Opinion
VIEWPOINT
Samuel T. Wilkinson, MD Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut. Deepak Cyril D’Souza, MBBS, MD Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut, and Schizophrenia and Neuropharmacology Research Group, VA Connecticut Healthcare System, West Haven, Connecticut.
Corresponding Author: Deepak Cyril D’Souza, MBBS, MD, Department of Psychiatry, Yale University School of Medicine, Psychiatry Service 116A, VA Connecticut Healthcare System, 950 Campbell Ave, West Haven, CT 06516 (deepak.dsouza @yale.edu).
Problems With the Medicalization of Marijuana “Medical” marijuana is approvedin 21 states and the District of Columbia for numerous conditions, including glaucoma, Crohn disease, posttraumatic stress disorder, epilepsy, Alzheimer disease, and chemotherapyinduced nausea and vomiting. Both the number of states and the number of approved indications for medical marijuana are expected to increase. Physicians will bear the responsibility of prescribing marijuana and thus have an obligation to understand the issues involved in its “medicalization.” Medical marijuana differs significantly from other prescription medications. Evidence supporting its efficacy varies substantially and in general falls short of the standards required for approval of other drugs by the US Food and Drug Administration (FDA). Some evidence suggests that marijuana may have efficacy in chemotherapy-induced vomiting, cachexia in HIV/AIDS patients, spasticity associated with multiple sclerosis, and neuropathic pain. However, the evidence for use in other conditions—including posttraumatic stress disorder, glaucoma, Crohn disease, and Alzheimer disease—relies largely on testimonials instead of
Prescription drugs are produced according to exacting standards to ensure uniformity and purity of active constituents and excipients. Because regulatory standards of the production process vary by state, the composition, purity, and concentration of the active constituents of marijuana are also likely to vary. This is especially problematic because unlike most other prescription medications that are single active compounds, marijuana contains more than 100 cannabinoids, terpenoids, and flavonoids that produce individual, interactive, and entourage effects. Although THC is believed to be the principal psychoactive constituent of marijuana, other cannabinoids present in marijuana may have important effects that may offset THC’s negative effects. For instance, cannabidiol has been shown to have anxiolytic and antipsychotic effects that might offset the anxiogenic and psychotogenic potential of THC.2,3 Yet cannabidiol is sometimes bred out to increase the THC potency of some medical marijuana strains.4 Benefits notwithstanding, the potential harms associated with medical marijuana need to be carefully considered. No other prescription medication is smoked; concerns remain about the long-term risks of respiratory probA significant but largely overlooked lems associated with smoking marijuana, which are a subject of active problem with the medical marijuana investigation.5 THC is already available in movement is the message the public a pill approved by the FDA, yet this form infers from its legalization and seems to be less desirable to those seeking medical marijuana; this may in part be increasing prevalence. because its euphoric effects are not immediate and cannot be reliably conadequately powered, double-blind, placebo-controlled trolled, unlike smoked marijuana.6 Furthermore, there randomized clinical trials. For most of these condi- is evidence that marijuana exposure is associated with tions, medications that have been subjected to the rig- an increased risk of psychotic disorders in vulnerable orous approval process of the FDA already exist. Fur- individuals.7 Clearly, some but not all individuals are at thermore, the many conditions for which medical risk of psychosis with exposure to marijuana, but it is not marijuana is approved have no common etiology, possible to identify at-risk individuals. In individuals with pathophysiology, or phenomenology, raising skepti- established psychotic disorders, marijuana use has a cism about a common mechanism of action. negative effect on the course and expression of the There is no clear optimal dose of marijuana for its illness.7 Furthermore, recent findings suggest that longvarious approved conditions. The concentration of term marijuana exposure is associated with structural Δ9-tetrahydrocannabinol (THC) and other cannabi- brain changes as well as a decline in IQ.8 noids in each marijuana cigarette, the size of cigaThe current system of dispensing marijuana does rettes, and the quantity of smoke inhaled by users can not safeguard adequately against the potential for divary considerably. The relative lack of controlled clini- version and abuse. Many states, for instance, allow pacal trial data makes finding the appropriate dose even tients to grow their own marijuana. Furthermore, marimore challenging. Furthermore, given that medical juana may be contaminated with pesticides, herbicides, marijuana is approved for mostly chronic conditions or fungi, the latter being especially dangerous to immuthat require long-term dosing, physicians must be nocompromised individuals such as patients with HIV/ aware of the development of tolerance and depen- AIDS or cancer.9 Central regulatory oversight by the FDA dence (as evidenced by downregulation of the brain makes possible the recall of harmful drugs or contamicannabinoid receptors), as well as withdrawal on nated batches and the dissemination of new informadiscontinuation.1 tion about drug safety. Is there sufficient oversight to
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Copyright 2014 American Medical Association. All rights reserved.
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Opinion Viewpoint
monitor potential contamination of marijuana, especially when patients are permitted to grow it themselves? A significant but largely overlooked problem with the medical marijuana movement is the message the public infers from its legalization and increasing prevalence. There is an increasing perception, paralleling trends in legalization, that marijuana is not associated with significant or lasting harm; data from 3 decades indicate that among adolescents, risk perception is inversely proportional to prevalence of cannabis use. 4 As legalization has spread for medical or recreational purposes, it is possible that the perception of risk by adolescents will continue to decrease, with a subsequent increase in use. This is especially problematic given that many of the negative effects of marijuana are most pronounced in adolescents.10 Projections of substantial revenue rather than evidence-based medicine may explain the eagerness of many states to legalize medical marijuana. Physicians have been invited to participate in the development of medical marijuana programs late in the process. In some instances (eg, Connecticut), legislators approved medical ARTICLE INFORMATION Published Online: May 20, 2014. doi:10.1001/jama.2014.6175. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr D’Souza reports that he has received research grant support administered through Yale University School of Medicine from AbbVie and Pfizer Inc and is a consultant for Bristol-Meyers Squibb and Johnson & Johnson. No other disclosures were reported.
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marijuana but consulted physicians with relevant expertise only afterward. An unmet need remains for treatments of a number of debilitating medical conditions. Specific constituents of marijuana may have therapeutic promise for specific symptoms associated with these disorders. However, if marijuana is to be used for medical purposes, it should be subjected to the same evidence-based review and regulatory oversight as other medications prescribed by physicians. Potentially therapeutic compounds of marijuana should be purified and tested in randomized, double-blind, placebo- and activecontrolled clinical trials. Toward this end, the federal government should actively support research examining marijuana’s potentially therapeutic compounds. These compounds should be approved by the FDA (not by popular vote or state legislature), produced according to good manufacturing practice standards, distributed by regulated pharmacies, and dispensed via a conventional and safe route of administration (such as oral pills or inhaled vaporization). Otherwise, states are essentially legalizing recreational marijuana but forcing physicians to act as gatekeepers for those who wish to obtain it.
2. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94. 3. Bhattacharyya S, Morrison PD, Fusar-Poli P, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2010;35(3):764-774. 4. Kleber HD, DuPont RL. Physicians and medical marijuana. Am J Psychiatry. 2012;169(6):564-568.
REFERENCES
5. Callaghan RC, Allebeck P, Sidorchuk A. Marijuana use and risk of lung cancer: a 40-year cohort study. Cancer Causes Control. 2013;24(10):1811-1820.
1. Budney AJ, Hughes JR. The cannabis withdrawal syndrome. Curr Opin Psychiatry. 2006;19(3):233-238.
6. Cooper ZD, Comer SD, Haney M. Comparison of the analgesic effects of dronabinol and smoked
marijuana in daily marijuana smokers. Neuropsychopharmacology. 2013;38(10):1984-1992. 7. Castle DJ, Murray RM, D’Souza DC, eds. Marijuana and Madness. 2nd ed. New York, NY: Cambridge University Press; 2012. 8. Meier MH, Caspi A, Ambler A, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012;109(40):2657-2664. 9. Verweij PE, Kerremans JJ, Voss A, Meis JF. Fungal contamination of tobacco and marijuana. JAMA. 2000;284(22):2875. 10. Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370(9584):319-328.
JAMA June 18, 2014 Volume 311, Number 23
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/17/2015
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VIEWPOINT
Samuel T. Wilkinson, MD Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut. Deepak Cyril D’Souza, MBBS, MD Department of Psychiatry, Yale School of Medicine, New Haven, Connecticut, Abraham Ribicoff Research Facilities, Connecticut Mental Health Center, New Haven, Connecticut, and Schizophrenia and Neuropharmacology Research Group, VA Connecticut Healthcare System, West Haven, Connecticut.
Corresponding Author: Deepak Cyril D’Souza, MBBS, MD, Department of Psychiatry, Yale University School of Medicine, Psychiatry Service 116A, VA Connecticut Healthcare System, 950 Campbell Ave, West Haven, CT 06516 (deepak.dsouza @yale.edu).
Problems With the Medicalization of Marijuana “Medical” marijuana is approvedin 21 states and the District of Columbia for numerous conditions, including glaucoma, Crohn disease, posttraumatic stress disorder, epilepsy, Alzheimer disease, and chemotherapyinduced nausea and vomiting. Both the number of states and the number of approved indications for medical marijuana are expected to increase. Physicians will bear the responsibility of prescribing marijuana and thus have an obligation to understand the issues involved in its “medicalization.” Medical marijuana differs significantly from other prescription medications. Evidence supporting its efficacy varies substantially and in general falls short of the standards required for approval of other drugs by the US Food and Drug Administration (FDA). Some evidence suggests that marijuana may have efficacy in chemotherapy-induced vomiting, cachexia in HIV/AIDS patients, spasticity associated with multiple sclerosis, and neuropathic pain. However, the evidence for use in other conditions—including posttraumatic stress disorder, glaucoma, Crohn disease, and Alzheimer disease—relies largely on testimonials instead of
Prescription drugs are produced according to exacting standards to ensure uniformity and purity of active constituents and excipients. Because regulatory standards of the production process vary by state, the composition, purity, and concentration of the active constituents of marijuana are also likely to vary. This is especially problematic because unlike most other prescription medications that are single active compounds, marijuana contains more than 100 cannabinoids, terpenoids, and flavonoids that produce individual, interactive, and entourage effects. Although THC is believed to be the principal psychoactive constituent of marijuana, other cannabinoids present in marijuana may have important effects that may offset THC’s negative effects. For instance, cannabidiol has been shown to have anxiolytic and antipsychotic effects that might offset the anxiogenic and psychotogenic potential of THC.2,3 Yet cannabidiol is sometimes bred out to increase the THC potency of some medical marijuana strains.4 Benefits notwithstanding, the potential harms associated with medical marijuana need to be carefully considered. No other prescription medication is smoked; concerns remain about the long-term risks of respiratory probA significant but largely overlooked lems associated with smoking marijuana, which are a subject of active problem with the medical marijuana investigation.5 THC is already available in movement is the message the public a pill approved by the FDA, yet this form infers from its legalization and seems to be less desirable to those seeking medical marijuana; this may in part be increasing prevalence. because its euphoric effects are not immediate and cannot be reliably conadequately powered, double-blind, placebo-controlled trolled, unlike smoked marijuana.6 Furthermore, there randomized clinical trials. For most of these condi- is evidence that marijuana exposure is associated with tions, medications that have been subjected to the rig- an increased risk of psychotic disorders in vulnerable orous approval process of the FDA already exist. Fur- individuals.7 Clearly, some but not all individuals are at thermore, the many conditions for which medical risk of psychosis with exposure to marijuana, but it is not marijuana is approved have no common etiology, possible to identify at-risk individuals. In individuals with pathophysiology, or phenomenology, raising skepti- established psychotic disorders, marijuana use has a cism about a common mechanism of action. negative effect on the course and expression of the There is no clear optimal dose of marijuana for its illness.7 Furthermore, recent findings suggest that longvarious approved conditions. The concentration of term marijuana exposure is associated with structural Δ9-tetrahydrocannabinol (THC) and other cannabi- brain changes as well as a decline in IQ.8 noids in each marijuana cigarette, the size of cigaThe current system of dispensing marijuana does rettes, and the quantity of smoke inhaled by users can not safeguard adequately against the potential for divary considerably. The relative lack of controlled clini- version and abuse. Many states, for instance, allow pacal trial data makes finding the appropriate dose even tients to grow their own marijuana. Furthermore, marimore challenging. Furthermore, given that medical juana may be contaminated with pesticides, herbicides, marijuana is approved for mostly chronic conditions or fungi, the latter being especially dangerous to immuthat require long-term dosing, physicians must be nocompromised individuals such as patients with HIV/ aware of the development of tolerance and depen- AIDS or cancer.9 Central regulatory oversight by the FDA dence (as evidenced by downregulation of the brain makes possible the recall of harmful drugs or contamicannabinoid receptors), as well as withdrawal on nated batches and the dissemination of new informadiscontinuation.1 tion about drug safety. Is there sufficient oversight to
jama.com
JAMA June 18, 2014 Volume 311, Number 23
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/17/2015
2377
Opinion Viewpoint
monitor potential contamination of marijuana, especially when patients are permitted to grow it themselves? A significant but largely overlooked problem with the medical marijuana movement is the message the public infers from its legalization and increasing prevalence. There is an increasing perception, paralleling trends in legalization, that marijuana is not associated with significant or lasting harm; data from 3 decades indicate that among adolescents, risk perception is inversely proportional to prevalence of cannabis use. 4 As legalization has spread for medical or recreational purposes, it is possible that the perception of risk by adolescents will continue to decrease, with a subsequent increase in use. This is especially problematic given that many of the negative effects of marijuana are most pronounced in adolescents.10 Projections of substantial revenue rather than evidence-based medicine may explain the eagerness of many states to legalize medical marijuana. Physicians have been invited to participate in the development of medical marijuana programs late in the process. In some instances (eg, Connecticut), legislators approved medical ARTICLE INFORMATION Published Online: May 20, 2014. doi:10.1001/jama.2014.6175. Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr D’Souza reports that he has received research grant support administered through Yale University School of Medicine from AbbVie and Pfizer Inc and is a consultant for Bristol-Meyers Squibb and Johnson & Johnson. No other disclosures were reported.
2378
marijuana but consulted physicians with relevant expertise only afterward. An unmet need remains for treatments of a number of debilitating medical conditions. Specific constituents of marijuana may have therapeutic promise for specific symptoms associated with these disorders. However, if marijuana is to be used for medical purposes, it should be subjected to the same evidence-based review and regulatory oversight as other medications prescribed by physicians. Potentially therapeutic compounds of marijuana should be purified and tested in randomized, double-blind, placebo- and activecontrolled clinical trials. Toward this end, the federal government should actively support research examining marijuana’s potentially therapeutic compounds. These compounds should be approved by the FDA (not by popular vote or state legislature), produced according to good manufacturing practice standards, distributed by regulated pharmacies, and dispensed via a conventional and safe route of administration (such as oral pills or inhaled vaporization). Otherwise, states are essentially legalizing recreational marijuana but forcing physicians to act as gatekeepers for those who wish to obtain it.
2. Leweke FM, Piomelli D, Pahlisch F, et al. Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia. Transl Psychiatry. 2012;2:e94. 3. Bhattacharyya S, Morrison PD, Fusar-Poli P, et al. Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology. 2010;35(3):764-774. 4. Kleber HD, DuPont RL. Physicians and medical marijuana. Am J Psychiatry. 2012;169(6):564-568.
REFERENCES
5. Callaghan RC, Allebeck P, Sidorchuk A. Marijuana use and risk of lung cancer: a 40-year cohort study. Cancer Causes Control. 2013;24(10):1811-1820.
1. Budney AJ, Hughes JR. The cannabis withdrawal syndrome. Curr Opin Psychiatry. 2006;19(3):233-238.
6. Cooper ZD, Comer SD, Haney M. Comparison of the analgesic effects of dronabinol and smoked
marijuana in daily marijuana smokers. Neuropsychopharmacology. 2013;38(10):1984-1992. 7. Castle DJ, Murray RM, D’Souza DC, eds. Marijuana and Madness. 2nd ed. New York, NY: Cambridge University Press; 2012. 8. Meier MH, Caspi A, Ambler A, et al. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012;109(40):2657-2664. 9. Verweij PE, Kerremans JJ, Voss A, Meis JF. Fungal contamination of tobacco and marijuana. JAMA. 2000;284(22):2875. 10. Moore TH, Zammit S, Lingford-Hughes A, et al. Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review. Lancet. 2007;370(9584):319-328.
JAMA June 18, 2014 Volume 311, Number 23
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://jama.jamanetwork.com/ by a Ndsu Library Periodicals User on 05/17/2015
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