NEWS & VIEWS PHARMACOLOGY
Cannabis in neurology—a potted review Richard Hosking and John Zajicek
Discovery of the endogenous cannabinoid signalling system unleashed substantial new research into several neurological conditions. A recent systematic review suggests that medical marijuana can improve a number of symptoms—particularly spasticity—in multiple sclerosis, but cannabinoids can have adverse psychological effects and their comparative effectiveness is unknown. Hosking, R. & Zajicek, J. Nat. Rev. Neurol. advance online publication 8 July 2014; doi:10.1038/nrneurol.2014.122
Cannabis attracts attention. The war on drugs and controversy over legalization contrasts with renewed interest in alternative therapies and anecdotal reports of patient benefit. A growing understanding of cannabis pharmacology has revealed important molecular mechanisms that relate to neural communication and inflammation, and several licensed preparations of medical cannabis are now available (Box 1). A recent systematic review published in Neurology by Barbara Koppel and colleagues provides timely guidelines for the use of medical marijuana in selected neurological disorders.1 The evidence summarized in the review by Koppel et al. supports a role for cannabis in the symptomatic treatment of multiple sclerosis (MS), but its efficacy in Huntington disease (HD), Parkinson disease (PD) and epilepsy is unknown.
‘‘
…cannabinoids should be investigated … using the same evidence-based criteria as for all other drugs
’’
Cannabis is thought to derive its name from ancient Sanskrit and Hebrew texts, where it means ‘fragrant cane’, and the plant has been of medicinal interest for millennia. The first clinical study involving cannabis was conducted in 19th-century Calcutta by Irish physician Sir William O’Shaughnessy, who introduced Indian hemp to Victorian medicine. 2 However, it was not until the 1960s that Raphael
Mechoulam and colleagues in Israel identi fied the major psychoactive cannabinoid delta-9-tetrahydrocannabinol (Δ9-THC), which led to the discovery of an extensive endogenous lipid signalling system.3 There are currently over 100 known cannabinoids that have diverse effects at both cannabinoid and non-cannabinoid receptors. Cannabinoid receptor 1 (CB1) is the most common G-protein-coupled receptor in the CNS. High densities of CB1 within the cerebellum, basal ganglia, hippocampus and cerebral cortex correlate with the capacity of cannabis to produce motor and cognitive impairment. This psychoactivity—a property that not all cannabinoids possess—is largely mediated by Δ9-THC. Cannabinoid receptor 2 (CB2) mRNA is found within cells of the immune system including lymphocytes, monocytes and microglia, although current problems with antibody specificity complicate receptor localization. The major ligands for these receptors are endogenous cannabinoids, such as anandamide and 2-arachidonoylglycerol, which are derived from arachidonic acid and demonstrate marked overlap with prostag landin signalling. 4 The actions of these ‘endocannabinoids’ are complex, as are those of plant-derived cannabinoids, which, in addition to receptor stimulation, might have antioxidant properties. Cannabinoid receptors are present in all major pain pathways, and the analgesic effects of cannabinoids are likely to be mediated by postsynaptic retrograde inhibition of neurotransmission via CB1.
NATURE REVIEWS | NEUROLOGY
An alternative mechanism might involve CB2 activation on microglia and peripheral inflammatory cells.3 Endocannabinoids are hydrolysed by several enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) and diacyl glycerol lipase (DAGL). Most information on these mechanisms derives from animal studies, but while animal models have provided many of the important tools for dissecting complex immunological processes, they rarely replicate the pathological features of human disease.5 Koppel and colleagues reviewed the full text of 64 papers from a total of 1,730 abstracts published between January 1948 and November 2013.1 This search yielded 34 studies that met the authors’ inclusion criteria. Eight of the included studies were rated as Class I evidence according to the American Academy of Neurology classification for therapeutic articles. The authors Box 1 | Cannabinoids Cannabis sativa The botanical name for the hemp plant from which cannabis is obtained Marijuana A synonym for cannabis that also refers to the dried flowers and leaves Cannabinoids Plant-derived compounds and endogenous or synthetic analogues Delta-9-tetrahydrocannabinol (Δ9-THC) The main plant-derived psychoactive cannabinoid; the relative amount of Δ9-THC in a preparation determines the extent of psychological effects Cannabidiol (CBD) The main non-psychoactive plant-derived cannabinoid Endocannabinoids Endogenous lipid signalling molecules that are widespread throughout the body Oral cannabis extract Extracts such as Cannador, a capsule with a defined THC:CBD ratio (2.50:1.25 mg) Dronabinol (Marinol) Oral synthetic Δ9-THC Nabilone (Cesamet) Oral synthetic cannabinoid similar to Δ9-THC Nabiximols (Sativex) Herbal oromucosal spray with a defined THC:CBD ratio (2.7:2.5 mg)
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS addressed several questions, including the efficacy of cannabinoids for treating MS symptoms of spasticity, central pain, painful spasms, bladder dysfunction and involuntary movements including tremor. They also assessed the use of cannabinoids in HD, levodopa-induced dyskinesias in PD, cervical dystonia, the tics of Tourette syndrome, and seizure frequency in epilepsy. The main finding of Koppel and co- workers was that oral cannabis extract (see Box 1) is effective in treating spasticity, central pain and painful spasms in patients with MS. Nabiximols and THC are also likely to be effective for these indications. Nabiximols is probably effective in reducing urinary frequency, but no formulation was felt to improve MS‑related tremor. Oral cannabis extract was found to be probably ineffective in treating levodopa-induced dyskinesias in PD; no discernible effect was found for any cannabinoid on the remaining neurological disorders. Koppel et al. point out that the risk of serious adverse psychological effects was nearly 1%. The comparative effectiveness of medical marijuana relative to other therapies for these indications is unknown. We welcome evidence-based guidelines for cannabinoid use in neurological disease, and Koppel et al. have provided an excellent systematic review of current clinical research. The limitations of the present study reflect those of the original studies. These include problems with subjective patient-centred rating scales; objective clinical scales with potential interobserver variability; the risk of unblinding owing to the psychoactive properties of the drugs; and often-substantial placebo effects that make treatment effects difficult to establish. An additional issue, not specific to cannabis preparations, is the difficulty of identi fying responders within heterogeneous populations, which has led to novel trial designs and will continue to tax medical ingenuity. Importantly, the studies included in the Koppel et al. review used a wide range of formulations with different cannabinoid content, methods of administration and dose. Cannabinoids are intensely lipophilic and readily cross the blood–brain barrier, but the absorption and bioavailability of preparations are highly variable, partly due to first-pass metabolism (metabolization before the drug reaches the systemic circulation), which oromucosal administration attempts to reduce.
Titration speed can affect the development of unwanted psychoactive effects, but the current available evidence suggests that these effects resolve on dose reduction or drug cessation. Smoked marijuana causes the most rapid rise in plasma THC concentration, which then quickly falls as a result of tissue distribution. 3 However, combustion alters cannabinoid activity, and the attendant risks of inhaled carcinogens are an additional cause for concern. Furthermore, a recent study shows that patients with MS who smoke cannabis have greater cognitive impairment than those who do not use this drug.6 Beyond symptom amelioration, the potential of cannabinoids as neuroprotec tive agents has created a great deal of interest. Although the overall results of a recent dronabinol study of neuroprotection in progressive MS were negative, subgroup analysis did suggest a possible early treatment effect in less-disabled patients.7 Polymorphisms in the gene encoding CB1 could influence the inflammatory neurodegenerative process in MS,8 and receptor downregulation after continued exposure to THC might mitigate the effects of this drug in certain brain regions.9 In patients with HD, loss of CB1 from the striatum could be an important pathogenic factor. Data from animal models suggest that abnormal huntingtin protein indirectly reduces CB1 expression in striatal neurons, leading to increased excitotoxicity and decreased levels of brain-derived neurotrophic factor. Early treatment with CB1 agonists might prevent these changes.10 Cannabidiol lacks psychoactivity and has shown promise as a neuroprotective agent in preclinical studies. An alternative strategy to prevent adverse psychological reactions that could also be of use in neuroprotective studies is to increase endocannabinoid signalling or ‘tone’ using inhibitors of the constitutive hydrolytic enzymes FAAH, MAGL and DAGL. In fact, this could be one mechanism by which cannabidiol acts, because its general activity at cannabinoid receptors is low. Cannabis research has paralleled advances in opioid pharmacology, whereby a psychoactive plant extract has led to the discovery of endogenous signalling systems with thera peutic relevance. We agree that cannabin oids should be investigated and prescribed using the same evidence-based criteria as
2 | ADVANCE ONLINE PUBLICATION
for all other drugs. Systematic assessment of this evidence, such as the present review by Koppel and co-workers, can greatly aid clinical decisions. The current data, however, are limited, and we look forward to future randomized controlled trials investigating the symptom-alleviating and neuroprotective potential of cannabinoids. Clinical Neurology Research Group, Plymouth University Peninsula Schools of Medicine and Dentistry, Room N13, ITTC Building 1, Davy Road, Tamar Science Park, Plymouth PL6 8BX, UK (R.H., J.Z.). Correspondence to: J.Z. [email protected] Acknowledgements J.Z. has received funding to conduct studies of cannabinoids in multiple sclerosis from the UK Medical Research Council. Competing interests J.Z. has received funding from the Institut für klinische Forschung, Berlin, which manufactures Cannador. R.H. declares no competing interests. 1.
Koppel, B. S. et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 82, 1556–1563 (2014). 2. O’Shaughnessy, W. B. On the preparations of the Indian Hemp, or Gunjah, (Cannabis Indica): their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases. Prov. Med. J. Retrosp. Med. Sci. 123, 363–369 (1843). 3. Hosking, R. D. & Zajicek, J. P. Therapeutic potential of cannabis in pain medicine. Br. J. Anaesth. 101, 59–68 (2008). 4. Nomura, D. K. et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334, 809–813 (2011). 5. Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004). 6. Pavisian, B. et al. Effects of cannabis on cognition in patients with MS: a psychometric and MRI study. Neurology 82, 1879–1887 (2014). 7. Zajicek, J. et al. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. Lancet Neurol. 12, 857–865 (2013). 8. Rossi, S. et al. Association between a genetic variant of type‑1 cannabinoid receptor and inflammatory neurodegeneration in multiple sclerosis. PLoS One 8, e82848 (2013). 9. Lazenka, M. F., Selley, D. E. & Sim-Selley, L. J. Brain regional differences in CB1 receptor adaptation and regulation of transcription. Life Sci. 92, 446–452 (2013). 10. Blazquez, C. et al. Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease. Brain 134, 119–136 (2011).
www.nature.com/nrneurol © 2014 Macmillan Publishers Limited. All rights reserved
Cannabis in neurology—a potted review Richard Hosking and John Zajicek
Discovery of the endogenous cannabinoid signalling system unleashed substantial new research into several neurological conditions. A recent systematic review suggests that medical marijuana can improve a number of symptoms—particularly spasticity—in multiple sclerosis, but cannabinoids can have adverse psychological effects and their comparative effectiveness is unknown. Hosking, R. & Zajicek, J. Nat. Rev. Neurol. advance online publication 8 July 2014; doi:10.1038/nrneurol.2014.122
Cannabis attracts attention. The war on drugs and controversy over legalization contrasts with renewed interest in alternative therapies and anecdotal reports of patient benefit. A growing understanding of cannabis pharmacology has revealed important molecular mechanisms that relate to neural communication and inflammation, and several licensed preparations of medical cannabis are now available (Box 1). A recent systematic review published in Neurology by Barbara Koppel and colleagues provides timely guidelines for the use of medical marijuana in selected neurological disorders.1 The evidence summarized in the review by Koppel et al. supports a role for cannabis in the symptomatic treatment of multiple sclerosis (MS), but its efficacy in Huntington disease (HD), Parkinson disease (PD) and epilepsy is unknown.
‘‘
…cannabinoids should be investigated … using the same evidence-based criteria as for all other drugs
’’
Cannabis is thought to derive its name from ancient Sanskrit and Hebrew texts, where it means ‘fragrant cane’, and the plant has been of medicinal interest for millennia. The first clinical study involving cannabis was conducted in 19th-century Calcutta by Irish physician Sir William O’Shaughnessy, who introduced Indian hemp to Victorian medicine. 2 However, it was not until the 1960s that Raphael
Mechoulam and colleagues in Israel identi fied the major psychoactive cannabinoid delta-9-tetrahydrocannabinol (Δ9-THC), which led to the discovery of an extensive endogenous lipid signalling system.3 There are currently over 100 known cannabinoids that have diverse effects at both cannabinoid and non-cannabinoid receptors. Cannabinoid receptor 1 (CB1) is the most common G-protein-coupled receptor in the CNS. High densities of CB1 within the cerebellum, basal ganglia, hippocampus and cerebral cortex correlate with the capacity of cannabis to produce motor and cognitive impairment. This psychoactivity—a property that not all cannabinoids possess—is largely mediated by Δ9-THC. Cannabinoid receptor 2 (CB2) mRNA is found within cells of the immune system including lymphocytes, monocytes and microglia, although current problems with antibody specificity complicate receptor localization. The major ligands for these receptors are endogenous cannabinoids, such as anandamide and 2-arachidonoylglycerol, which are derived from arachidonic acid and demonstrate marked overlap with prostag landin signalling. 4 The actions of these ‘endocannabinoids’ are complex, as are those of plant-derived cannabinoids, which, in addition to receptor stimulation, might have antioxidant properties. Cannabinoid receptors are present in all major pain pathways, and the analgesic effects of cannabinoids are likely to be mediated by postsynaptic retrograde inhibition of neurotransmission via CB1.
NATURE REVIEWS | NEUROLOGY
An alternative mechanism might involve CB2 activation on microglia and peripheral inflammatory cells.3 Endocannabinoids are hydrolysed by several enzymes, including fatty acid amide hydrolase (FAAH), monoacylglycerol lipase (MAGL) and diacyl glycerol lipase (DAGL). Most information on these mechanisms derives from animal studies, but while animal models have provided many of the important tools for dissecting complex immunological processes, they rarely replicate the pathological features of human disease.5 Koppel and colleagues reviewed the full text of 64 papers from a total of 1,730 abstracts published between January 1948 and November 2013.1 This search yielded 34 studies that met the authors’ inclusion criteria. Eight of the included studies were rated as Class I evidence according to the American Academy of Neurology classification for therapeutic articles. The authors Box 1 | Cannabinoids Cannabis sativa The botanical name for the hemp plant from which cannabis is obtained Marijuana A synonym for cannabis that also refers to the dried flowers and leaves Cannabinoids Plant-derived compounds and endogenous or synthetic analogues Delta-9-tetrahydrocannabinol (Δ9-THC) The main plant-derived psychoactive cannabinoid; the relative amount of Δ9-THC in a preparation determines the extent of psychological effects Cannabidiol (CBD) The main non-psychoactive plant-derived cannabinoid Endocannabinoids Endogenous lipid signalling molecules that are widespread throughout the body Oral cannabis extract Extracts such as Cannador, a capsule with a defined THC:CBD ratio (2.50:1.25 mg) Dronabinol (Marinol) Oral synthetic Δ9-THC Nabilone (Cesamet) Oral synthetic cannabinoid similar to Δ9-THC Nabiximols (Sativex) Herbal oromucosal spray with a defined THC:CBD ratio (2.7:2.5 mg)
ADVANCE ONLINE PUBLICATION | 1 © 2014 Macmillan Publishers Limited. All rights reserved
NEWS & VIEWS addressed several questions, including the efficacy of cannabinoids for treating MS symptoms of spasticity, central pain, painful spasms, bladder dysfunction and involuntary movements including tremor. They also assessed the use of cannabinoids in HD, levodopa-induced dyskinesias in PD, cervical dystonia, the tics of Tourette syndrome, and seizure frequency in epilepsy. The main finding of Koppel and co- workers was that oral cannabis extract (see Box 1) is effective in treating spasticity, central pain and painful spasms in patients with MS. Nabiximols and THC are also likely to be effective for these indications. Nabiximols is probably effective in reducing urinary frequency, but no formulation was felt to improve MS‑related tremor. Oral cannabis extract was found to be probably ineffective in treating levodopa-induced dyskinesias in PD; no discernible effect was found for any cannabinoid on the remaining neurological disorders. Koppel et al. point out that the risk of serious adverse psychological effects was nearly 1%. The comparative effectiveness of medical marijuana relative to other therapies for these indications is unknown. We welcome evidence-based guidelines for cannabinoid use in neurological disease, and Koppel et al. have provided an excellent systematic review of current clinical research. The limitations of the present study reflect those of the original studies. These include problems with subjective patient-centred rating scales; objective clinical scales with potential interobserver variability; the risk of unblinding owing to the psychoactive properties of the drugs; and often-substantial placebo effects that make treatment effects difficult to establish. An additional issue, not specific to cannabis preparations, is the difficulty of identi fying responders within heterogeneous populations, which has led to novel trial designs and will continue to tax medical ingenuity. Importantly, the studies included in the Koppel et al. review used a wide range of formulations with different cannabinoid content, methods of administration and dose. Cannabinoids are intensely lipophilic and readily cross the blood–brain barrier, but the absorption and bioavailability of preparations are highly variable, partly due to first-pass metabolism (metabolization before the drug reaches the systemic circulation), which oromucosal administration attempts to reduce.
Titration speed can affect the development of unwanted psychoactive effects, but the current available evidence suggests that these effects resolve on dose reduction or drug cessation. Smoked marijuana causes the most rapid rise in plasma THC concentration, which then quickly falls as a result of tissue distribution. 3 However, combustion alters cannabinoid activity, and the attendant risks of inhaled carcinogens are an additional cause for concern. Furthermore, a recent study shows that patients with MS who smoke cannabis have greater cognitive impairment than those who do not use this drug.6 Beyond symptom amelioration, the potential of cannabinoids as neuroprotec tive agents has created a great deal of interest. Although the overall results of a recent dronabinol study of neuroprotection in progressive MS were negative, subgroup analysis did suggest a possible early treatment effect in less-disabled patients.7 Polymorphisms in the gene encoding CB1 could influence the inflammatory neurodegenerative process in MS,8 and receptor downregulation after continued exposure to THC might mitigate the effects of this drug in certain brain regions.9 In patients with HD, loss of CB1 from the striatum could be an important pathogenic factor. Data from animal models suggest that abnormal huntingtin protein indirectly reduces CB1 expression in striatal neurons, leading to increased excitotoxicity and decreased levels of brain-derived neurotrophic factor. Early treatment with CB1 agonists might prevent these changes.10 Cannabidiol lacks psychoactivity and has shown promise as a neuroprotective agent in preclinical studies. An alternative strategy to prevent adverse psychological reactions that could also be of use in neuroprotective studies is to increase endocannabinoid signalling or ‘tone’ using inhibitors of the constitutive hydrolytic enzymes FAAH, MAGL and DAGL. In fact, this could be one mechanism by which cannabidiol acts, because its general activity at cannabinoid receptors is low. Cannabis research has paralleled advances in opioid pharmacology, whereby a psychoactive plant extract has led to the discovery of endogenous signalling systems with thera peutic relevance. We agree that cannabin oids should be investigated and prescribed using the same evidence-based criteria as
2 | ADVANCE ONLINE PUBLICATION
for all other drugs. Systematic assessment of this evidence, such as the present review by Koppel and co-workers, can greatly aid clinical decisions. The current data, however, are limited, and we look forward to future randomized controlled trials investigating the symptom-alleviating and neuroprotective potential of cannabinoids. Clinical Neurology Research Group, Plymouth University Peninsula Schools of Medicine and Dentistry, Room N13, ITTC Building 1, Davy Road, Tamar Science Park, Plymouth PL6 8BX, UK (R.H., J.Z.). Correspondence to: J.Z. [email protected] Acknowledgements J.Z. has received funding to conduct studies of cannabinoids in multiple sclerosis from the UK Medical Research Council. Competing interests J.Z. has received funding from the Institut für klinische Forschung, Berlin, which manufactures Cannador. R.H. declares no competing interests. 1.
Koppel, B. S. et al. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology 82, 1556–1563 (2014). 2. O’Shaughnessy, W. B. On the preparations of the Indian Hemp, or Gunjah, (Cannabis Indica): their effects on the animal system in health, and their utility in the treatment of tetanus and other convulsive diseases. Prov. Med. J. Retrosp. Med. Sci. 123, 363–369 (1843). 3. Hosking, R. D. & Zajicek, J. P. Therapeutic potential of cannabis in pain medicine. Br. J. Anaesth. 101, 59–68 (2008). 4. Nomura, D. K. et al. Endocannabinoid hydrolysis generates brain prostaglandins that promote neuroinflammation. Science 334, 809–813 (2011). 5. Mestas, J. & Hughes, C. C. Of mice and not men: differences between mouse and human immunology. J. Immunol. 172, 2731–2738 (2004). 6. Pavisian, B. et al. Effects of cannabis on cognition in patients with MS: a psychometric and MRI study. Neurology 82, 1879–1887 (2014). 7. Zajicek, J. et al. Effect of dronabinol on progression in progressive multiple sclerosis (CUPID): a randomised, placebo-controlled trial. Lancet Neurol. 12, 857–865 (2013). 8. Rossi, S. et al. Association between a genetic variant of type‑1 cannabinoid receptor and inflammatory neurodegeneration in multiple sclerosis. PLoS One 8, e82848 (2013). 9. Lazenka, M. F., Selley, D. E. & Sim-Selley, L. J. Brain regional differences in CB1 receptor adaptation and regulation of transcription. Life Sci. 92, 446–452 (2013). 10. Blazquez, C. et al. Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease. Brain 134, 119–136 (2011).
www.nature.com/nrneurol © 2014 Macmillan Publishers Limited. All rights reserved
