Marijuana

Pronunciation

Scientific Name(s): Cannabis sativa L. More than a dozen other species names have been used to describe marijuana. Family: Cannabaceae.

Common Name(s):A variety of common names have been attributed to the plant. There are, however, specific terms for the various plant parts and extracts. These include: anascha and kif (resinous material and flowering tops mixed with the leaves); banji , hemp , cannabis , shesha , dimba , dagga , suma , vingory , and machona (entire plant); bhang and sawi (dried mature leaves); charas (resinous material); ganga (flowering tops); hashish and esrar (resinous material with flowering tops); and marijuana or marihuana (leaves and flowering tops). Commercial preparations include dronabinol ( Marinol ), an FDA schedule III drug; , THC plus cannabidiol ( Cannador ), not approved in the United States; Sativex ( Cannabis extracts) spray, recently approved (2010) in the United Kingdom; and nabilone ( Cesamet ), an FDA schedule III drug.

Uses

The use of medical marijuana for the management of chemotherapy-induced nausea, glaucoma, spasticity in multiple sclerosis, and neuropathic pain has been clinically demonstrated to some extent. The likelihood of undesirable adverse reactions limits its applications, and therapeutic use may be limited to either concomitant therapy or when conventional therapy has failed.

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Dosing

Clinical studies use a wide range of preparations and usually allow dosage titration for effect, making standard dosage recommendations difficult. A large, multicenter trial used initial doses of 5 mg of oral delta-9-tetrahydrocannabinol (THC) daily, self-titrated up to 25 mg THC daily for up to 52 weeks in multiple sclerosis. Estimates of relative efficacy for THC compared with codeine for pain are 10 mg THC to 60 mg codeine.

Contraindications

Contraindications have not been identified. The benefits versus risks of the use of cannabis extracts should be carefully weighed in individuals with psychosocial disorders.

Pregnancy/Lactation

Information regarding safety and efficacy of medicinal marijuana in pregnancy and lactation is lacking. Avoid use. In retrospective studies, marijuana use has had a modest effect on fetal growth. THC crosses the placental barrier and is excreted in breast milk.

Interactions

None well documented. Potentiation of analgesic medicines can be expected.

Adverse Reactions

The use of medical marijuana or cannabinoid preparations is mainly considered safe and devoid of major adverse reactions. Impairments in cognitive and motor function may limit it use.

Toxicology

Marijuana has a strong potential for abuse and is classified as a schedule Ι drug. No consensus exists as to the risk of lung cancer from smoked medical marijuana, or the risk of psychotic events from oral cannabinoid consumption. All risk factors should be considered in the context of applications for medical marijuana in intractable diseases. Long-term toxicity due to nonmedical (recreational) cannabis includes increased risk of psychotic, respiratory, and cardiovascular events, as well as cancer.

Botany

Cannabis is a leafy annual, with some varieties attaining heights of more than 3 m. The stalk may grow 7.6 to 10 cm thick, is square and hollow, and has ridges running along its length. Each leaf has 5 to 11 soft-textured leaflets, 18 to 25 cm long, radiating from the top of the stalk. The leaflets are narrow and lance-shaped with regular sawblade-like dentation. The plant is dioecious, having male or female flowers on different plants. The female plants have heavy foliage, while the male plants are more sparse. The resin mixture is found in the glandular hairs of the leaflets and floral bracts and is called hashish. Cannabis is cultivated worldwide for fiber, seed oil, and hashish. 1 , 2

History

The use of cannabis dates back more than 4,000 years in central Asia. It has been used for the treatment of catarrh, leprosy, fever, dandruff, hemorrhoids, obesity, asthma, urinary tract infections, loss of appetite, inflammatory conditions, and cough. It has also been used as a source of fiber for ropes and clothing. The plant's sedative effects were recognized by the ancient Chinese, but the widespread use of the plant for its psychoactive effects began in the past century. 3 , 4

Cannabis as marijuana is a schedule 1 controlled substance in the United States, with synthetic cannabinoids registered for specific indications as Marinol (THC as dronabinol), indicated as an antiemetic for chemotherapy-induced nausea and vomiting and the treatment of AIDS-related wasting syndrome, and Cesamet (nabilone), used as an antiemetic in cancer patients. The orobuccal spray Sativex is approved for multiple sclerosis spasticity in Canada and use was recently approved in the United Kingdom. 5 , 6 , 7

Chemistry

More than 420 different compounds have been isolated from cannabis and reported in chemical literature. The most commonly described compounds are the cannabinoids (THC, cannabidiol, cannabiniol, and 60 other related compounds). In addition, marijuana contains alkaloids, steroidal compounds, and mixtures of volatile components. 5 , 6 , 8 Synthetic cannabinoids include nabilone, ajulemic acid, HU-210, and WIN 55,212-2, some of which are nonpsychotropic agonists of cannabinoid receptors. 9 , 10

The concentration of THC varies in different parts of the plant, being higher in the bracts, flowers, and leaves and lower in the stems, seeds, and roots. THC concentration varies from insignificant amounts in hemp varieties to 3% to 6% in smoked marijuana and more than 6% in the resinous, compressed paste obtained from the dried flowers. Different cultivation methods and varieties contribute to variations in potency. 5 , 11

Analysis of cannabis includes methods such as gas chromatography, high-performance liquid chromatography, random amplification of polymorphic DNA, and thin layer chromatography. These methods are useful in sample differentiation, forensic analysis, and other applications. 12 , 13 , 14 , 15 Radioimmunoassay of hair for marijuana presence in the body has also been performed. 16

Uses and Pharmacology

Both exogenous and endogenous cannabinoids act on 2 receptors: CB1 receptors are found primarily in the CNS but also in lung, reproductive, and vascular endothelial tissue; CB2 receptors are found mainly in peripheral and immune-related tissue, but also in retinal and microglia cells. 5 , 8 , 17 Due to the illegality of marijuana possession and use in many jurisdictions, data from clinical trials is limited and much of the relevant documentation is based on retrospective data or case studies. 18

Appetite stimulant

Dronabinol is indicated for use as an appetite stimulant in HIV patients, although limited data exist. Self-reported increases in appetite (data obtained from surveys) have not been demonstrated in prospective, blind, and randomized clinical trials, with no improvements in quality of life measures found and no weight gain over placebo. 10 , 19

Cancer/chemotherapy-induced nausea and vomiting
Animal data

Cannabinoids, including THC, have been studied in rodents for their potential in inhibiting tumor growth via the induction of apoptosis and inhibition of angiogenesis. 20

Clinical data

Synthetic cannabinoid analogs dronabinol and nabilone have been approved by the FDA for the treatment of recalcitrant chemotherapy-induced nausea and vomiting; however, clinical data on efficacy of THC and medicinal cannabis is equivocal and the incidence of adverse events is higher than that of standard neuroleptics. 10 , 19 , 21 , 22 , 23 Some studies suggest greater efficacy in specific age groups (ie, children) with causative chemotherapeutic agents and with different delivery methods. 10 , 21 , 22

Glaucoma
Animal data

Studies in rats and rabbits suggest cannabinoids act via various mechanisms in the eye. Suppression of dopamine and presynaptic transmitter release from cones and bipolar retinal cells has been demonstrated, 24 as well as mydriasis due in part to action via sympathomimetic pathways. 25 Reduced intraocular pressure has also been demonstrated in rabbits possibly through cyclooxygenase pathways. 26

Clinical data

Clinical trials are generally lacking or of very small sample size. An early study achieved reductions in intraocular pressure at 1 hour after 2 g of marijuana was smoked via a water pipe, 27 with case reports suggesting similar findings. 28 , 29 An open-label study conducted by ophthalmologists found an initial reduction in intraocular pressure in 9 subjects with glaucoma unresponsive to standard therapy. However, the effect was not sustained at the end of the 9-month study and all participants elected to discontinue the therapy. Oral THC up to a maximum of 20 mg 4 times a day was used. 30 In another small study (N = 8), a single topical application of THC was effective in reducing the intraocular pressure after 30 minutes to a maximum effect at 60 minutes. 31 A randomized, double-blind, crossover study (N = 6) evaluating oromucosal delivery of THC and cannabidiol found THC to have some effect, but not cannabidiol. Intraocular pressure returned to baseline at 4 hours. 32

Multiple sclerosis
Animal data

Studies from in vitro and animal experiments support the effectiveness of cannabinoids in multiple sclerosis, including the reduction of oligodendrocyte and neuronal cell death, influence on inflammation and microglial migration, and enhancement of remyelination. 33 , 34 Experimentally, it has been demonstrated that antagonism of CB1 receptors (but not CB2 receptors) inhibits spasticity, but can sometimes transiently worsen it. 8

Clinical data

A number of small studies on marijuana use in multiple sclerosis have been published, as well as a large (N = 667) multicenter trial conducted in the United Kingdom. 33 , 35 , 36 , 37 , 38 Despite availability of clinical data from these trials, a definitive role for the use of cannabis extracts or its analogs in multiple sclerosis is still lacking. This is due in part to difficulty in obtaining objective clinical measures of reductions in spasticity, as most trials use self-reporting as the primary outcome measure. 8 , 33 , 34 The multicenter Cannabinoids in Multiple Sclerosis (CAMS) study found no effect on the primary outcome of muscle spasticity at 15 weeks; however, at 12 months a small improvement was found over baseline. 37 , 38 , 39 Improvements in self-reported outcomes of pain, spasticity, and spasms, and quality of sleep were recorded. No functional improvement in tremor was found in a short-term trial. 40

Improvements in urge incontinence were demonstrated in the CAMS study and other open-label trials. 8 , 33 , 41 Decreased incontinence episode rate was observed in both treatment arms of the study as well as in the placebo arm, but improvement was greater with cannabinoids compared with placebo. 41

Pain

Surveys reveal widespread usage of cannabis to manage pain among patients with HIV, multiple sclerosis, rheumatoid arthritis, and cancer. 42 , 43 , 44 THC has been shown to affect brain-derived neurotrophic factor involved in the health of neurons and modulate neuroplasticity, which may be relevant in processes underlying learning and memory. 45

Animal data

Results from experiments conducted in animals provide support for a therapeutic role in the management of pain. 46 , 47 Experiments are focusing on finding cannabinoid derivatives devoid of psychoactive properties, such as ajulemic acid. 9

Clinical data

Clinical trials investigating the efficacy of cannabis and derivatives have been conducted on acute postoperative pain, induced pain in volunteers, and chronic pain, including neuropathic pain and pain due to cancer. 48 Studies evaluating efficacy in postoperative pain have produced mixed results, with some reporting no difference compared with placebo (single dose of 5 mg of THC) and others showing a dose-dependent effect. 48 , 49 , 50 In volunteers, no effect on experimental pain (eg, pressure, heat, cold, electrical) was found with a single dose of 20 mg THC. 51 Similarly, no effect on the pain threshold was found in one study, while a modest analgesic effect was found in another. 52 , 53

In systematic reviews of clinical trials in chronic and neuropathic pain, including multiple sclerosis, HIV, and diabetic neuropathies, low to moderate decreases in pain have been demonstrated, with estimates of relative efficacy for THC compared with codeine for pain as 10 mg THC to 60 mg codeine. 8 , 48 , 54 , 55 The value of these results is moderated by a simultaneous increase in adverse events, with number-needed-for-harm estimates between 5 and 8 on visual analog scales for cognitive and motor function adverse events. 55 Clinical trials conducted after these reviews produced mixed results, with some, 56 , 57 but not all, 58 , 59 demonstrating greater pain reduction with THC than with placebo.

Other effects
CNS

Limited studies have evaluated the efficacy of cannabinoids in sleep disorders, 60 , 61 , 62 anxiety, 63 , 64 dyskinesia, 65 and Tourette syndrome 66 , 67 with mixed results.

Lipids

Hempseed oil has shown no benefit with regard to changes in the lipid profile, plasma glucose, or insulin. 68 , 69

Dosage

Clinical studies use a wide range of preparations and usually allow dosage titration for effect, making standard dosage recommendations difficult.

Glaucoma

Doses of 25 to 50 mcg topical THC, 31 and 5 mg oromucosal THC 32 reduced the intraocular pressure in studies in patients with resistant glaucoma. Delivery site and preparations may influence ophthalmic effects. 26

Multiple sclerosis

A large, multicenter trial used initial doses of 5 mg oral THC daily, self-titrated up to 25 mg THC daily for up to 52 weeks. 38

Pain

Estimates of relative efficacy for THC compared with codeine for pain are 10 mg THC to 60 mg codeine 48 THC is distributed rapidly throughout the body, especially to tissues with high lipid content. Approximately 80% to 90% of an IV dose of THC is excreted in urine and the remainder is excreted in feces via the bile. 70

Pregnancy/Lactation

Information regarding safety and efficacy of medicinal marijuana in pregnancy and lactation is lacking. Avoid use. In retrospective studies, marijuana use has had a modest effect on fetal growth. Some mild developmental abnormalities have been associated with maternal use of the drug during pregnancy, but were not sustained in the long term (at 3 years of age), and no apparent differences in IQ were noted. Data, however, are inconsistent. 71 , 72 , 73 THC crosses the placental barrier and is excreted in breast milk. 72 Lower baseline plasma prolactin levels have been demonstrated with frequent cannabis use. 74

Interactions

None well documented. Potentiation of analgesic medicines can be expected. 75 A study conducted in rats found that cannabis inhibited the CYP-450 pathway. 47

Adverse Reactions

Medical marijuana or its analogs are regarded as having a relatively positive safety profile, but supportive studies are limited. 6 High doses are rarely fatal; however, a narrow dosing index exists between desired medicinal benefit and undesirable adverse reactions. Study dropouts are commonly recorded, due mainly to the impairment of cognitive ability (eg, attention, working memory) and GI disturbances. 6 , 76 , 77 Nonserious adverse events due to medicinal cannabinoid use were found to be 1.86 times higher than those seen with placebo in a systematic review of clinical studies. 77 White lesions in the mouth similar to chemical burns have been reported with the use of oromucosal cannabinoids. 78 Increases in plasma cortisol due to administered THC have been demonstrated, 74 and increases in heart rate and both transient hypotension and increased systolic blood pressure have also been recorded. 2 An increased risk of cardiovascular events, such as acute myocardial infarction, has been suggested. 71

No serious adverse events were reported in a 12-month study of cannabis use in multiple sclerosis patients. 38 A systematic review of studies using medicinal cannabinoids, but not nabilone, found no difference in serious adverse events and no difference in death versus placebo. 77 A study evaluating the use of oral Cannador in postoperative pain was terminated due to a vasovagal event in 1 patient. 50

Toxicology

No consensus exists on the risk of lung cancer from smoked medical marijuana, despite a plausible biological rationale and epidemiological data. The risks of medical marijuana should be considered in the context of applications in intractable diseases. 71 , 79 Likewise, the potential for addiction and risk of inducing mental illness is debated. 80 A systematic review found an increased risk of psychotic outcomes with the use of cannabis (odds ratio 1.41; 95% CI 1.20 to 1.65). 81

A systematic review of long-term toxicity due to nonmedical (recreational) cannabis use found increased risks for psychotic, respiratory, and cardiovascular events, as well as for cancers of the lung, head and neck, brain, cervix, prostate, and testis. 73 Heavy cannabis use is also associated with bone loss. 73

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