How THC Affects the Dopamine System

The use of cannabis for medicinal purpose goes back several centuries. Ancient physicians prescribed the herb for the relief of a number of pain conditions, from earache to childbirth.

By the late 18th century, early editions of American medical journals recommend cannabis seeds and roots for the treatment of inflamed skin, incontinence and venereal disease, and later cannabis, widely used to ease the pain of rheumatism, was helpful against discomfort and nausea in cases of rabies, cholera and tetanus.

However, by the end of the 19th century, attitudes towards cannabis as a useful medicinal plant changed when an increasing number of the US population developed an addiction to morphine, then widely used as a medicinal product.¹

The Controlled Substances Act of 1970 classified cannabis and its derivatives in schedule I, reserved for drugs with a high potential for abuse and no medical use.² Currently the cultivation, possession, and/or use of cannabis for recreational purpose is illegal under U.S. federal law.³

Because of the current laws governing cannabis, its use as a pain-reliever is highly restricted. In 1996, California became the first state to legalize medical use of marijuana.⁴ A wave of states have followed suite, and currently, medicinal use of cannabis is legal in 28 US states, including Washington, DC.

The push to end prohibition of cannabis use has gathered momentum, and 17 of the 28 states in which cannabis is legal for medicinal use were legalized between 2010 and 2016. Overall, 46 states allow some form of medicinal marijuana or decriminalization.³ 

One of the consequences of the increasing relaxation of the laws governing cannabis use, albeit for medicinal purposes, is the risk of increasing relaxation of its recreational use. Currently, only 4 states have legalized recreational marijuana use for adults 21 years of age and older.⁵

However, it has been reported that half of the young people in the US, including adolescents have used cannabis for recreational purpose, and continued relaxation of the laws is likely to increase this number. In fact in Europe, cannabis has superseded heroin as the recreational drug of choice.⁶

Although the medicinal effects of cannabis have been known for centuries, its impact on health (eg, on cognition and psychophysiology), while well documented, are poorly understood.^7-10 Extensive cannabis use is known to be associated with increased risk of mental disorders, including psychosis, addiction, depression, suicidality, cognitive impairment, and amotivation.⁶

In the current review, the authors present evidence indicating that Δ⁹-tetrahydrocannabinol (THC) is the main psychoactive ingredient in cannabis, and that the acute psychoactive effects of THC is elicited through the endocannabinoid type 1 receptor (CB₁), and partially through the type 2 receptor (CB₂).⁶

Cannabis appears to elicit some of its undesirable effects by modulating the dopamine (DA) system. Studies in animals and human subjects using functional magnetic resonance imaging and positron emission tomography suggest that acute THC exposure generally increases DA synthesis and neuronal activity in the brain, and causes morphological changes in DA neurons. 

Repeated exposure to THC or chronic cannabis use leads to blunting of DA synthesis and release, and reduction of DA transporter density.^6,11

Human studies involving chronic cannabis users can be difficult to interpret due to the confounding effects from chronic tobacco and alcohol use. However, a recent study demonstrated that when the confounding effects from comorbid substance dependence are absent, chronic cannabis users have lower levels of DA release.¹²

These complex effects of THC raise concerns for the well-being and mental health of the increasing number of young Americans who use cannabis and its synthetic analogues as their recreational drug of choice.

Animal and human studies have also shown that THC exposure in utero leads to reduced levels of proteins involved in brain function, as well as reduced DA release. This observation poses some concerns, as THC intake in users is on the rise, with increases in the THC content of cannabis, the appearance of potent synthetic THC analogues, and increasing consumption of cannabis through e-cigarettes and edible products.

The effects of THC on DA production and neuronal function, as well as its potential to change the morphology of the DA neurons, represents a significant concern, particularly when it is consumed during adolescence, a critical period for brain developmental. These effects may negatively impact adulthood, potentially increasing the risk of long-term addiction, poor education and occupational potential.

More research is needed to better understand the complexity of the THC-DA system interaction, the differences between acute and chronic exposure, and the reversibility of those effects.

Summary and Clinical Applicability

While the health impact of chronic cannabis use has been well documented, recent evidence shows that THC, the main psychoactive component of cannabis, has an impact on the morphology, production and function of the brain DA system.

In adolescent users, these effects take place during important stages of brain development, and may have long-term impact. 

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References

1. Stack P. Suddath C. Brief History of Medicinal Marijuana. Published online Wednesday, Oct. 21, 2009. Accessed November 26, 2016.
2. Eddy M. Medical Marijuana: Review and Analysis of Federal and State Policies. Published online April 2, 2010. Accessed November 26, 2016.
3. Smith DE. Marijuana: A Fifty-Year Personal Addiction Medicine Perspective. J Psychoactive Drugs. 2016;48(1):3-10. 
4. ProCon.Org. 28 Legal Medical Marijuana States and DC. Last updated on: 11/9/2016.
5. Estoup AC1, Moise-Campbell C1, Varma M1, Stewart DG1. The Impact of Marijuana Legalization on Adolescent Use, Consequences, and Perceived Risk. Subst Use Misuse. 2016;51(14):1881-1887.
6. Bloomfield MA, Ashok AH, Volkow ND, Howes OD. The effects of Δ9-tetrahydrocannabinol on the DA system. Nature. 2016;539(7629):369-377.
7. Feeney KE, Kampman KM. Adverse effects of marijuana use. Linacre Q. 2016;83(2):174-178.
8. Phillips JG, Ogeil RP. Cannabis, alcohol use, psychological distress, and decision-making style. J Clin Exp Neuropsychol. 2016 Nov 23:1-13. [Epub ahead of print]
9. Palamar JJ, Fenstermaker M, Kamboukos D, Ompad DC, Cleland CM, Weitzman M. Adverse psychosocial outcomes associated with drug use among US high school seniors: a comparison of alcohol and marijuana. Am J Drug Alcohol Abuse. 2014;40(6):438-446. 
10. Sherif M, Radhakrishnan R, D’Souza DC, Ranganathan M. Human Laboratory Studies on Cannabinoids and Psychosis. Biol Psychiatry. 2016;79(7):526-538. 
11. Sami MB, Rabiner EA, Bhattacharyya S. Does cannabis affect DArgic signaling in the human brain? A systematic review of evidence to date. Eur Neuropsychopharmacol. 2015;25(8):1201-1224.
12. van de Giessen E, Weinstein JJ, Cassidy CM, et al. Deficits in striatal DA release in cannabis dependence. Mol Psychiatry. 2016 Mar 22. [Epub ahead of print]