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The Endocannabinoid System and Drug Addiction

The Endocannabinoid System and Drug Addiction

February 25, 2019

Drug addiction is a chronic relapse disorder for which very few effective treatments are available. In 2013, the National Institute on Drug Abuse estimated that nearly 23 million Americans needed treatment for drug and alcohol problems, but less than 1% received it [1].

The endocannabinoid system (ECS) has been identified as a potential target in the science of drug addiction because it plays a role in reward and motivation processes and effects [2]:


  • CB1 receptors are found in reward-centered areas of the brain (e.g., the dopaminergic mesolimbic system).
  • Activation of CB1 receptors stimulates dopaminergic neurotransmission.
  • Blockade of CB1 receptors reduces dopaminergic neurotransmission.
  • Levels of endocannabinoids change in response to reward processing.


It has been suggested that disposition toward addiction may be the result of a genetic mutation to the cannabinoid receptor 1 gene (CNR1) [3]. Stress may also promote drug-seeking behavior through its natural effects on the ECS, namely via corticosteroid-induced mobilization of 2-arachidonoylglycerol and subsequent CB1 attenuation of inhibitory transmission [4]. The endocannabinoid and opioid systems may have synaptic interactions and do have overlapping functions related to pain relief and pleasure enhancement [5].  The interplay of the ECS and drug addiction is not completely understood at the molecular level, but the neurobiological basis is significant.  

Reward pathways in the brain. Source: Arias-Carrión, Oscar, et al. (2010)


Modulating the ECS to Heal Drug Addiction


Managing ECS signaling may block the reinforcing effects of drugs like opioids, cocaine, and alcohol, and help prevent relapse [6]. CB1 receptor activation has shown some potential for opioid withdrawal, but use was limited by undesired psychoactive effects [7].


Chronic administration of CB1 receptor antagonists, on the other hand, has illustrated strong potential for morphine withdrawal [6]. Cannabinoid antagonists may also curb alcohol motivation and intake [8]. Cannabidiol (CBD), unlike tetrahydrocannabinol (THC), is a non-competitive receptor antagonist and may therefore have significant therapeutic potential in creating the blockade effect that dampens addictive tendencies. 

A 2018 study published in the Journal of Neuropsychopharmacology reported that rats with cocaine and alcohol dependency demonstrated a lack of drug-seeking behavior after CBD was administered at 24 hour intervals for 7 days. It also reduced anxiety and impulsivity. Five months after experiment completion, the rats were still wholly reinstated [9]. In 2019, Frontiers in Psychiatry declared that “early research supports CBD’s promise,” as a potential therapeutic agent for addiction, but that more research is needed [10].


For those suffering the consequences of drug addiction, modulating the ECS with cannabinoid antagonists like CBD offers hope and a ray of light in an otherwise bleak predicament.

  1. Nationwide Trends: Substance Dependence/Abuse and Treatment. National Institute on Drug Abuse, 2015.
  2. Solinas, M, et al. The Endocannabinoid System in Brain Reward Processes. British Journal of Pharmacology, 2009;154(2):369–83. doi:10.1038/bjp.2008.130
  3. López-Moreno, Jose Antonio, et al. The Genetic Basis of the Endocannabinoid System and Drug Addiction in Humans. Journal of Psychopharmacology, 2011: 26 (1):133–143. doi:10.1177/0269881111416689
  4. Mcreynolds, Jayme R., et al. Stress Promotes Drug Seeking Through Glucocorticoid-Dependent Endocannabinoid Mobilization in the Prelimbic Cortex. Biological Psychiatry, 2018;84(2):85–94. doi:10.1016/j.biopsych.2017.09.024
  5. Mitchell, Marci R., et al. Endocannabinoid-Enhanced ‘Liking’ in Nucleus Accumbens Shell Hedonic Hotspot Requires Endogenous Opioid Signals. Cannabis and Cannabinoid Research, 2018;3(1):166–70. doi:10.1089/can.2018.0021
  6. Parolaro, Daniela, et al. Role of Endocannabinoids in Regulating Drug Dependence. Neuropsychiatric Disease and Treatment, 2008;3:711–21. doi:10.2147/ndt.s976
  7. Lofwall, Michelle R., et al. Opioid Withdrawal Suppression Efficacy of Oral Dronabinol in Opioid Dependent Humans. Drug and Alcohol Dependence, 2016; 164:143–50. doi:10.1016/j.drugalcdep.2016.05.002
  8. Colombo, Giancarlo, et al. Endocannabinoid System and Alcohol Addiction: Pharmacological Studies. Pharmacology Biochemistry and Behavior, 2005; 81(2):369-80.
  9. Gonzalez-Cuevas, Gustavo, et al. Unique Treatment Potential of Cannabidiol for the Prevention of Relapse to Drug Use: Preclinical Proof of Principle. Neuropsychopharmacology, 2018;43(10):2036–45. doi:10.1038/s41386-018-0050-8.
  10. Chye, Yann, et al. The Endocannabinoid System and Cannabidiol’s Promise for the Treatment of Substance Use Disorder. Frontiers in Psychiatry, 2019. doi: 10.3389/fpsyt.2019.00063
  11. Arias-Carrión, Oscar, et al. Dopaminergic Reward System: a Short Integrative Review. International Archives of Medicine, 2010;3(1):24. doi:10.1186/1755-7682-3-24


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