As an emergency physician in inner cities such as Detroit and Baltimore for the last 25 years, I am, unfortunately, very familiar with caring for patients with addiction. Over the years, I have seen the nomenclature change from drug abuse to substance abuse, to now substance use disorder. I became interested and started my cannabis medical practice because of the opioid crisis and my dismay at my unwitting participation in it, while trying to help my patients. I feel the agencies like the FDA that are supposed to protect our patients have instead shielded the pharmaceutical companies like Purdue, who like the tobacco companies, also hid the addictive nature of their products.
Addiction specialists describe a general model of addiction as a chronic relapsing disorder that is characterized by a compulsive desire and use of a substance, with an inability to control it, despite all the negative consequences.[1] They talk about three circular phases[2], described by a cycle of behaviors modified by the central nervous system circuitry[3]. A brief general overview describes the reward centers in the nucleus accumbens part of the basal ganglia that drives the intoxication and binge use, while the withdrawal and negative effects are driven by the changes in the amygdala, leading to the preoccupation and anticipation of the substance driven by the prefrontal cortex starting the cycle again.
All drugs of abuse increase dopamine release, the neurotransmitter associated with our pleasure and reward systems that drive and reinforce use[4] [5]. While the two main cannabinoids in cannabis, THC and CBD, can both affect dopamine responses, it is believed that THC, which is the psychoactive component, is responsible for cannabis’ addictive potential and abuse liability[6] [7].
Additionally, over the last two decades, there has been a marked increase in the potency of cannabis with ever-increasing levels of THC[8]. The DEA reports rises from 1-2% THC found in confiscated marijuana from years ago to upwards of 20% THC today. With respect to THC, animal models[9] [10] have shown that THC does have characteristics of an abuse liability with drug dependence, associated increased dopaminergic activity, withdrawal syndrome and it does induce animals to self-administer the drug.
In humans, it is believed that chronic cannabis use, especially in adolescents, leads to addiction or addictive behaviors. Approximately 9% of all users in the US, one-fifth of whom began using as adolescents, have cannabis use disorder[11]. It is defined by the DMS-5[12] problematic use with significant impairment occurring within a 12-month period.
CBD is the other major cannabinoid in cannabis; however, it is nonintoxicating. In part, this may be related to the fact that it does not have an affinity for the CB1 receptors, and it may actually be a negative allosteric modulator for the CB1 receptor[13] weakening the binding of THC and thus making THC’s psychoactive effects much less, depending on the CBD concentration and ratio compared to THC.
CBD has some anxiolytic properties which are proposed to be due to its 5HT 1A (serotonin) agonist activity but is not considered hedonic on its own in human or animal studies[14], which is why it is proposed to not have abuse liability. Additionally, while not fully understood, it is proposed that CBD’s influence on both opioid and dopamine receptors, which play a role in our brain’s motivation and reward system, may lessen drug cravings and withdrawal symptoms in addiction of other substances[15]. Human studies [16] have shown it may actually help with addiction and withdrawal symptoms even in cannabis use disorder. And animal studies[17] have shown that topical CBD can attenuate the self-administration of cocaine and alcohol in relapsed-stressed rats.
To answer the initial question of which component of cannabis has an abuse potential/liability, in my opinion, it is THC not CBD. But having practiced for so many years treating addicts of all kinds, my opinion is that the majority of those who have dangerous addictions are not those with cannabis use disorder. In fact, this disorder was only recently added to the DSM-5[18] which, combined from DSM-4 the two separate entities of substance abuse (with its negative social context) and substance dependence (with it physiological and psychological context).
Additionally, as a physician it was always difficult to even assess much of the available research because as a schedule 1 drug, the federal government and NIDA are biased and have historically only funded research for cannabis that showed harm, so even while writing this paper, you have to take what you are reading with the proverbial grain of salt.
When comparing withdrawal symptoms of cannabis use disorder, most agree that opioid and cocaine withdrawal is much worse than cannabis and is a bigger issue with regards to relapse, while alcohol and benzodiazepine withdrawal can be fatal if not properly treated. Cannabis use disorder is not associated with deaths from overdoses like we have seen, every day with the opioid crisis. Yes, of course, we need to keep cannabis out of the hands of minors and adolescents, and we need to make sure that just like with alcohol no one is driving while under the influence. And while using cannabinoids for addiction treatment is intriguing, we do need more research, as there is some conflicting evidence on whether it is actually reducing opioids deaths in states that have legalized it[19] [20].
In my medical cannabis practice today, while long-term use may cause some dependence, I am not seeing lives ruined as they have been with opioids, cocaine, methamphetamines, or alcohol, nor have I seen the physical carnage that tobacco addiction has caused. And my colleagues in states where recreational cannabis is also legal have said the same things to me too.
[1] National Institute on Drug Abuse. The Science of Drug Use and Addiction the Basics. Published July 2, 2018. https://www.drugabuse.gov/publications/media-guide/science-drug-use-addiction-basics. Accessed December 5, 2019.
[2] Zehra A., Burns J., Lui C., Manza P., Wiers C., Volkow N., Wang G., Cannabis Addiction and the Brain: A Review. Journal of Neuroimmune Pharmacology. 2018; 13: 438-452.
[3] Koob G., Volkow N., Neurobiology of Addiction. Lancet Psychiatry. 2016; 3: 760-773.
[4] Solinas M., Belujon P., et. al. Dopamine and Addiction: What We Have Learned From 40 Years of Research. Journal of Neural Transmission. 2019; 126(4): 481-516.
[5] Wenzel J., Cheers J., Endocannabinoid Regulation of Reward and Reinforcement Through Interaction with Dopamine and Endogenous Opioid Signaling. Neuropsychopharmacology Reviews. 2018; 43: 103-115.
[6] Patel J., Marwaha R., Cannabis Use Disorder. Stat Pearls. Updated June 5, 2019. https://www.ncbi.nlm.nih.gov/books/NBK538131/. Accessed December 5, 2019.
[7] Oleson E., Cheer J., A Brain on Cannabinoids: The Role of Dopamine Release in Reward Seeking. Cold Spring Harbor Perspectives in Medicine. Published August 1, 2012. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3405830/. Accessed December 5, 2019.
[8] ElSohly M., Mehmedic Z., Foster S., Gon C., Chandra S., Church J., Changes in Cannabis Potency Over the Last 2 Decades (1995-2014): Analysis of Current Data in the US. Biological Psychiatry. 2016; 79(7): 613-619
[9] White J., Abuse and Dependence Potential of Cannabis Sativa and Nabiximols. 38th Expert Committee on Drug Dependence. Updated2016. https://www.who.int/medicines/access/controlled-substances/Abuse_and_dependence_potential.pdf?ua=1. Accessed December 5, 2019.
[10] Lupica C., Riegel A., Hoffman A., Marijuana and Cannabinoid Regulation of Brain Reward Circuits. British Journal of Pharmacology. 2004; 143(2): 227-234.
[11] Volkow, N., Baler R., Compton W., Weiss S., Adverse Health Effects of Marijuana Use. New England Journal of Medicine. 2014; 370 (23): 2219-2227.
[12] Patel J., Marwaha R., Cannabis Use Disorder. Stat Pearls. Updated June 5, 2019. https://www.ncbi.nlm.nih.gov/books/NBK538131/. Accessed December 5, 2019.
[13] Laprarie R., Bagher A., Kelly M., Denovan-Wright E., Cannabidiol is a negative Allosteric Modulator of the Cannibinoid CB1 Receptor. British Journal of Pharmacology. 2015; 172(20): 4790-4805.
[14] Prud’homme M., Cata R., Justras-aswad D., Cannabidiol as an Intervention for Addictive Behaviors: A Systematic Review of Evidence. Substance Abuse. 2015; 9: 33-38.
[15] Jikomes N., CBD : What Does it Do and How Does it affect the brain and Body. Leafly. Published October 10, 2109. https://www.leafly.com/news/cbd/what-does-cbd-do. Accessed December5, 2019.
[16] Prud’homme M., Cata R., Justras-aswad D., Cannabidiol as an Intervention for Addictive Behaviors: A Systematic Review of Evidence. Substance Abuse. 2015; 9: 33-38.
[17]Gonzalez-CuevasG., Weiss F., et. al. Unique Treatment Potential of Cannabidiol for the Prevention of Relapse to Drug Use: Preclinical Proof of Principle. Neuropsychopharmacology. 2018; 43(10): 2036-2045.
[18] Hasin D., Grant B., et. al. DSM-5 Criteria for Substance Use Disorder: Recommendations and Rationale. American Journal of Psychiatry. 2013; 170(8): 834-851.
[19] Bachhuber M., Saloner B., CunninghamC., Medical Cannabis Laws and Opioid Overdose Mortality in United States, 1999-2010. The Journal of the American Medical Association. 2014; 174(10): 1668-1673.
[20] Shover C., Gordon S., Humphreys K., Association Between Medical Cannabis Laws and Opioid Overdose Mortality Has reversed Over Time. Proceeding of the National Academy of Sciences. 2019; 116(26): 12624-12626.
