New insights into cannabis dependence


A common variation in a human gene that affects the brain’s reward processing circuit increases vulnerability to the rewarding effects of the main psychoactive ingredient of cannabis in adolescent females, but not males, according to preclinical research by Weill Cornell Medicine investigators.

As adolescence represents a highly sensitive period of brain development with the highest risk for initiating cannabis use, these findings in mice have important implications for understanding the influence of genetics on cannabis dependence in humans.

The brain’s endocannabinoid system regulates activity of cannabinoids that are normally produced by the body to influence brain development and regulate mood, as well as those from external sources, such as the psychoactive ingredient THC, also known as Δ9-tetrahydrocannabinol, which is found in cannabis.

An enzyme called fatty acid amide hydrolase (FAAH) breaks down a cannabinoid called anandamide that is naturally found in the brain and is most closely related to THC, helping to remove it from circulation.

In the study, published Feb. 12 in Science Advances, the investigators examined mice harboring a human gene variant that causes FAAH to degrade more easily, increasing overall anandamide levels in the brain.

They discovered that the variant resulted in an overactive reward circuit in female–but not male adolescent mice–that resulted in higher preference for THC in females.

Previous clinical studies linked this FAAH variant with increased risk for problem drug use, but no studies had specifically looked at the mechanistic effect on cannabis dependence.

“Our study shows that a variant in the FAAH gene, which is found in about one-third of people, increases vulnerability to THC in females and has large-scale impact on brain regions and pathways responsible for processing reward,” said lead author Dr. Caitlin Burgdorf, a recent doctoral graduate from the Weill Cornell Graduate School of Medical Sciences.

“Our findings suggest that genetics can be a contributing factor for increased susceptibility to cannabis dependence in select populations.”

The team found that female mice with the FAAH variant showed an increased preference for the environment in which they’d been exposed to THC over a neutral environment when they were exposed to the substance during adolescence, and the effect persisted into adulthood.

However, if female mice with this variant were exposed to THC for the first time in adulthood, there was no increased preference for THC.

These findings in mice parallel observations in humans that a select population of females are more sensitive to the effects of cannabis and demonstrate a quicker progression to cannabis dependence.

“Our findings suggest that we have discovered a genetic factor to potentially identify subjects at risk for cannabis dependence,” said Dr. Burgdorf.

The investigators also found that the genetic variant led to increased neuronal connections and neural activity between two regions of the brain heavily implicated in reward behavior. Next, the team reversed the overactive reward circuit in female mice and found that decreasing circuit activity dampened the rewarding effects of THC.

As substance abuse disorders often emerge during adolescence, the investigators say this study has significant implications for translating these findings to inform developmental and genetic risk factors for human cannabis dependence.

“Our study provides new insights into cannabis dependence and provides us with a circuit and molecular framework to further explore the mechanisms of cannabis dependence,” said co-senior author Dr. Anjali Rajadhyaksha, professor of neuroscience in pediatrics and associate professor of neuroscience in the Feil Family Brain and Mind Research Institute and a member of the Drukier Institute for Children’s Health at Weill Cornell Medicine.

The brain’s endocannabinoid system regulates activity of cannabinoids that are normally produced by the body to influence brain development and regulate mood, as well as those from external sources, such as the psychoactive ingredient THC, also known as Δ9-tetrahydrocannabinol, which is found in cannabis.

Although genetic factors are increasingly found to be associated with risk for other types of addiction, very few studies have investigated genetic factors associated with increasing risk for cannabis dependence.

“In the future, we could use the presence of this FAAH genetic variant to potentially predict if an individual is more likely to be vulnerable to cannabis dependence,” said co-senior author, Dr. Francis Lee, chair of the Department of Psychiatry at Weill Cornell Medicine and psychiatrist-in-chief at NewYork-Presbyterian/Weill Cornell Medical Center.

“We are getting one step closer to understanding exactly how neurodevelopmental and genetic factors play interrelated roles to increase susceptibility for cannabis dependence.”

Additional authors on the study were Dr. Deqiang Jing, Ruirong Yang and Chienchum Huang from the Department of Psychiatry at Weill Cornell Medicine; Drs. Teresa A. Milner and Dr. Virginia M. Pickel from the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine; Dr. Matthew N. Hill from departments of Cell Biology and Anatomy and Psychiatry at University of Calgary; and Dr. Ken Mackie from the Department of Psychological and Brain Sciences at Indiana University Bloomington.

Funding: This research was supported by the National Institute of Health (Grants T32DA039080, R01DA08259, R01HL098351, R01HL136520, R01DA042943, R01NS052819, R01DA029122), Weill Cornell’s Mowrer Memorial Graduate Student Fellowship, NewYork-Presbyteri

Cannabis: mechanistic considerations

Cannabis contains a number of chemically active compounds, including cannabinoids, terpenoids, flavonoids, and alkaloids.29

The most active constituent is the cannabinoid, THC, which is responsible for the well-characterized psychotropic effects associated with cannabis use.

There are, however, over 100 other active cannabinoids that have been identified, each which modulates one or more components of the body’s ECS.30 

A basic knowledge of the ECS is essential to understand how cannabis may be beneficial in patients with IBD.

The ECS consists of cannabinoid receptors, endogenous ligands for these receptors, and the enzymes for their synthesis and degradation.17,30 T

he human body naturally produces endocannbinoids, which are lipid-mediators that bind to cannabinoid receptors, found throughout the body (Figure 1).

This complex system is involved in regulating a number of cognitive and physiological processes in the central nervous system including pain, mood, appetite, stress, and memory.17,31,32 

In addition, the ECS regulates physiological processes outside of the brain, including those in the heart, gastrointestinal tract, reproductive system, and bone, to name a few.3337 Physiological and pharmacological studies have demonstrated the ECS is widely distributed throughout the gastrointestinal tract, and is involved in regulation of food intake, emesis, gastric secretion, gastric and intestinal motility, visceral sensation, and intestinal inflammation.38

The cannabinoids found in cannabis (phytocannabinoids) act as exogenous ligands for several of the receptors of the ECS.29 Several synthetic cannabinoids structurally analogous to the endocannabinoids have also been developed, and these share a similar biological action.

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Object name is 10.1177_1756284819870977-fig1.jpg
A schematic representation of the sites of action of cannabis (depicted by the cannabis leaf) in the brain gut axis. Cannabis acts predominantly on CB1 in the brain and the enteric nervous system of the gastrointestinal tract. CB2 receptors, located on immune cells, are also sites of action of cannabis, and these cells will be increased in states of inflammation. CB1 receptors may also regulate gut barrier function at the level of the epithelium. Visceral pain is regulated by CB1 receptors on spinal primary afferents and in the spinal cord. Nausea and vomiting is regulated by CB1 and possibly CB2 receptors in the brainstem (vomiting) and the insular cortex (nausea). Adapted from Maccarrone and colleagues.39

The two primary endocannabinoid receptors that have been isolated are the G-protein coupled cannabinoid receptors CB1 and CB2.40CB1 receptors are located primarily on neural tissue including central and peripheral neurons as well as the enteric nervous system (Figure 1).41 

CB2 receptors are also expressed in the central nervous system, although most are located in immune tissues, including neutrophils, macrophages, epithelial cells, and subsets of T and B cells.41,42 In general, CB1 signaling mediates neuromodulatory function, while CB2 signaling mediates immunomodulatory activity.

CB1 receptors are important in the control of gastrointestinal motility and gastric intestinal secretion.37,43 CB1 receptor agonists were shown to reduce gastrointestinal propulsion and transit in animal models.44,45 

Although the action on secretory function has been less studied, one study did demonstrate that gastric acid secretion was reduced with CB1 activation.46 This suggests a therapeutic potential for the treatment of diarrhea in patients with IBD.

CB1 receptor activation has also been demonstrated to increase appetite, and to promote food intake and energy conservation.47

Several in vitro studies have demonstrated the importance of both the CB1 and CB2 in modulating intestinal inflammation. CB1 and CB2 receptor agonists reduced experimentally induced intestinal inflammation in several murine studies, whereas antagonists were shown to exacerbate inflammation.4850 

The ECS was physiologically involved in protecting against excessive colonic inflammation with activation of these receptors, dampening smooth muscle irritation and controlling cellular pathways involved in inflammatory responses.50 

Activation of the CB1 and CB2 receptors was also demonstrated to reduce visceral sensitivity and pain associated with colonic distention in animal models.5153

In addition to CB1 and CB2, other molecular targets for the cannabinoids have been identified, including the G-protein coupled receptors 18, 55, and 119 (GRP55 and GRP119); the peroxisome proliferator-activated receptor (PPAR); the serotonin-1A receptor (5-HT1A); and the transient receptor potential vanilloid 1 (TRPV1.)38,5456 

The administration of cannabis, through its interaction with the various receptors of the ECS, modulates the gastrointestinal system by increasing appetite and reducing nausea, gastric secretions, intestinal contractility, peristalsis, visceral sensation as well as intestinal inflammation (Figure 1).38

Cannabis use in patients with IBD

Patients with IBD often turn to complementary medications, including various forms of cannabis, to combat symptoms related to their disease.

Patients have reported using cannabis to relieve symptoms of abdominal pain, nausea, diarrhea, anorexia, as well as to improve mood and quality of life.5759 

In an anonymous questionnaire-based study, IBD patients reported that cannabis improved abdominal pain (83.9%), abdominal cramping (76.8%), joint pain (48.2%), and, to a lesser extent, diarrhea (28.6%).57

Large epidemiological studies to determine the proportion of people with IBD that use cannabis have been difficult to perform due to the legalities associated with cannabis use. Several patient-reported studies indicate that between 6.8 and 17.6% of IBD patients actively use cannabis.27,5760

A Spanish study demonstrated that 10% of IBD patients used cannabis; however, only one-third of these patients informed their physician about active use.27 A larger internet based survey of 1666 IBD patients across the United States reported that only 12.8% had discussed use with their physician.61

A Canadian study performed in 2011 evaluated 291 patients with IBD and found that 11.6% with UC and 16% with CD were active users,58 with 51% of patients with UC and 48% of patients with CD reporting cannabis use during their lifetime.

In this latter study, patients with a history of abdominal surgery, chronic analgesic use, and complementary medicine use were more likely to use cannabis for symptom relief.

A large population-based study explored the patterns of cannabis use in patients with IBD.60 They demonstrated that patients with IBD were more likely to have used cannabis as compared with non-IBD controls.60 Patients with IBD also had an earlier age of onset of cannabis use (15.7 years versus 19.6 years).

There does appear to be a high rate of cannabis use among younger patients with IBD, with a study in a pediatric IBD clinic (18–21 years of age) reporting that 70% of 53 patients surveyed were current or past marijuana users.62

Weill Cornell Medicine


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