Description

• Cannabis is from the flowering plant Cannabis sativa L. - subspecies sativa.
• Cannabis is a drug that produces euphoria and reduces anxiety.
• It can cause dependence but addiction, as shown by increasing use and inability to discontinue use, is uncommon.
• The drug can be used occasionally without causing significant social or mental problems. Withdrawal may cause anxiety and disturbed sleep in heavy users.
• Cannabis is associated rarely and unpredictably with a range of psychotic symptoms.
• Cannabis was reclassified from a class C to class B drug in January 2009.^[1]

Pathophysiology

• Cannabis can be smoked or ingested, eg herbal tea, butter paste.
• When cannabis is ingested it produces cannabinoids which results in its psychological and physical effects.
• The most active of these is tetrahydrocannabinol (THC).

Epidemiology^[2]

• It is estimated that 4% of the world's population use cannabis - with rates of 10% up to 30% in Europe.
• The number of cannabis smokers is on the increase.
• Over 2 million people in the UK smoke cannabis.^[3]

Presentation

• Cannabis induces a relaxed state characterised by a series of disconnected thoughts.
• There may also be: Psychological effects
  • Relaxation
  • Euphoria
  • Alteration in perception of time, colour and space
  • Short-term memory loss
  • Irritability
  Physical effects
  • Dry mouth
  • Dry eyes
  • Bloodshot eyes
  • Increased heart rate
• Effects are prolonged for 2-3 hours after smoking with no clear evidence of hangover or lasting effect
• Ability to drive and operate machinery is impaired due to effects on motor skills and depth perception
• Symptoms of schizophrenia may be worsened

Complications

Schizophrenia

• Cannabis use is associated with an increased risk of schizophrenia symptoms not related to a pre-existing psychosis.^[4]
• Early cannabis use (<15 years) brings greater risk for schizophrenia than use before the age of 18 years.
• Risk is specific to cannabis and not other drugs.
• Although most young people use cannabis without problems, a minority experience harmful results. 1 in 10 young people, who used cannabis by the age of 15 years developed schizophreniform disorder by age 26 compared with 3% of rest.
• Cannabis may also be associated with a short-lived psychosis but this may simply represent the initial signs of schizophrenia.^[3]

Depression^[3]

• Use of cannabis in adolescence increases the risk of developing depression and/or anxiety later in life.

Dependence

• For some years the general feeling was that cannabis does not produce dependence.
• However dependence is common and difficult to treat.^[5]
• Animals exhibit a withdrawal syndrome and a similar problem is being recognised in humans.^[6]

Respiratory function

Regular high dose users develop episodes of acute bronchitis, wheezing and coughing with changes in pulmonary function. These changes in lung function can be long-term. It is unclear whether these effects are related to the concurrent use of tobacco or cocaine or cannabis directly. Furthermore, tobacco smoking and smoking marijuana is associated with increased respiratory illness amongst other symptoms.^[7]

Cognitive function

Some tests have shown a reduction in cognitive function in long-term regular users but this has to be confirmed.^[8]

Use of cannabis in medical treatment

There have been studies looking at the beneficial effects of cannabis in cancer, AIDS, depression, nausea when using chemotherapy and various neurological diseases, eg multiple sclerosis.^[9] However, the efficacy is unclear at present and there are concerns regarding its safety.

• The only cannabis-related preparation currently available for legal medical use is Sativex®.^[10]
• It was granted a Notice of Compliance with Conditions in Canada (the equivalent of a UK Medicines Act license) in April 2005.
• It remains an unlicensed drug in the UK and in the rest of Europe. The last official comment from the Medicines Healthcare Regulatory Agency (MHRA) was a statement in December 2007. This clarified that an application for a marketing authorisation for Sativex Oromucosal Spray had been submitted by the manufacturers in August 2006. Before that the product been supplied on a named patient basis in the UK. As of December 2007 1200 patients had been prescribed it on this basis. The report stated that whilst sufficient information had been submitted concerning the pharmacodynamics of the drug, further evidence about the efficacy and safety of Sativex would be required before a license could be considered, should the manufacturer choose to submit it.
• Sativex is a buccal spray containing the active ingredients delta-9-tetrahydrocannabinol 27 mg/ml and cannabidiol 25 mg/ml, which are both extracts of the hemp plant Cannabis sativa Linne.
• Sublingual tablets and an inhaled preparation were being investigated but there is no recent information concerning these routes.^[11]

Indications^[10]

• Sativex is intended for use as an adjunct for the symptomatic relief of neuropathic pain in adult patients with multiple sclerosis (MS).
• Other therapeutic uses of Sativex which have been explored include the relief of muscle spasm in MS, non-MS neuropathic pain,^[11] cancer pain^[12] and MS bladder dysfunction.^[13]
• Areas identified for further development include spinal cord injury,^[14] rheumatoid arthritis,^[15] and peripheral neuropathy secondary to diabetes and AIDS.^[11]

Contraindications

• Known or allergy to cannabinoids or other constituents of Sativex (propylene glycol, ethanol or peppermint oil)^[11]
• Patients with significant hepatic disease (due to the ethanol content), renal dysfunction (cannabinoids are excreted via the kidney)^[11]
• Serious cardiovascular disease, eg IHD, significant arrhythmias, unstable hypertension, severe cardiac failure (sympathoexcitation, bradycardia and cardiovascular depression in animal experiments)^[16]
• A history of schizophrenia or other psychotic disorder
• History of substance abuse including alcohol abuse - Sativex has addictive potential and should be avoided^[11]
• Reproductive issues:
  • Evidence that even mild to moderate cannabinoid use in pregnancy is associated with symptoms of ADHD (inattention, impulsivity), increased externalising behavior, decreased general cognitive functioning, and deficits in learning and memory tasks.^[17]
  • Women of reproductive age should use reliable contraception
  • Spermatogenesis can be affected^[18]
  • Male and female patients should maintain reliable contraception for the duration of therapy and for three months after^[19]
• Lactation - degree with which cannabinoids are excreted in breast milk is unknown,^[11] but it is thought likely that the risk is significant. Sativex is therefore contraindicated in lactating mothers.^[10]
• Safety and efficacy of Sativex not yet been established in patients under the age of 18.^[19]

Warnings and special precautions^[10]

• Warn patients they may get 'intoxication-type reactions' - eg sudden changes in mood, decreased cognitive performance and memory, alteration in perception of reality and time, and lack of inhibition. These effects are dose-related.
• Patients should be warned not to drive or do any activity which involves judgement or co-ordination whilst taking Sativex.
• Use with caution in patients with pre-existing heart disease, arrhythmias, cardiac failure, poorly controlled hypertension, bradycardia, tachycardia and postural hypotension.
• Epilepsy - there is evidence that seizure threshold is related to activity at CB1 and CB2 receptor sites.
• There is limited data on use in the elderly, so patients should be carefully monitored.

Dosage and administration^[11]

• Patients should start with one spray every four hours up to a maximum of four sprays a day, and then self-titrate according to response.
• Warn the patient that it can take a week or more to find the right dose and to watch for symptoms of intoxication.
• Pre-marketing trials found that the average dose used was five sprays a day. There is limited evidence with doses higher than twelve sprays daily, although some patients may require this.
• The patient should spray directly below the tongue or towards the inside of the cheek, varying the site at each dose. Avoid spraying on inflamed areas. The spray should never be aimed at the pharynx as this can cause irritation.

Adverse effects^[11]

• The commonest adverse effects during pre-marketing trials were headache, impaired balance, depressed mood and irritation at the site of administration.
• Syncopal attacks relating to postural hypotension have been identified.
• One case of a causal relationship between Sativex and suicidal ideation could not be ruled out, but the incidence of depression was consistent with that observed in populations of multiple sclerosis patients followed for a prolonged period of time.
• Hallucinations, episodes of paranoia and other psychotic symptoms have also been reported.

Monitoring^[11]

No routine laboratory monitoring is required other than that necessary to monitor the patient's condition and any concomitant medication. The patient should however be assessed regularly to see whether continued administration of Sativex is appropriate, due to its addictive potential.^[11]

Interactions^[10]

• Sativex can potentiate the action of opioids, particularly fentanyl and alfentanil, and amitriptyline.
• Cannabinoids are also known to have an affect on drugs which rely on protein-binding transport systems, such as verapamil, so post-marketing trials are likely to identify many more interactions in the future.^[11][20]

Prescribing an unlicensed drug^[21][22]

A drug which is not yet licensed for UK use can be prescribed on a named patient basis, but be aware of the following issues:

• The doctor who signs the prescription takes full responsibility for the outcome and cannot cite the pharmaceutical company as co-defendant in any civil legal action arising from a serious untoward event.
• Make sure that both you and the patient are fully conversant with the contra-indications, special precautions, and adverse reactions.
• Record the issues you discussed with the patient.
• Monitor the patient regularly.