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Internal Medicine Journal 45 (2015)
H O W I T R E AT
Medical use of cannabis: an addiction medicine perspective J. Cook,1 D. M. Lloyd-Jones,1 E. Ogden1 and Y. Bonomo1,2 1
Department of Addiction Medicine, St Vincent’s Hospital and 2Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
Key words medical marijuana, medicinal cannabis, THC, therapeutic use. Correspondence Jon Cook, Department of Addiction Medicine, St Vincent’s Hospital, Melbourne, PO Box 2900, 38 Fitzroy Street, Fitzroy, Vic. 3065, Australia. Email: [email protected]
Abstract The use of cannabis for medical purposes, evident throughout history, has become a topic of increasing interest. Yet on the present medical evidence, cannabis-based treatments will only be appropriate for a small number of people in specific circumstances. Experience with cannabis as a recreational drug, and with use of psychoactive drugs that are prescribed and abused, should inform harm reduction in the context of medical cannabis.
Received 23 November 2014; accepted 7 February 2015. doi:10.1111/imj.12761
The use of cannabis for medical purposes, evident throughout history, has become a topic of increasing media interest in recent months. A formal evidence base for several medical indications is gradually building and pharmaceutical cannabis preparations are being produced.1 Major changes in the legal status of cannabis in the United States have occurred, with several states legalising possession of small amounts of marijuana for medical purposes, chronic pain being the most prominent indication.2 There are calls for similar legislation in Australia. Legal cannabis production and its marketing is fast emerging as a major new industry. In Australia, a 2013 New South Wales parliamentary committee was generally supportive of medical cannabis, but noted that ‘on the present medical evidence, cannabis based treatments will only be appropriate for a small number of people in specific circumstances’.3 Announcement of a trial of medical marijuana in New South Wales has now received support of the Council of Australian Governments. A strong evidence base for assessing the balance between therapeutic benefits and potential harms is however lacking. The wealth of experience in addiction practice and policy can offer an important contribution to the debate about medical cannabis.
Funding: None. Conflict of interest: None.
Cannabis and cannabinoids Cannabis is a generic term used for drugs that are made from any of the genus cannabis plants, most commonly Cannabis sativa. Cannabis is a heterogeneous product, containing over 400 chemicals and 60 cannabinoids, with two major constituents: Δ9-tetrahydrocannabinol (Δ9-THC or THC) and cannabidiol.4,5 THC is responsible for most of the psychoactive effects of cannabis, including the ‘high’. Cannabidiol has antipsychotic and anxiolytic properties and may offset some of the psychoactive effects of THC; the ratio between THC and cannabidiol is likely to be important.5 Both THC and cannabidiol content vary considerably between different sources and preparations of cannabis, making cannabis a very variable drug with unpredictable pharmacological and psychological activity.5 Understanding of the endogenous cannabinoid system is relatively new, with cannabinoid receptors first isolated in the last 25 years.6 The endocannabinoid system is involved in analgesia, cognition, memory, locomotor activity, appetite, vomiting and immune control.4 Two separate cannabis receptors have to date been identified: CB1 and CB2, and the endocannabinoids anandamide and 2-arachidonoyl glycerol have been isolated.4,6 Most of the effects of cannabis preparations, including the well-known psychotropic effects, are based on the agonistic action of THC on the CB1 receptors. Several cannabis preparations are now being produced.7 Nabiximols, an oromucosal spray of botanical cannabis extract, containing 2.7 mg THC and 2.5 mg CBD
© 2015 Royal Australasian College of Physicians
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Cook et al.
per 0.1 mL, was registered by the Therapeutic Goods Administration (TGA) in 2012 for use in multiple sclerosis.8 Dronabinol, a synthetic THC oral capsule, has been licenced in the USA for the treatment of nausea and vomiting caused by cytostatic therapy and for loss of appetite in human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome (AIDS)-related cachexia. Nabilone oral capsules, a synthetic analogue of THC, has been registered for treatment of the side-effects of chemotherapy in Britain.1,9
Therapeutic indications A recent review of data from randomised controlled trials reported evidence for medical cannabis for several indications.1 Cannabis extract in multiple sclerosis significantly reduced spasticity and the frequency of spasms and significantly improved sleep quality compared with placebo. Numerous studies have demonstrated that cannabinoids were just as effective against chemotherapy-related nausea and vomiting as standard anti-emetics, and may be as effective as ondansetron. All seven studies examining anorexia in HIV and AIDS patients have shown a positive effect of dronabinol and cannabis cigarettes in the treatment of poor appetite. Chronic neuropathic pain and pain in multiple sclerosis have been shown to respond to cannabinoids, though the magnitude of effect is modest.1,10 Small controlled studies have indicated that cannabinoids may also be effective against chronic pain of other causes including tumour pain, rheumatism and fibromyalgia.1,10 Little or no effect has been found in patients with acute pain.1 In Australia, TGA approval has only been obtained for use of nabiximols in multiple sclerosis, and only for the narrow indication of ‘symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy’.8 Pharmaceutical Benefits Scheme listing for this indication was rejected in 2013 as it was not shown to be superior to standard care and is inferior to standard care in terms of safety.11 While cannabinoids have been shown to be effective in nausea and vomiting, they have not been shown to be more effective than other safer medication. A role in HIV was questioned in a recent review,12 and has lessened with the advent of effective and better tolerated retroviral medication. TGA approval has not been obtained for these indications. The potential role of cannabis in the treatment of chronic pain is an area attracting increasing interest, as chronic pain is common, debilitating and lacking in thera-
peutic options.10 Interest particularly lies in developing CB1 and CB2 receptor agonists that act outside the blood– brain barrier.9 This is on the basis that many of the ‘unwanted effects’ of cannabinoid receptor agonists are caused by their activation of CB1 receptors located within the brain, and beneficial effects such as pain relief occur outside the central nervous system. CB2-specific agonists may have roles in certain types of cancer, cardiovascular, immunological and inflammatory conditions.9 There is also interest in potential therapeutic effects of cannabidiol, currently in trial in the USA for use as a treatment for Dravet syndrome – a form of severe childhood epilepsy.
Risks and harms Cannabis use has not been directly associated with toxic deaths, although the emergence of synthetic cannabinoids may change this observation.13 Notwithstanding this, cannabis use can cause significant harms.14 Cannabinoids are widely used recreationally for the pleasurable and relaxing effects, but unwanted psychotropic effects including anxiety and panic attacks can occur even in the context of deliberate intoxication.6 A strong link exists between early onset cannabis and later mental health; a study of 1600 Australian school students 14–15 years old followed for 7 years found those who used cannabis regularly had increased risk of depression.15 There is strong epidemiological evidence that early onset cannabis is associated with subsequent psychotic disorder in young adulthood.16,17 A 2007 meta-analysis pooling 35 longitudinal, population-based studies demonstrated an elevated odds ratio of 1.41 for psychosis in individuals who had ever used cannabis, with findings consistent with a dose–response effect.16 Cannabis is also shown to result in a poor prognosis for those with an established vulnerability to psychosis.17 Cannabis use can lead to dependence syndrome, with well-documented withdrawal symptoms including restlessness, insomnia, anxiety, aggression, anorexia, muscle tremor and autonomic effects.6,18 Adult lifetime prevalence rates suggest that 9% of cannabis users develop cannabis dependence,19 with higher rates in young people.20 Cannabis is the most common substance after alcohol for which admission for detoxification is sought.21 Presentations to hospitals following ingestion or inhalation of illicit synthetic cannabis are also on the rise.13 There is growing evidence linking cannabis use with cognitive impairment. Cannabis acutely impairs cognitive and psychomotor performance, with effects including slowing of reaction time, motor incoordination, defects in short-term memory, difficulty in concentration and impairment in complex tasks.6 Impairment due to © 2015 Royal Australasian College of Physicians
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cannabis is increasingly recognised as a factor in road trauma;22 acute cannabis consumption is associated with an increased risk of a motor vehicle accident, especially for fatal collisions.23 Ongoing cannabis use is associated with poor academic achievement and a below expected performance in measures of intelligence in adulthood.24 Further, cessation of cannabis use did not fully restore neuropsychological functioning among adolescent-onset cannabis users.24 Other general health effects of cannabis that have been described include airway injury with regular use leading to symptoms of chronic bronchitis.25 Cannabis use also has implications for fertility, immunosuppression, cardiac health and psychomotor performance.14,26
Perspective Our experience with use of psychoactive drugs that are prescribed and abused can inform harm reduction in the context of medical cannabis. There are valuable lessons to heed from the exponential rise in use of prescription opiate and other pharmaceuticals and associated deaths,27,28 the increasing rates of alcohol and drugs (both illicit and prescribed) in road trauma,29 and the heavy burden of disease of mental health disorders, especially in young people.30,31 The history of morphine as medicine, with varying levels of medical and recreational use, regulation and criminalisation, offers insight into the challenges now faced with medical cannabis.32 Absence of regulation of laudanum and morphine in the 19th and early 20th century resulted in widespread inappropriate use, including for infantile diarrhoea, with resultant infantile deaths. Conversely government and media condemnation of opioid use in the context of a flourishing illegal market can lead to underutilisation of opioids and inadequate management of pain.32,33
References 1 Grotenhermen F, Müller-Vahl K. The therapeutic potential of cannabis and cannabinoids. Dtsch Ärztebl Int 2012; 109: 495–501. 2 Marcoux RM, Larrat EP, Vogenberg FR. Medical marijuana and related legal aspects. P T 2013; 38: 612. 3 General Purpose Standing Committee No. 4. The Use of Cannabis for Medical Purposes (Report 27). Sydney: NSW Parliament; 2013. [cited 2014 Nov 22]. Available from URL: http://www .parliament.nsw.gov.au/prod/parlment/
The substantial appeal of cannabis to the community is clear, it being the most commonly used illicit drug. The number of Australians using cannabis increased from 1.6 million in 2007 to 1.9 million in 2010.34 This level of appeal perhaps in part explains the apparent incongruity between the high level of interest in cannabis as medicine and the limited therapeutic role that can be recommended on current evidence. Recreational use of cannabis and its criminalisation and decriminalisation fall outside the scope of this article, but blurring of the line between recreational and medical use of cannabis is recognised, and creates confusion around advocacy for its use as medicine.35 The implications of availability of cannabis beyond the clinical context therefore need careful consideration. The therapeutic potential for medical cannabis cannot be ignored and the commencement of therapeutic trials is to be applauded. As with any other pharmacological agent, the underlying neurobiological mechanisms of action, clinical efficacy, dose-response, clinical pharmacokinetics, efficacy and toxicity in special population groups such as the elderly, cost-effectiveness and rigorous controls around production of high quality pharmaceuticals need to be systematically addressed. Such exploration should occur as a priority for those indications where no other therapeutic avenue is available, such as severe childhood epilepsy. Formulations that have greater cannabidiol content such as nabiximols are particularly appealing given that cannabidiol appears to attenuate paranoia and euphoria and produces little intoxication, tolerance or withdrawal.36 Strategies to reduce diversion and public harms such as permits, authority scripts and regular review should also be considered. As the medical role for cannabis becomes clear, thought is required into preventing predictable associated harms.
committee.nsf/0/fdb7842246a5ab71ca 257b6c0002f09b/$FILE/Final%20Report %20-%20The%20use%20of%20 cannnabis%20for%20medical %20purposes.pdf 4 Kumar R, Chambers W, Pertwee R. Pharmacological actions and therapeutic uses of cannabis and cannabinoids. Anaesthesia 2001; 56: 1059–68. 5 Potter DJ, Clark P, Brown MB. Potency of Δ9–THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology. J Forensic Sci 2008; 53: 90–4.
6 Ashton CH. Pharmacology and effects of cannabis: a brief review. Br J Psychiatry 2001; 178: 101–6. 7 Mather LE. For debate: (re)introducing medical cannabis. Med J Aust 2013; 199: 759–61. 8 Department of Health Therapeutic Goods Administration. Australian Public Assessment Report for Nabiximols. Canberra: Australian Government; 2013. [cited 2014 Nov 22]. Available from URL: http://www.tga.gov.au/ auspar/auspar-nabiximols 9 Pertwee RG. Targeting the endocannabinoid system with cannabinoid receptor agonists:
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pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci 2012; 367: 3353–63. Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol 2011; 72: 735–44. Pharmaceutical Benefits Advisory Committee. Public Summary Document: Nabiximols Oral Spray. 2013 [cited 2014 Oct 10]. Available from URL: http:// www.pbs.gov.au/info/industry/listing/ elements/pbac-meetings/psd/2013-07/ nabiximols Lutge EE, Gray A, Siegfried N. The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS. Cochrane Database Syst Rev 2013; CD005175. Williams S, Taylor P, Page C, Martin J. Clinical research in synthetic cannabinoids – do we need a national approach? Med J Aust 2014; 201: 317–19. Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet 2009; 374: 1383–91. Patton GC, Coffey C, Carlin JB, Degenhardt L, Lynskey M, Hall W. Cannabis use and mental health in young people: cohort study. Br Med J 2002; 325: 1195–8. Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 2007; 370: 319–28. Van Os J, Bak M, Hanssen M, Bijl R, De Graaf R, Verdoux H. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol 2002; 156: 319–27. Budney AJ, Hughes JR. The cannabis withdrawal syndrome. Curr Opin Psychiatry 2006; 19: 233–8. Anthony JC, Warner LA, Kessler RC. Comparative epidemiology of
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dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey. Exp Clin Psychopharmacol 1994; 2: 244. Coffey C, Carlin JB, Degenhardt L, Lynskey M, Sanci L, Patton GC. Cannabis dependence in young adults: an Australian population study. Addiction 2002; 97: 187–94. Australian Institute of Health and Welfare. Alcohol and other drug treatment services in Australia 2009–10: report on the National Minimum Data Set. Canberra. 2011 [cited 2014 Oct 27]. Available from URL: http://www.aihw .gov.au/publication-detail/?id =10737420496 Mura P, Chatelain C, Dumestre V, Gaulier J, Ghysel M, Lacroix C et al. Use of drugs of abuse in less than 30-year-old drivers killed in a road crash in France: a spectacular increase for cannabis, cocaine and amphetamines. Forensic Sci Int 2006; 160: 168–72. Asbridge M, Hayden JA, Cartwright JL. Acute cannabis consumption and motor vehicle collision risk: systematic review of observational studies and meta-analysis. Br Med J 2012; 344: e536. Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RS et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. PNAS 2012; 109: E2657–64. Tashkin DP. Effects of marijuana smoking on the lung. Anna Am Thorac Soc 2013; 10: 239–47. Ashton CH. Adverse effects of cannabis and cannabinoids. Br J Anaesth 1999; 83: 637–49. Bohnert AS, Valenstein M, Bair MJ, Ganoczy D, McCarthy JF, Ilgen MA et al. Association between opioid prescribing patterns and opioid overdose-related deaths. JAMA 2011; 305: 1315–21.
28 Rintoul AC, Dobbin MD, Drummer OH, Ozanne-Smith J. Increasing deaths involving oxycodone, Victoria, Australia, 2000–09. Inj Prev 2010; 17: 254–9. 29 Drummer OH. The role of drugs in road safety. Aust Prescr 2008; 31: 33–5. 30 Milnes A, Pegrum K, Nebe B, Topfer A, Gaal L, Zhang J et al. Young Australians: Their Health and Wellbeing 2011. Canberra: Australian Institute of Health and Welfare; 2011. [cited 2014 Nov 23]. Available from URL: http://www.aihw.gov.au/WorkArea/ DownloadAsset.aspx?id=10737419259 31 McLaren J. Cannabis and Mental Health: Put into Context. Sydney: University of New South Wales; 2008. [cited 2014 Oct 27]. Available from URL: https://ncpic .org.au/static/pdfs/young-people-training -package/cannabis-and-mental-health -put-into-context.pdf 32 Matthew Grant JPAU. A functional dependence? A social history of the medical use of morphine in Australia. Med J Aust 2014; 200: 230–2. 33 Forbes K. Opioids: beliefs and myths. J Pain Palliat Care Pharmacother 2006; 20: 33–5. 34 Australian Institute of Health and Welfare. 2010 National Drug Strategy Household Survey Report, Drug Statistics Series No. 25. Cat. No. PHE 145. Canberra: AIHW; 2011. [cited 2014 Oct 27]. Available from URL: http://www .aihw.gov.au/WorkArea/DownloadAsset .aspx?id=10737421314 35 Bostwick JM, ed. Blurred boundaries: the therapeutics and politics of medical marijuana. Mayo Clinic Proceedings; Elsevier, 2012. 36 Allsop DJ, Copeland J, Lintzeris N, Dunlop AJ, Montebello M, Sadler C et al. Nabiximols as an agonist replacement therapy during cannabis withdrawal: a randomized clinical trial. JAMA Psychiatry 2014; 71: 281–91.
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Internal Medicine Journal 45 (2015)
H O W I T R E AT
Medical use of cannabis: an addiction medicine perspective J. Cook,1 D. M. Lloyd-Jones,1 E. Ogden1 and Y. Bonomo1,2 1
Department of Addiction Medicine, St Vincent’s Hospital and 2Department of Medicine, The University of Melbourne, Melbourne, Victoria, Australia
Key words medical marijuana, medicinal cannabis, THC, therapeutic use. Correspondence Jon Cook, Department of Addiction Medicine, St Vincent’s Hospital, Melbourne, PO Box 2900, 38 Fitzroy Street, Fitzroy, Vic. 3065, Australia. Email: [email protected]
Abstract The use of cannabis for medical purposes, evident throughout history, has become a topic of increasing interest. Yet on the present medical evidence, cannabis-based treatments will only be appropriate for a small number of people in specific circumstances. Experience with cannabis as a recreational drug, and with use of psychoactive drugs that are prescribed and abused, should inform harm reduction in the context of medical cannabis.
Received 23 November 2014; accepted 7 February 2015. doi:10.1111/imj.12761
The use of cannabis for medical purposes, evident throughout history, has become a topic of increasing media interest in recent months. A formal evidence base for several medical indications is gradually building and pharmaceutical cannabis preparations are being produced.1 Major changes in the legal status of cannabis in the United States have occurred, with several states legalising possession of small amounts of marijuana for medical purposes, chronic pain being the most prominent indication.2 There are calls for similar legislation in Australia. Legal cannabis production and its marketing is fast emerging as a major new industry. In Australia, a 2013 New South Wales parliamentary committee was generally supportive of medical cannabis, but noted that ‘on the present medical evidence, cannabis based treatments will only be appropriate for a small number of people in specific circumstances’.3 Announcement of a trial of medical marijuana in New South Wales has now received support of the Council of Australian Governments. A strong evidence base for assessing the balance between therapeutic benefits and potential harms is however lacking. The wealth of experience in addiction practice and policy can offer an important contribution to the debate about medical cannabis.
Funding: None. Conflict of interest: None.
Cannabis and cannabinoids Cannabis is a generic term used for drugs that are made from any of the genus cannabis plants, most commonly Cannabis sativa. Cannabis is a heterogeneous product, containing over 400 chemicals and 60 cannabinoids, with two major constituents: Δ9-tetrahydrocannabinol (Δ9-THC or THC) and cannabidiol.4,5 THC is responsible for most of the psychoactive effects of cannabis, including the ‘high’. Cannabidiol has antipsychotic and anxiolytic properties and may offset some of the psychoactive effects of THC; the ratio between THC and cannabidiol is likely to be important.5 Both THC and cannabidiol content vary considerably between different sources and preparations of cannabis, making cannabis a very variable drug with unpredictable pharmacological and psychological activity.5 Understanding of the endogenous cannabinoid system is relatively new, with cannabinoid receptors first isolated in the last 25 years.6 The endocannabinoid system is involved in analgesia, cognition, memory, locomotor activity, appetite, vomiting and immune control.4 Two separate cannabis receptors have to date been identified: CB1 and CB2, and the endocannabinoids anandamide and 2-arachidonoyl glycerol have been isolated.4,6 Most of the effects of cannabis preparations, including the well-known psychotropic effects, are based on the agonistic action of THC on the CB1 receptors. Several cannabis preparations are now being produced.7 Nabiximols, an oromucosal spray of botanical cannabis extract, containing 2.7 mg THC and 2.5 mg CBD
© 2015 Royal Australasian College of Physicians
677
Cook et al.
per 0.1 mL, was registered by the Therapeutic Goods Administration (TGA) in 2012 for use in multiple sclerosis.8 Dronabinol, a synthetic THC oral capsule, has been licenced in the USA for the treatment of nausea and vomiting caused by cytostatic therapy and for loss of appetite in human immunodeficiency virus (HIV)/ acquired immune deficiency syndrome (AIDS)-related cachexia. Nabilone oral capsules, a synthetic analogue of THC, has been registered for treatment of the side-effects of chemotherapy in Britain.1,9
Therapeutic indications A recent review of data from randomised controlled trials reported evidence for medical cannabis for several indications.1 Cannabis extract in multiple sclerosis significantly reduced spasticity and the frequency of spasms and significantly improved sleep quality compared with placebo. Numerous studies have demonstrated that cannabinoids were just as effective against chemotherapy-related nausea and vomiting as standard anti-emetics, and may be as effective as ondansetron. All seven studies examining anorexia in HIV and AIDS patients have shown a positive effect of dronabinol and cannabis cigarettes in the treatment of poor appetite. Chronic neuropathic pain and pain in multiple sclerosis have been shown to respond to cannabinoids, though the magnitude of effect is modest.1,10 Small controlled studies have indicated that cannabinoids may also be effective against chronic pain of other causes including tumour pain, rheumatism and fibromyalgia.1,10 Little or no effect has been found in patients with acute pain.1 In Australia, TGA approval has only been obtained for use of nabiximols in multiple sclerosis, and only for the narrow indication of ‘symptom improvement in patients with moderate to severe spasticity due to multiple sclerosis who have not responded adequately to other antispasticity medication and who demonstrate clinically significant improvement in spasticity related symptoms during an initial trial of therapy’.8 Pharmaceutical Benefits Scheme listing for this indication was rejected in 2013 as it was not shown to be superior to standard care and is inferior to standard care in terms of safety.11 While cannabinoids have been shown to be effective in nausea and vomiting, they have not been shown to be more effective than other safer medication. A role in HIV was questioned in a recent review,12 and has lessened with the advent of effective and better tolerated retroviral medication. TGA approval has not been obtained for these indications. The potential role of cannabis in the treatment of chronic pain is an area attracting increasing interest, as chronic pain is common, debilitating and lacking in thera-
peutic options.10 Interest particularly lies in developing CB1 and CB2 receptor agonists that act outside the blood– brain barrier.9 This is on the basis that many of the ‘unwanted effects’ of cannabinoid receptor agonists are caused by their activation of CB1 receptors located within the brain, and beneficial effects such as pain relief occur outside the central nervous system. CB2-specific agonists may have roles in certain types of cancer, cardiovascular, immunological and inflammatory conditions.9 There is also interest in potential therapeutic effects of cannabidiol, currently in trial in the USA for use as a treatment for Dravet syndrome – a form of severe childhood epilepsy.
Risks and harms Cannabis use has not been directly associated with toxic deaths, although the emergence of synthetic cannabinoids may change this observation.13 Notwithstanding this, cannabis use can cause significant harms.14 Cannabinoids are widely used recreationally for the pleasurable and relaxing effects, but unwanted psychotropic effects including anxiety and panic attacks can occur even in the context of deliberate intoxication.6 A strong link exists between early onset cannabis and later mental health; a study of 1600 Australian school students 14–15 years old followed for 7 years found those who used cannabis regularly had increased risk of depression.15 There is strong epidemiological evidence that early onset cannabis is associated with subsequent psychotic disorder in young adulthood.16,17 A 2007 meta-analysis pooling 35 longitudinal, population-based studies demonstrated an elevated odds ratio of 1.41 for psychosis in individuals who had ever used cannabis, with findings consistent with a dose–response effect.16 Cannabis is also shown to result in a poor prognosis for those with an established vulnerability to psychosis.17 Cannabis use can lead to dependence syndrome, with well-documented withdrawal symptoms including restlessness, insomnia, anxiety, aggression, anorexia, muscle tremor and autonomic effects.6,18 Adult lifetime prevalence rates suggest that 9% of cannabis users develop cannabis dependence,19 with higher rates in young people.20 Cannabis is the most common substance after alcohol for which admission for detoxification is sought.21 Presentations to hospitals following ingestion or inhalation of illicit synthetic cannabis are also on the rise.13 There is growing evidence linking cannabis use with cognitive impairment. Cannabis acutely impairs cognitive and psychomotor performance, with effects including slowing of reaction time, motor incoordination, defects in short-term memory, difficulty in concentration and impairment in complex tasks.6 Impairment due to © 2015 Royal Australasian College of Physicians
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Medical use of cannabis
cannabis is increasingly recognised as a factor in road trauma;22 acute cannabis consumption is associated with an increased risk of a motor vehicle accident, especially for fatal collisions.23 Ongoing cannabis use is associated with poor academic achievement and a below expected performance in measures of intelligence in adulthood.24 Further, cessation of cannabis use did not fully restore neuropsychological functioning among adolescent-onset cannabis users.24 Other general health effects of cannabis that have been described include airway injury with regular use leading to symptoms of chronic bronchitis.25 Cannabis use also has implications for fertility, immunosuppression, cardiac health and psychomotor performance.14,26
Perspective Our experience with use of psychoactive drugs that are prescribed and abused can inform harm reduction in the context of medical cannabis. There are valuable lessons to heed from the exponential rise in use of prescription opiate and other pharmaceuticals and associated deaths,27,28 the increasing rates of alcohol and drugs (both illicit and prescribed) in road trauma,29 and the heavy burden of disease of mental health disorders, especially in young people.30,31 The history of morphine as medicine, with varying levels of medical and recreational use, regulation and criminalisation, offers insight into the challenges now faced with medical cannabis.32 Absence of regulation of laudanum and morphine in the 19th and early 20th century resulted in widespread inappropriate use, including for infantile diarrhoea, with resultant infantile deaths. Conversely government and media condemnation of opioid use in the context of a flourishing illegal market can lead to underutilisation of opioids and inadequate management of pain.32,33
References 1 Grotenhermen F, Müller-Vahl K. The therapeutic potential of cannabis and cannabinoids. Dtsch Ärztebl Int 2012; 109: 495–501. 2 Marcoux RM, Larrat EP, Vogenberg FR. Medical marijuana and related legal aspects. P T 2013; 38: 612. 3 General Purpose Standing Committee No. 4. The Use of Cannabis for Medical Purposes (Report 27). Sydney: NSW Parliament; 2013. [cited 2014 Nov 22]. Available from URL: http://www .parliament.nsw.gov.au/prod/parlment/
The substantial appeal of cannabis to the community is clear, it being the most commonly used illicit drug. The number of Australians using cannabis increased from 1.6 million in 2007 to 1.9 million in 2010.34 This level of appeal perhaps in part explains the apparent incongruity between the high level of interest in cannabis as medicine and the limited therapeutic role that can be recommended on current evidence. Recreational use of cannabis and its criminalisation and decriminalisation fall outside the scope of this article, but blurring of the line between recreational and medical use of cannabis is recognised, and creates confusion around advocacy for its use as medicine.35 The implications of availability of cannabis beyond the clinical context therefore need careful consideration. The therapeutic potential for medical cannabis cannot be ignored and the commencement of therapeutic trials is to be applauded. As with any other pharmacological agent, the underlying neurobiological mechanisms of action, clinical efficacy, dose-response, clinical pharmacokinetics, efficacy and toxicity in special population groups such as the elderly, cost-effectiveness and rigorous controls around production of high quality pharmaceuticals need to be systematically addressed. Such exploration should occur as a priority for those indications where no other therapeutic avenue is available, such as severe childhood epilepsy. Formulations that have greater cannabidiol content such as nabiximols are particularly appealing given that cannabidiol appears to attenuate paranoia and euphoria and produces little intoxication, tolerance or withdrawal.36 Strategies to reduce diversion and public harms such as permits, authority scripts and regular review should also be considered. As the medical role for cannabis becomes clear, thought is required into preventing predictable associated harms.
committee.nsf/0/fdb7842246a5ab71ca 257b6c0002f09b/$FILE/Final%20Report %20-%20The%20use%20of%20 cannnabis%20for%20medical %20purposes.pdf 4 Kumar R, Chambers W, Pertwee R. Pharmacological actions and therapeutic uses of cannabis and cannabinoids. Anaesthesia 2001; 56: 1059–68. 5 Potter DJ, Clark P, Brown MB. Potency of Δ9–THC and other cannabinoids in cannabis in England in 2005: implications for psychoactivity and pharmacology. J Forensic Sci 2008; 53: 90–4.
6 Ashton CH. Pharmacology and effects of cannabis: a brief review. Br J Psychiatry 2001; 178: 101–6. 7 Mather LE. For debate: (re)introducing medical cannabis. Med J Aust 2013; 199: 759–61. 8 Department of Health Therapeutic Goods Administration. Australian Public Assessment Report for Nabiximols. Canberra: Australian Government; 2013. [cited 2014 Nov 22]. Available from URL: http://www.tga.gov.au/ auspar/auspar-nabiximols 9 Pertwee RG. Targeting the endocannabinoid system with cannabinoid receptor agonists:
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pharmacological strategies and therapeutic possibilities. Philos Trans R Soc Lond B Biol Sci 2012; 367: 3353–63. Lynch ME, Campbell F. Cannabinoids for treatment of chronic non-cancer pain; a systematic review of randomized trials. Br J Clin Pharmacol 2011; 72: 735–44. Pharmaceutical Benefits Advisory Committee. Public Summary Document: Nabiximols Oral Spray. 2013 [cited 2014 Oct 10]. Available from URL: http:// www.pbs.gov.au/info/industry/listing/ elements/pbac-meetings/psd/2013-07/ nabiximols Lutge EE, Gray A, Siegfried N. The medical use of cannabis for reducing morbidity and mortality in patients with HIV/AIDS. Cochrane Database Syst Rev 2013; CD005175. Williams S, Taylor P, Page C, Martin J. Clinical research in synthetic cannabinoids – do we need a national approach? Med J Aust 2014; 201: 317–19. Hall W, Degenhardt L. Adverse health effects of non-medical cannabis use. Lancet 2009; 374: 1383–91. Patton GC, Coffey C, Carlin JB, Degenhardt L, Lynskey M, Hall W. Cannabis use and mental health in young people: cohort study. Br Med J 2002; 325: 1195–8. Moore TH, Zammit S, Lingford-Hughes A, Barnes TR, Jones PB, Burke M et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet 2007; 370: 319–28. Van Os J, Bak M, Hanssen M, Bijl R, De Graaf R, Verdoux H. Cannabis use and psychosis: a longitudinal population-based study. Am J Epidemiol 2002; 156: 319–27. Budney AJ, Hughes JR. The cannabis withdrawal syndrome. Curr Opin Psychiatry 2006; 19: 233–8. Anthony JC, Warner LA, Kessler RC. Comparative epidemiology of
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