Deep Dive: The Endocannabinoid System and Depression

Updated: Oct 20

This 1650-word Higher Learning LV Deep Dive is provided at no cost until November 15.

A December 2021 research study entitled "Reviewing the Role of the Endocannabinoid System in the Pathophysiology of Depression" that was published in the journal Frontiers in Pharmacology summarized existing literature and prior studies regarding "the role of the endocannabinoid system in depression" with the goal of including this information in "a holistic picture for a better understanding of the relationship between the two."

"The present review aims to provide a concise overview of the existing knowledge on the endocannabinoid system and its influence on the development of [depression]," declared the study.

Understanding Major Depressive Disorder

According to the Mayo Clinic, Major Depressive Disorder (MDD) is a mood condition that causes "a persistent feeling of sadness and loss of interest." Also called clinical depression, it affects how sufferers "feel, think, and behave and can lead to a variety of emotional and physical problems." The famous clinic explained that MDD patients are sometimes plagued by hopelessness and that day-to-day activities may become challenging. "Sometimes [patients] may feel as if life isn't worth living."

It described how major depressive disorder is more than "just a bout of the blues" and that it is not a weakness on the part of the sufferer. "Depression may require long-term treatment," noted the clinic.

Depression Statistics

The U.S. National Institute of Mental Health reports that MDD is "one of the most common mental disorders in the United States." The institute explained that it may manifest in some individuals as "severe impairments that interfere with or limit one's ability to carry out major life activities."

"According to the World Health Organization, between 264 and 322 million people suffer major depression globally."

It reported that, among U.S. adults 18 and older, roughly 21 million (nine percent of the adult population) experienced "at least one major depressive episode." The institute notes that MDD is more prevalent among adult females (11 percent of whom experience it) compared to males (six percent). Depression is most common among young adults, where it afflicts 17 percent of those 18 to 25. It is also common among those who "report having multiple (two or more) races," where it is suffered by 16 percent.

The present study reported that, according to the World Health Organization, between 264 and 322 million people suffer major depression globally (2018 data). It is roughly twice as common in females as in males, but the underlying cause of this gender gap is unknown.

The Study

The study defined MDD as "the most common mood disorder" and that it is characterized by "the loss of interest or pleasure in activities, unjustified feelings of worthlessness, and presence of depressed mood or aversion to activity."

The study's authors reported that untreated MDD "is the leading cause of suicide." "On this basis, the impact of MDD in society should not be dismissed," noted the scientists. The most common treatment for this common mental disease is antidepressant pharmaceutical drugs "combined with psychiatric or psychological treatment." The study reported the relatively poor results obtained from these conventional treatments, noting that "less than 50 percent of patients accomplish full remission after the first pharmacological treatment."

"Less than 50 percent of patients accomplish full remission of depression after pharmacological treatment."

"Although this field of research is relatively novel, there exist millennia-old reports about the use of the Cannabis Sativa plant as a medicinal herb to treat conditions like anxiety and mania," reported the research.

Cannabis Common for Depression

The study noted that prior research revealed that depression is the third most common reason reported for the use of medical cannabis and that those who did so experienced an 86 percent reduction in their MDD symptoms.

The research reported that cannabinoid-based medications are currently being investigated in clinical trials involving human test subjects, but that current "evidence on the use of these substances is scarce and future research is needed."

Endocannabinoid System Explained

The study reported that the endocannabinoid system is present in not only humans, but "most vertebrates" and that it appears to either influence or control major bodily functions such as mood, appetite, sleep, pain, various cognitive functions (including memory), sex drive and reproduction, and even immune function. Unfortunately, much is unknown about the ECS due to the fact that it was discovered only as recently as the early 1990s by Israeli researchers involving Dr. Raphael Mechoulam.

The researchers explained that the ECS and its specialized microscopic cellular receptors populate two areas of the body, the brain and central nervous system (CNS) and what medical professionals call "the periphery," meaning any part of the body outside of the brain and CNS. Both zones feature the two major types of cellular receptors of the ECS, CB1 and CB2. However, the CB1 variety is more dense in the brain and CNS while the CB2 type is most common in the periphery. That said, CB2 receptors have been shown to appear in the brain and CNS and CB1 are found throughout the periphery.

"The ECS appears to influence and control major bodily functions such as mood, appetite, sleep, pain, cognitive function and memory), sex drive and reproduction, and even immune function."

But the ECS and its network of cellular receptors are only half of the picture. This special system also is responsible for producing specialized chemical compounds called endocannabinoids that help orchestrate the ECS's management of the bodily functions mentioned above, including sleep, appetite, and pain. Called anandamide (AEA) and 2-arachidonoylglycerol (2-AG), these molecules are manufactured on-demand by the body under a variety of circumstances, including stress, when the body is suffering pain, and when a disease or disorder is present.

In fact, endocannabinoids have been revealed to be the true cause of the phenomenon of runner's high (not the endogenous opioid endorphin) during which those indulging in sustained or intense exercise experience psychoactive effects (similar to those delivered by delta-9 and delta-8 tetrahydrocannabinol (THC) from the cannabis plant). To learn more about this topic, see the Higher Learning LV article Runner's High Results from Endocannabinoids.

Interestingly, cannabis-deprived THC and cannabidiol (CBD) from hemp have been shown to mimic 2-AG and anandamide within the endocannabinoid system, binding with the same CB1 and CB2 receptors (including a list of other receptor types) and producing many of the same effects (including anandamide's role in runner's high and the infamous psychoactivity delivered by THC).

Cognitive Deficits & The ECS

The study reported that "the proper interplay between all the elements of the ECS is essential for the homeostatic maintenance of a number of physiological, cognitive, behavioral, and emotional processes." Therefore, theorized the study's authors, dysregulation of the ECS (something called a lack of homeostasis) may lead to "cognitive deficits."

Research involving animals "has established a clear symptomatic overlap between ECS alterations and depression."

The research explained that research involving animals "has established a clear symptomatic overlap between ECS alterations and MDD" and that this dynamic has also been witnessed in humans. It reported that female patients diagnosed with depression "presented altered endocannabinoid levels in serum compared to healthy participants." The study summarized that the existing scientific evidence indicates "a clear role of the ECS in the pathophysiology of MDD in humans" and that the CB1 receptors may play a special role.


The study reported with certainty that "the correct functioning of the ECS is imperative for maintaining mental health," but noted that additional preclinical and clinical studies are "crucial for a better understanding of its mechanisms."

It noted that the functionality of the ECS and its role in mood and cognitive functions is extremely complex and that this complexity "deeply challenges the development of cannabinoid-based therapies" for the treatment of conditions such as MDD.

Focus on CBD

The scientists made special note of the hemp-derived phytocannabinoid CBD. They reported that it has been shown to exert "neuroprotective and anti-inflammatory effects." Unlike traditional pharmaceutical drugs that typically target a single type of receptor, CBD has been shown to target 65 "molecular targets across the body."

They noted that consumers are using CBD for "multiple psychiatric conditions," including anxiety and depression, as well as non-psychiatric issues such as pain and sleep disorders. The study reported that research to date has indicated that CBD features an acceptable safety profile, meaning that it is well tolerated and non-addictive.

ECS Involved in MDD Causal Channels

The study reported that the mechanisms causing depression are complex, nuanced, and not fully understood. "A sole etiology or a unitary construct as the cause of MDD cannot explain the constellation of symptoms exhibited by depressed patients," observed the researchers.

However, it was able to report with certainty that the various potential causes of MDD, including genetic influences, neuroinflammation (inflammation of the brain and CNS), and neurogenesis (the growth of new brain cells and neurons) "can all be integrated into the context of endocannabinoid signaling." The study explained that this is also the case for other mental disorders, including autism, Post-traumatic Stress Disorder, and schizophrenia.


The study concluded that the human endocannabinoid system is extremely complicated and intertwined with other bodily systems, making a clear understanding of its mechanisms difficult and necessitating the participation of a variety of scientific and medical disciplines.

"The ECS is a very complex system with a variety of functions which we are only beginning to understand," summarized the scientists. They concluded that ECS regulation "plays an important role in vulnerability to stress, a major risk factor for MDD," but that other mechanisms may be at play and that individual patients suffering depression may arrive at their condition via a multitude of causes, including genetic and environmental factors.

"Narrow and focused research will not be able to uncover [the] intricate workings" of the endocannabinoid system.

The researchers stated that their results serve as a reminder that "narrow and focused research will not be able to uncover [the] intricate workings" of the endocannabinoid system and the role that it plays in depression and--more specifically--the effective treatment and prevention of major depression.

They also concluded that evidence supports the role of the ECS receptors CB1 and CB2 in depression and its treatment, via a number of pathways and mechanisms and various molecules, including the endocannabinoids 2-AG and anandamide and the phytocannabinoids CBD and THC. "Overall, this review proposes the ECS as a unitary entity of the most important recognized pathways leading to major depressive disorder," reported the study.

View the original study.

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