Bachhuber MA, Saloner B, Cunningham CO, Barry CL. Medical cannabis laws and opioid analgesic overdose mortality in the United States, 1999-2010. JAMA Intern Med. 2014;174(10):1668-1673.
The purpose of this study was to determine the association between the presence of state medical cannabis laws and opioid analgesic overdose mortality. A time-series analysis was conducted of medical cannabis laws and state-level death certificate data in the United States from 1999 to 2010; all 50 states were included. Associations between mortality rates and the presence of laws establishing a medical cannabis program in the state in which the deceased had lived were calculated.
Age-adjusted opioid analgesic overdose death rates per 100,000 population were calculated for each state. Regression models were developed and included state and year fixed effects, the presence of 3 different policies regarding opioid analgesics, and the state-specific unemployment rate.
Three states (California, Oregon, and Washington) had medical cannabis laws in effect before 1999. Ten states (Alaska, Colorado, Hawaii, Maine, Michigan, Montana, Nevada, New Mexico, Rhode Island, and Vermont) enacted medical cannabis laws between 1999 and 2010. States with medical cannabis laws had a 24.8% lower mean annual opioid overdose mortality rate (95% confidence interval [CI]: –37.5% to –9.5%; P=0.003) compared with states without medical cannabis laws. Examination of the association between medical cannabis laws and opioid analgesic overdose mortality in each year after implementation of the law showed that such laws were associated with a lower rate of overdose mortality that generally strengthened over time: year 1, –19.9% (95% CI: –30.6% to –7.7%; P=0.002); year 2, –25.2%, (95% CI: –40.6% to –5.9%; P=0.01); year 3, –23.6% (95% CI: –41.1% to –1.0%; P=0.04); year 4, –20.2% (95% CI: –33.6% to –4.0%; P=0.02); year 5, –33.7% (95% CI: –50.9% to –10.4%; P=0.008), and year 6, –33.3% (95% CI: –44.7% to –19.6%; P<0.001). In secondary analyses, the findings remained similar. Medical cannabis laws are associated with significantly lower state-level opioid overdose mortality rates. Further investigation is required to determine how medical cannabis laws may interact with policies aimed at preventing opioid analgesic overdose.
These results are dramatic and suggest that legalizing marijuana for medical purposes may actually save lives. Legalizing marijuana was associated with a 25% decrease in deaths from opioid overdoses a year. According to the study authors, this translates to about 1,729 fewer deaths than expected in 2010. This contrasts the view held by the US government, which still characterizes cannabis as a dangerous Class 1 narcotic—a substance with no medicinal benefits and high potential for abuse. This current study stands in sharp contrast to older theories that cannabis is a gateway drug to more dangerous narcotics. Instead, the opposite may be true; cannabis may be an exit strategy for individuals who have become reliant on more dangerous drugs.1
If further studies confirm this trend with prospective data, then cannabis looks like a viable means of blunting the risks inherent in narcotic usage.
Opiate drugs work because the human body makes natural opiates called endorphins and encephalons. The receptors for these endogenous chemicals are ubiquitous in the body, particularly in the central nervous system. Opium poppies produce a chemical that mimics these endogenous-opiates and binds to the same receptor sites in our brains.
Cannabis plants produce chemicals that also bind to receptors in the body that were intended for other internally generated endogenous neurotransmitters. Because these receptor sites were first identified as binding sites for isolates from cannabis, all of the chemicals that bind to these sites, even the endogenously produced ones, are referred to as cannabinoids. The main reason humans produce cannabinoids endogenously is to turn down noxious stimuli, and the main function of this endocannabinoid system may be to regulate pain signaling and perception in the body.2
A variety of pain types have been reported to respond to tetrahydrocannabinol (THC) and cannabidiol (CBD), the principal cannabinoids found in cannabis, including neuropathic pain, hyperalgesia, allodynia muscle spasticity, and nociceptive pain. Anecdotal and preclinical data indicate a synergy between the 2 main cannabinoid types, THC and CBD, in reducing pain.3
Cannabinoids are involved in the regulation of a great many other body functions aside from pain, including blood pressure,4 appetite,5 metabolism,6 digestion,7 body temperature,8 bone maintenance,9 lipogenesis, liver health,10 fertility,11 moods,12 anxiety,13 immunity,14 and inflammatory responses.15
The two main endogenous cannabinoids, the chemicals made normally in the body, are anandamide (AEA), which binds to cannabinoid (CB)1 receptors, and 2-acylglycerol (2-AG), which acts on both CB1 and CB2 receptors. The exogenous cannabinoid CBD, which is found in cannabis, inhibits the enzymatic clearance of AEA and stimulates release of 2AG from vesicles. Thus cannabis ingestion augments the action of the endogenous cannabinoids in the body. Cannabis plants are reported to contain at least 68 different cannabinoids, though some estimates put the number as high as 108. The plant also contains abundant terpenes, which constitute the aromatic compounds that give cannabis its distinct flavors and odors.16
CB1 receptors are particularly abundant in the central nervous system, adipose tissue, liver, lungs, uterus, and placenta. Activation of central and peripheral nervous system CB1s can be analgesic. CB1 receptors on gamma-aminobutyric acid interneurons disinhibit pain projection neurons. CB1 receptors also alter memory and motor functions. All of the psychoactive, mental, and perceptual effects, considered to be negative effects of cannabis ingestion, are from CB1 activity.17
CB2 receptors are found in the liver, spleen, gastrointestinal tract, heart, bones, and kidneys and in the peripheral nervous system. There are more CB1 and CB2 receptors present in the body than opiate receptors. Neither CB1 nor CB2 receptors are located in the brain stem, a fact that is often cited to explain why cannabis overdoses do not shut down autonomic functions and result in death the way opioids do. Cannabinoids are in fact synergistic with opiates for analgesia.18 Thus cannabis may assist in opiate drug withdrawal or dose reduction. Lower dose requirements for pain relief may relate to the lower rates of overdose, as seen in this current study. Lower opiate dose requirements for pain relief could also lower many other risks and harms.
While this paper looked only at overdose death from opioid use, recent research suggests that cannabis use may protect against toxicity from methamphetamine overdoses as well.19
Although federal regulators still consider cannabis to possess no medicinal value and classify it as a high-risk narcotic, there are instances in which the courts and local police forces consider cannabis as a reasonable form of harm reduction.20
Dependency rates among cannabis users is about 9%, a lower proportion than for alcohol, tobacco, and most other abused drugs.21 The hallmarks of dependency are compulsion; craving; loss of control of intake; continued use despite negative consequences in physical health or social, recreational, or work activities or relationships; tolerance; persistent desire to reduce intake but inability to do so; and withdrawal reactions.
Withdrawal is less problematic with cannabis than with other narcotics. Heavy cannabis users who suddenly withdraw may experience irritability, anger, aggression, restlessness, agitation, sleep disorders, strange dreams, depression, hyperhidrosis, loss of appetite, weight loss, or rebound intraocular pressure increase. Withdrawal symptoms tend to peak between days 2 and 4, and end within 7 to 14 days. N-acetyl-cysteine has been reported to assist in breaking cannabis dependence.22
The low cost and accessibility of cannabis products provide an attractive alternative to costlier drugs such as opiates, cocaine, methamphetamines, and alcohol.23 The ideas that cannabis use may help patients taper off with less risk of dependency and withdrawal symptoms and that access to cannabis may replace riskier drugs are certainly intriguing and constitute a paradigm shift from even the recent past.
While the scarcity of large-scale studies requires practitioners to use caution in guiding our patients, it certainly seems that cannabis may reduce use of other, more harmful medications. If further studies confirm this trend with prospective data, then cannabis looks like a viable means of blunting the risks inherent in narcotic usage.
- Marlatt GA. Harm reduction: come as you are. Addict Behav. 1996;21(6):779-788.
- Campbell FA, Tramèr MR, Carroll D, Reynolds DJ, Moore RA, McQuay HJ. Are cannabinoids an effective and safe treatment option in the management of pain? A qualitative systematic review. BMJ. 2001;323(7303):13-16.
- Martín-Sánchez E, Furukawa TA, Taylor J, Martin JL. Systematic review and meta-analysis of cannabis treatment for chronic pain. Pain Med. 2009;10(8):1353-1368.
- Schaich CL, Shaltout HA, Brosnihan KB, Howlett AC, Diz DI. Acute and chronic systemic CB1 cannabinoid receptor blockade improves blood pressure regulation and metabolic profile in hypertensive (mRen2)27 rats. Physiol Rep. 2014 Aug 28;2(8). pii: e12108.
- Flores A, Maldonado R, Berrendero F. Cannabinoid-hypocretin cross-talk in the central nervous system: what we know so far. Front Neurosci. 2013 Dec 20;7:256.
- Boon MR, Kooijman S, van Dam AD, et al. Peripheral cannabinoid 1 receptor blockade activates brown adipose tissue and diminishes dyslipidemia and obesity. FASEB J. 2014 Aug 25. pii: fj.13-247643. [Epub ahead of print]
- Sharkey KA, Darmani NA, Parker LA. Regulation of nausea and vomiting by cannabinoids and the endocannabinoid system. Eur J Pharmacol. 2014 Jan 5;722:134-146.
- Monge-Roffarello B, Labbe SM, Roy MC, et al. The PVH as a site of CB1-mediated stimulation of thermogenesis by MC4R agonism in male rats. Endocrinology. 2014;155(9):3448-3458.
- Idris AI. Role of cannabinoid receptors in bone disorders: alternatives for treatment. Drug News Perspect. 2008;21(10):533-540.
- Alswat KA. The role of endocannabinoids system in fatty liver disease and therapeutic potentials. Saudi J Gastroenterol. 2013;19(4):144-151.
- Lewis SE, Rapino C, Di Tommaso M, et al. Differences in the endocannabinoid system of sperm from fertile and infertile men. PLoS One. 2012;7(10):e47704.
- Crowe MS, Nass SR, Gabella KM, Kinsey SG. The endocannabinoid system modulates stress, emotionality, and inflammation. Brain Behav Immun. 2014 Jun 19. pii: S0889-1591(14)00172-X. [Epub ahead of print]
- Bluett RJ, Gamble-George JC, Hermanson DJ, Hartley ND, Marnett LJ, Patel S. Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation. Transl Psychiatry. 2014 Jul 8;4:e408.
- Hernangómez M, Carrillo-Salinas FJ, Mecha M, et al. Brain innate immunity in the regulation of neuroinflammation: therapeutic strategies by modulating CD200-CD200R interaction involve the cannabinoid system. Curr Pharm Des. 2014;20(29):4707-4722.
- Krustev E, Reid A, McDougall JJ. Tapping into the endocannabinoid system to ameliorate acute inflammatory flares and associated pain in mouse knee joints. Arthritis Res Ther. 2014;16(5):437. [Epub ahead of print]
- Grotenhermen F, Russo E. Cannabis and Cannabinoids: Pharmacology, Toxicology and Therapeutic Potential. Bend, OR: Hawthorne Integrative Healing Press; 2002.
- Borgelt LM, Franson KL, Nussbaum AM, Wang GS. Pharmacologic and clinical effects of medical cannabis. Pharmacotherapy. 2013;33(2):195-209.
- Abrams DI, Couey P, Shade SB, Kelly ME, Benowitz NL. Cannabinoid-opioid interaction in chronic pain. Clin Pharmacol Ther. 2011;90(6):844-851.
- Nader J, Rapino C, Gennequin B, et al. Prior stimulation of the endocannabinoid system prevents methamphetamine-induced dopaminergic neurotoxicity in the striatum through activation of CB2 receptors. Neuropharmacology. 2014 Apr 5. pii: S0028-3908(14)00109-9. [Epub ahead of print]
- Cohen PJ. Medical marijuana: the conflict between scientific evidence and political ideology. Part one of two. J Pain Palliat Care Pharmacother. 2009;23(1):4-25.
- Budney AJ, Roffman R, Stephens RS, Walker D. Marijuana dependence and its treatment. Addict Sci Clin Pract. 2007;4(1):4-16.
- Gray KM, Carpenter MJ, Baker NL, et al. A double-blind randomized controlled trial of N-acetylcysteine in cannabis-dependent adolescents. Am J Psychiatry. 20121;169(8):805-812.
- Reiman A. Cannabis as a substitute for alcohol and other drugs. Harm Reduct J. 2009 Dec 3;6:35.