A new study published in the Journal of Psychiatric Research (titled “Dual pharmacological inhibitor of endocannabinoid degrading enzymes reduces depressive-like behavior in female rats”) draws new light upon the potential link between endocannabinoids and Major Depressive Disorder. It draws a link within the brains of female patients. The potential significance of that link could be instrumental in treating those who suffer from this disorder.

An Overview of Major Depressive Disorder

MDD is a mood disorder that is primarily characterized by anhedonia (i.e., diminished interest or loss of pleasure in activities that were once pleasurable) or depressed mood. As outlined by the latest edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), a proper diagnosis of MDD must involve at least five of nine symptoms outlined by the criteria, with at least one of the symptoms involving either anhedonia or depressed mood. These symptoms must occur throughout at least two consecutive weeks.

Approximately 15% of people throughout the world will have experienced at least one incidence of MDD throughout their lifetime.1 In the US, the rate of MDD within the population has been quoted as high as 25%.2,3,4 Most who experience their first episode of MDD will do so in their 20s.2,3,4 Women are more commonly affected than men.1

The exact pathophysiology in regards to the origin and onset of MDD, has not yet been firmly rooted. However, it is understood to be multifactorial, involving both biological and psychological factors. A reduction in neurotransmitters (signal-transmitting cells existing throughout the human body), in particular, serotonin, noradrenaline, and dopamine have been linked to the pathophysiological basis of MDD.

In a similar respect to its pathophysiology, the treatment of depression is also multifactorial. This means that it involves pharmaceutical management, psychotherapy, and adherence to lifestyle changes. When addressing the potential reduction in neurotransmitters, pharmaceuticals that target these transmitters are commonly utilized in those who suffer from MDD. The most widely prescribed, entry-level class of pharmaceuticals for MDD are “Selective Serotonin Reuptake Inhibitors,” or SSRIs.

The Study

Finding its origins through examining the efficacy of current pharmaceuticals commonly prescribed to those with MDD, this study was in-part birthed from data, which suggests that many common antidepressants prescribed today are therapeutically inadequate. Therefore, this study sought to examine new therapeutic targets that could potentially be of greater efficacy to those afflicted with MDD. Due to the existing disparity of understanding in the neurobiology of depression in women compared to men, this study focused on the relationship between endocannabinoids and depressive behavior in females.


This study hypothesized that endocannabinoid levels in MDD patients would be lower in an area of the brain called the ventral striata. Therefore, the elevation of these endocannabinoids could reduce depressive-behavior.

The significance of the ventral striata is of note because the nucleus accumbens, which exists within the striata, has been proven to have substantial involvement within the reward and motivation systems in our body. Therefore, dysfunction within the striata, in particular regards to the nucleus accumbens, would thereby be associated with any behavioral deficit in reward and motivation, as may be seen in someone with MDD.


There were two focal points of interest to be examined in this study. The first was to assess the level of two endocannabinoids: N-arachidonoyl ethanolamide (AEA) & 2-arachidonoyl glycerol (2-AG) and another protein called Brain-Derived Neurotrophic Factor (BDNF) during a postmortem examination of the brains of human females.

The second point of interest involved using a particular type of rat as an animal model to assess the potential efficacy of an experimental class of antidepressant drugs developed to address the pathophysiological point-of-interest described in the study hypothesis. The Wistar Kyoto (WKY) rat is a type of rat used in the past to study the pathophysiology of depressive behavior, and so was used in this study. AEA and 2-AG endocannabinoid levels were also analyzed in the WKY rats. The rats selected for this study were also female.

There are enzymes throughout our body, which catalyze reactions that involve “substrates” and “products.” When an enzyme catalyzes a substrate, a product is formed. However, the initial substrate is depleted as a result.

Lock and key model. Degradation. metabolic processes. enzyme-substrate complex, substrate, product and active site. vector diagram for medical, educational and scientific use

In particular reference to this study, the enzymes that catalyze endocannabinoids are Fatty Acid Amide Hydrolase (FAAH) & Monoacyl Glycerol Lipase (MAGL). In theory, the pharmacological inhibition of FAAH and MAGL should lead to increased endocannabinoid levels through decreased degradation. The depressive behavior of female WKY rats was assessed in response to the administration of a pharmacological inhibitor of both FAAH and MAGL named “JZL195.”

enzyme inhibitor is a molecule that binds (blocking) to an enzyme and decreases its activity. competitive inhibition. vector diagram for medical, educational and scientific use
Notice how inhibition of the active site of an enzyme leads to decreased degradation of the substrate, leading to an increase in its availability throughout the body.


Lower levels of endocannabinoids and BDNF were found in the ventral striata of both human females with MDD and WKY rats. It was observed that after exposure to JZL195, the levels of endocannabinoids and BDNF levels in the ventral striatum had increased. Consequently, it was also found that after the administration of this drug, the depressive behavior in the female WKY rats had been reduced.


From the findings of this study, we can surmise that decreased levels of endocannabinoid and BDNF signaling in the ventral striatum has a correlation with depressive behavior and by extension, major depressive disorder. And as evidenced by the improvement in depressive behavior in female WKY rats upon exposure to pharmaceutical agent JZL195, we can conclude potential merit in using agents that enhance the levels of endocannabinoids within the body as a potential application in the management of depression.

Limitations and Conflicts of Interest

Although there are certain limitations of note regarding discrepancies in data collection and standardization within this study, these discrepancies are of minor significance when concerning the ability to present a very well planned and executed journal study on the particular topic of interest explored by the authors.

All of the information was tediously accounted for by the authors. They made an impressive effort to reduce false correlations, misleading data, or biases in their work.

This drawback merely lies within the premise of the study itself and its approach to the highly nebulous nature of clinical depression and our understanding of it. Depression is a disease that arises through a multitude of potential causes, and so, therefore, involves a multifactorial approach to treatment. Although studies like this are essential in adding to the depth of knowledge we have about specific conditions, there needs to be further research to determine if endocannabinoid deficiency is something inherent to people who have depression. Endocannabinoids are elevated during exercise and other activities that trigger a “reward” response in the brain. So one must question the notion of developing another pharmaceutical agent that can increase the levels of certain chemicals that are endogenous to the body.

Essentially, this is how most pharmaceuticals currently available for the treatment of depression act on the body. They work by decreasing the breakdown of other chemicals (serotonin, monoamine oxidase, norepinephrine), thereby increasing their availability. It is interesting to note that the authors themselves were driven to conduct this study partially based on their interpretation of data that suggests that the current pharmaceuticals available for MDD are ineffective. People who suffer from MDD may have lower levels of serotonin and norepinephrine. From this study, it is suggested that endocannabinoids also may undoubtedly be deficient. However, if we look at one of the initial driving motives for this study, the ineffective pharmaceutical treatment for MDD, we must ask if it is the pharmaceuticals themselves, and our dependency to quickly prescribe them. This poses the question if depression is, in fact, a multifactorial condition that therefore requires a holistic approach to treatment.

Although lab rats and other animals have been used in the past to help understand the pathophysiology of human conditions and conduct research on pharmaceutical agents, after extreme vetting, they reached their way into the standards of human treatment. In this particular instance, the use of a lab rat, even one that has been genetically modified to aid in the understanding of depression, is potentially problematic. Because depression is such a complex disease, one could question our ability to truly understand it through an animal model.

Final Thoughts

It is vital to play the role of “devil’s advocate” when reading the latest literature. We do this so we can find ways in which we can improve our techniques and expand upon our current knowledge. This study has provided us with a very valid suggestion that may push us towards a future in which endocannabinoids may be targeted more closely in those who suffer from MDD.

Because depression is a multifactorial disease, studies like this are essential in determining what those factors may potentially be, so we have the best set of knowledge in front of us when we decide how to treat them.


  1. Dong, Bin, et al. “Dual Pharmacological Inhibitor of Endocannabinoid Degrading Enzymes Reduces Depressive-like Behavior in Female Rats.” Journal of Psychiatric Research, vol. 120, 1 Jan. 2020, pp. 103–112., doi:10.1016/j.jpsychires.2019.10.010.
  2. Kessler RC, Berglund P, Demler O. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005; 62(6): pp. 593–602. doi: 10.1001/archpsyc.62.6.593
  3. Ganti L, Kaufman, MS, Blitzstein SM. First Aid for the Psychiatry Clerkship. McGraw Hill Professional; 2016: p. 36.
  4. Le T, Bhushan V, Chen V, King M. First Aid for the USMLE Step 2 CK. McGraw-Hill Education; 2015: p. 432.
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