB1 receptors are abundant in the periaqueductal grey matter, dorsal root ganglion and the spinal dorsal horn, which may explain the analgesic properties of THC.11 The CB1 receptor is also heavily populated in the basal ganglia, cerebellum, hippocampus, and the neocortex. This may help to explain the proposed psychological and motor effects of THC.
Upon the emergence of cannabinoid receptors, scientists believed there were natural ligands produced in the body (or endogenous cannabinoids), which also reacted with these receptors. Further research led to the discovery of anandamide in 1992, the most prominent endogenous cannabinoid.12 Another endogenous cannabinoid which has been well studied is 2-arachidonyl-glycerol (2-AG).
How Cannabinoids React in the Body
Cannabis is absorbed most rapidly via inhalation, avoiding hepatic metabolism and reaching targets in the brain inside a minute.
Through increasing GABAergic transmission (GABA is an inhibitory neurotransmitter in the CNS), cannabinoids are believed to control neurotransmission in the basal ganglia, by affecting dopaminergic uptake and inhibiting glutamate release.13 This theory is the backbone of the hypothesis which states that the cannabinoid system is involved in motor activity and could possibly treat movement disorders.
Research has shown that THC alters the permeability of cell membranes. Further research found that when cannabinoids bind to their receptors, they inhibit adenyl cyclase and therefore inhibit the synthesis of cyclic adenosine monophosphate (cAMP), which helps initiate nerve impulses. Upon binding, they also slow a nerves firing rate by opening potassium channels and decrease neurotransmitter release by closing calcium channels.14 Memory problems associated with cannabis may be due to THC interfering with acetylcholine, a neurotransmitter involved in memory.
THC is a reinforcing drug due to its ability to release dopamine within the brains reward system. This is achieved indirectly by switching off GABA interneurons that inhibit these dopaminergic pathways.15 Table 1 indicates how other specific cannabinoids function within the body.
May have anxiolytic/antipsychotic effects. Taken before THC it inhibits hepatic drug metabolism and thus increases the concentration of THC. It seems to antagonise the effects of THC when taken concurrently. Stimulates vanilloid receptors and inhibits the uptake of anandamide, also weakly inhibiting its hydrolysis.
Has 1/10 of the psychoactive effects of THC. It can increase sleep and decrease body temperature in high doses. May increase the duration of intoxication while decreasing the psychoactive effects of THC.
Acts pre-synaptically to inhibit the release of fast acting neuro-transmitters such as GABA and glutamine. Has milder effects than THC as it only mildly binds to cannabinoid receptors.
Table 1. Summary of the functions of some cannabinoids.8,16,17
One of the most studied and proven effects of cannabis is its ability to relieve a patient suffering from nausea and vomiting. This is especially true for patients undergoing chemotherapy who tend to develop such symptoms. It is normally effective in cases where other antiemetic drugs are not very useful. Oncologists have been allowed to administer Marinol (a synthetic capsule form of THC) since 1985.1 However, patients normally prefer to smoke cannabis instead as the effects are perceived immediately. This is illegal and also carries with it the risks associated with smoking cannabis.
Recent developments have seen the emergence of a new group of drugs known as selective 5-HT3 receptor antagonists. They have a higher efficacy than cannabinoids in the prevention of chemotherapy induced vomiting, with considerably fewer and less serious side effects. They have thus become more popular than cannabinoids, but they haven't entirely stopped the use of cannabinoids. 5-HT3 antagonists poorly control the delayed phase of emesis during chemotherapy, where cannabinoids are still highly effective.18
The appetite stimulant effect of cannabis has been thoroughly documented and studied. It is an effective solution for gaining weight in patients including those suffering from anorexia nervosa. After several studies it is has now been ruled safe for use in patients who have AIDS and as a result suffer from appetite and weight loss.19
Another well established use of cannabis is in the treatment of glaucoma. In sufferers it is seen to reduce intraocular pressure without any serious side effects.1
Multiple Sclerosis is a debilitating disease which can result in serious motor problems including tremors and sexual handicaps. Loss of coordination (ataxia) can also result and there is currently no legal drug which can treat both the tremors and symptoms of ataxia. The picture below shows the effect of cannabis on a multiple sclerosis sufferer, with comparable improvement in symptoms.20
Figure 2. The effect of cannabis on the symptoms of a multiple sclerosis sufferer.20
Many patients believe cannabis helps to relieve their epileptic symptoms to some extent. This however remains speculative due to the limited number of controlled studies, most evidence being anecdotal instead. Cannabidiol may be therapeutically beneficial as an adjunctive therapy or even on its own, but more research is required on its anticonvulsant properties. It is certainly a promising lead as cannabidiol lacks psychoactivity unlike THC. CB1 agonists stimulate activity in the substantia nigra pars reticulata, the site of action of anti-spasm drugs.21
The analgesic properties of cannabis are of particular interest to scientists, especially because they are a safer alternative to opioids. They also have a plethora of other proposed effects such as anticonvulsant, neuroprotective and sleep-inducing properties, so depending on the disease they may be a better solution to opioids. Cannabinoids selectively suppress nociceptive neurotransmission. Studies have shown that THC has a similar efficacy to codeine in the treatment of pain.22
Other possible uses of cannabis which require substantial research and are mostly evidence based, include the treatment of mood disorders and depression, tumours, asthma, Tourette's syndrome and cannabis as an anti-bacterial agent. All the medicinal effects of cannabis have been concluded in Table 2 along with their relevant studies.
Chemotherapy Induced Nausea & Vomiting
Reduce symptoms of nausea & vomiting.
56 patients who got no relief from standard antiemetic's smoked cannabis instead. 78% became symptom free.
Reduce intraocular pressure.
19 patients smoked cannabis for 35 days and another 24 smoked it for 94 days without developing tolerance to the effect on intraocular pressure.
5 children with severe epilepsy not controlled by standard anticonvulsants were given THC congeners. 3 remained the same, 1 was almost seizure free and the last was fully cured.
A separate study consisted of 16 patients who were given CBD or a placebo in addition to their current drugs. 3 patients showed complete improvement, 2 with partial improvement, 2 with minor improvement and 1 unchanged. All the patients who took the placebo remained unchanged apart from 1.
Reduce motor and sexual handicaps.
A 30 year old patient who took cannabis to treat his symptoms was now able to maintain an erection for half an hour. Before taking cannabis he was not able to ejaculate and erections lasted less than 5 minutes. His leg reflexes and hand tremors both improved.
A study investigated the ability of THC to suppress experimental autoimmune encephalitis (EAE), a laboratory model of multiple sclerosis in guinea pigs. 98% of those given the placebo died whereas 95% of those given THC survived, with mild or no symptoms.
Paraplegia and Quadriplegia
A paraplegic patient was given THC and codeine during different periods. Both improved quality of sleep and reduced pain, but only THC reduced muscle spasms.
139 patients were given either Marinol or a placebo for six weeks. 22% of those taking Marinol gained 5lbs or more, compared to just 10% of those taking placebo. Those taking Marinol remained at the same weight whereas those taking the placebo lost a pound on average. A reduction in nausea and vomiting and an improvement in mood and appetite were also seen in those taking Marinol.
A study found that THC inhibited the release of serotonin from the blood of migraine sufferers during an attack, and not at other times.
Depression and Mood Disorders
THC was given to 50 depressed patients and 36 showed clear improvement.
A double blind study of 57 patients with severe melancholia found no difference between THC and a placebo. However a significantly smaller dose than the previous study was used.
In another study 8 patients were given THC or a placebo for a week but THC did not relieve their symptoms. This may be because THC requires 2-3 weeks to show improvement.
Penicillin-resistant Bacterial Strains
Cannabidiolic acid has been shown to be effective against penicillin-resistant bacterial strains. Topical application reduced pain and prevented infection in burns.
Amputation was the only solution for a thumb infection which resisted all available antibiotics, until it was overcome by a cannabis extract.
THC has been seen to inactivate the herpes virus in experiments, so it could cure cold sores or genital herpes.
Experiments in mice involving treatment of cancer cells with THC or cannabinol, showed a reduction in tumour size by 25-82%. There is no human research however and little other research in this field.
Clinical trials show that THC reduces motor and vocal tics as well as behavioural problems, such as obsessive compulsive disorders.
THC can CBD have been shown to reduce toxic forms of oxygen that build up in tissues under stressful conditions.
Table 2. Summary of the disorders cannabis may treat and the evidence behind it.1,7,18,19,20,21,22,23
The adverse effects of cannabis consumption can be divided into two categories, acute and chronic effects. Acute effects include short term deficits in cognitive and psychomotor functioning, anxiety, panic and paranoia, as well as effects on the cardiovascular system. Chronic effects include psychosis, depression and other mental health problems, as well as tolerance and dependence. Many believe cannabis to be a gateway drug leading to the use of harder prohibited drugs such as opiates.
The effect of cannabis on schizophrenia is of significant interest as research seems to be contradictory. One study showed that schizophrenic patients who took cannabis showed no significant different in the symptoms they presented, compared to those who did not take cannabis. Rather, those taking cannabis had fewer delusions and negative symptoms. Another study came up with the opposite conclusion, that taking cannabis exacerbated symptoms of schizophrenia.1
Short term memory loss is an acute effect which probably occurs when cannabinoids bind to the many CB1 receptors in the hippocampus.24
When considering the reasons as to whether cannabis should have a role in medicine, the first thing which may come to mind is the smoking of cannabis. This is a great misconception and is probably due to the fact that the most popular method of cannabis consumption is by smoking. Most studies have in fact been conducted on specific compounds found in cannabis, which were taken orally. Other methods of administration include a nasal spray, rectal repositories and topical application. Smoking cannabis is extremely dangerous as many of the carcinogenic compounds found in tobacco smoke, are also found when smoking cannabis. Polycyclic aromatic hydrocarbons (PAH) are found in greater concentration in cannabis smoke than tobacco smoke. A study of the lungs of cannabis smokers showed that they had higher levels of an enzyme, which converts PAH into a cancer causing form.7,25
Cannabis smokers had double the number of alveolar macrophages compared to non-smokers, which showed that their lungs were fighting infection. It was also found that smoking cannabis reduced the ability of alveolar macrophages to kill tumour cells, as well as fungus and bacteria which caused disease. Macrophages appeared to be less efficient in producing cytokines. In terms of lung damage, smoking one cannabis joint is equal to two and a half cigarettes.26
The lethality of a drug is measured by a value called LD50. This is the dose that will cause death in 50% of people taking it. For cannabis in humans this is not known as there is no data it can be derived from.1 There have been no reported deaths related to overdosing from cannabis. Thus it has been stated that cannabis is therapeutically probably the safest substance known. The adverse effects of cannabis use have been summarised in Table 3.
Tachycardia starting within 15 minutes of administration, lasting for 3 hours.
Blood pressure raised in sitting position, but lowered in standing position.
Difference in blood pressure when a person rises after lying down, can be high enough to make a person faint.
Tolerance to these effects does develop.
Impaired cognition - researchers found blood flow abnormalities to the temporal lobe, responsible for auditory attention.
Psychomotor problems - a study on pilots found their performance was impaired up to a day after smoking cannabis.
Short term memory loss.
Anxiety, panic, paranoia, dysphoria, hallucinations and altered time perception.
Conjunctival hyperemia, reddening of the eyes due to dilated blood vessels.
Cardiac output and heart rate increase. People with existing cardiovascular problems have been advised not to take cannabis, as it can lead to a heart attack due to the increased myocardial demand.
Cannabis affects sex hormones, which is probably the cause of decreased ovulation and an altered menstrual cycle in women.
In a study of 1200 mothers, the children of those that had taken cannabis had reduced birth weight, shorter length and a smaller head size.
It was more common amongst children of mothers who smoked cannabis during pregnancy, to see deficits in language skills, memory, attention and visual perception tasks.
In a 204 pair case controlled study, children of women who smoked cannabis were 10 times more likely to develop non-lymphoblastic leukaemia.
Cannabinoids act as anti-adronergics in males and reduce sperm mobility and sperm count. Decreased levels of testosterone have also been noted.
In a study of 55,000 military recruits, the diagnosis of schizophrenia was increased over 6 times in those who smoked cannabis.
Long term cannabis use can result in psychosis and depression. Reductions in the brain regions (hippocampus and amygdala) associated with these disorders have been seen.
Cognitive effects can develop, worsen or become permanent with chronic use of cannabis.
Chronic bronchitis may develop as a result of smoking cannabis for long periods of time. Tumours have also been reported. Cannabis smoke leaves 3 times more tar and 5 times more carbon monoxide in the lungs than cigarette smoke, inflaming airways and reducing breathing capacity.
This is a personality change with symptoms of aimlessness, apathy, sloth, lack of ambition and uncommunicativeness. This can be due to hormone changes, sedation, brain damage or depression caused by cannabis. A single dose of THC lower sperm count and levels of other hormones in males.
Tolerance and Dependence
With the continued use of cannabis, tolerance can develop to its effects including any beneficial effects it may have. This means increased amount of cannabis is required to achieve the same effect. However this could be dangerous as increasing the dose could increase the risk of serious unwanted side effects. Dependence on cannabis may change the quality of life of a person. A person may decide to take cannabis for a period of time to treat a disorder, but later finds that they can't do without taking cannabis and become addicted to it.
One of the reasons why cannabis is depicted as being a really harmful drug, is due to the fact that it may lead to the use of more harmful drugs such as heroin.
Table 3. A summary of the adverse effects of cannabis.1,7,15,18,21,24,25,26,27,28
Cannabis Based Medications
There are 3 main drugs which have been developed based on cannabinoids. These are Dronabinol (Marinol), Nabilone (Cesamet) and Sativex. In Canada a person is permitted to possess cannabis for specific medical purposes. The patient must go through their GP in order to become registered and eligible to carry cannabis. The main drugs have been discussed in Table 4.21
Used to treat the wasting syndrome in AIDS and chemotherapy induced nausea and vomiting. Has been approved by the FDA and is only available in the USA.
Used as an antiemetic but has also been reported to treat MS and relieve pain. It is available for use in the UK and the USA strictly as an antiemetic.
THC and CBD
Developed in the UK by GW Pharmaceuticals LTD and is used to treat neural pain in multiple sclerosis. Sativex is available in Canada and can be imported into the UK on a named patient basis.
Analog of Dronabinol
Was used as a postoperative analgesic. However it had high rates of side effects including somnolence and dysphoria, which lead to its withdrawal as an analgesic. It is therefore no longer deemed an acceptable drug.
Ajulemic Acid (CT-3)
Derived from THC-11-oic acid
A new drug in the pipeline, showing considerable benefits as a strong analgesic and anti-inflammatory drug.
Table 4. Drugs developed from cannabis and/or cannabinoids.7,21,29,30
There seems to be a narrow window between the desirable effects and the undesirable effects of cannabis, such as intoxication and temporary impairments in motor and cognitive functions. Those with a history of cardiovascular disease should not be given THC and it can also exacerbate symptoms in people who suffer from schizophrenia. Smoking cannabis can lead to chronic bronchitis and cancers of the lung.31
On the other hand, cannabis is a very safe drug with the estimated fatal dose in humans being 15 g, well above the amount even heavy users could take in a day.32
Cannabis based medications have been proven to be beneficial in treating many disorders such as nausea and vomiting and AIDS wasting syndrome. A number of clinical trials have proven that cannabis (or cannabis constituents) may have some potential in medicine; to stimulate appetite, reduce pain, reduce tremors and treat nausea and vomiting for example. However, despite this resounding evidence, none or few clinical trials have compared their efficacy against newer drugs such as the 5-HT3 receptor antagonists or neurokinin-1-receptor-antagonists.
On the whole I believe a renewed interest is required into the beneficial effects of cannabis. Further research and clinical/controlled trials are required to compare the efficacy of cannabinoids against newer drugs with potentially fewer side effects. Cannabinoids or cannabis based medications should only be used as and when required if patients fail to respond adequately to conventional drugs. Smoking cannabis is certainly not an option or a route of administration due to its deleterious effects, which outweigh its potential benefits.