Connecting Your Endocannabinoid System and Mental Health

Connecting Your Endocannabinoid System and Mental Health

Dec 7, 2023 | Written by Matthew Lees, PhD | Reviewed by Scott Sherr, MD and Marion Hall

Named after the cannabis plant (Cannabis sativa) associated with its discovery, the endogenous cannabinoid (endocannabinoid) system is a significant physiological system involved in human health and well-being [1-3].

Throughout the body, endocannabinoids and their receptors form an intricate system that links the mind and body. While this offers a potential therapeutic avenue for treating notable health conditions, problems might also arise when the system isn’t functioning optimally.

Mental health disorders such as depression and anxiety represent the leading cause of disability worldwide and have a high prevalence compared to most other health conditions [4,5]. This has led to substantial public concern for such disorders, given this high prevalence, with cognition and emotionality being the most affected functions in neuropsychiatric disorders (i.e., depression, anxiety, schizophrenia) [6,7]. These disorders present a major public health challenge, particularly in Western nations like the United States [8], and they tend to manifest in childhood or adolescence, with later emergence often associated with comorbid conditions [9].

A dysregulated endocannabinoid system has a wide range of implications for overall health, but emerging research seems to suggest a prominent role in mental health disorders.

We’ve already discussed the endocannabinoid system itself in a previous article. The purpose of today’s article is to explore the mechanisms at play, as well as the influence of plant cannabinoids on mental health and potential workarounds.

The Physiological Basis of the Endocannabinoid System in Mental Health

The endocannabinoid system serves to modulate neurotransmission at inhibitory and excitatory synapses in the brain, specifically in brain regions associated with the regulation of emotions, motivation, pain, and cognition [10-14]. Our knowledge of this system has broadened considerably in recent decades and its discovery represents a hallmark in neuroscience.

The effects of cannabinoids are underpinned by cannabinoid receptors 1 and 2 (CB1R and CB2R). CB1Rs are ubiquitous throughout the brain and central nervous system, whereas CB2Rs are found in the peripheral nervous system, yet both receptors are activated by endocannabinoid binding [15]. Endogenous cannabinoids include 2-arachidonoyl glycerol and anandamide [16], but there are also exogenous cannabinoids such as tetrahydrocannabinol or THC (discussed below).

In the brain, CB1Rs are at their highest concentration in the hippocampus, basal ganglia, neocortex, and cerebellum, whereas a moderate presence is observed in the basolateral amygdala, hypothalamus, and midbrain [6,17-19].

There is evidence that in psychotic disorders and major depressive disorder, CB1Rs in the brain and peripheral blood endocannabinoids are altered in a significant manner [4]. Postmortem, peripheral, cerebrospinal, and in vivo imaging studies seem to corroborate this view, albeit the research basis for this is still in the rudimentary stages.

These findings are consistent with human and animal research that has implicated CB1Rs and the endocannabinoid system in anxiety-related disorders [6]. CB1R knockout mice (mice engineered to lack CB1Rs) showed increased anxiety compared with wild-type control mice across a variety of behavioral testing methods [20]. To varying extents, these observations seem to be replicated for depression and schizophrenia as well [6].

How do Exogenous Cannabinoids Affect Mental Health?

Cannabidiol (CBD) is the main non-psychotropic phytocannabinoid found in the cannabis plant, comprising up to 40% of its extract. It has promising therapeutic applications, including in neuropsychiatric disorders, with at least part of its action mediated through endocannabinoid system-induced neurotransmission [6]. There is a significant amount of genetic variation in the subjective effects of smoked cannabis, predominantly at the CNR1 gene [21], and this genetic variation seems to be a major factor in the positive or negative effects on mental health.

Among Troscriptions’ products, Blue Cannatine, Tro Calm, and Tro Zzz all have CBD as one of their main ingredients, so check them out if you’re interested!

Is Cannabis Use a Risk Factor for Mental Health Disorders?

Cannabis can be a risk factor for psychosis in genetically predisposed people and may lead to worse outcomes of the disease [22]. It may affect normal brain development during adolescence, increasing the risk for schizophrenia in adulthood [23]. The continuous activation of the endocannabinoid system, such as through chronic cannabis use, has been associated with an increased risk of schizophrenia [23,24]. A recent review indicates that the cannabidiol component of cannabis is therapeutic, whereas the THC component is the one implicated in psychosis and schizophrenia in at-risk populations [25].

In terms of genetic predisposition, alterations that affect the cannabinoid CNR1 gene could be related to schizophrenia. In schizophrenia, the endocannabinoid system is dysregulated (i.e., increased density of CB1 receptors in corticolimbic regions as well as greater levels of anandamide in the cerebrospinal fluid), which detrimentally impacts neurotransmitter function [23]. Interestingly, certain genetic alterations in the CNR1 gene can be neuroprotective against schizophrenia.

Are there Genetic Screening Methods for Different Types of Cannabis?

There are indeed companies that offer DNA tests to match people with the right type of cannabinoid products to minimize the risk of adverse mental health effects. For example, some offer endocannabinoid genotyping, precision matching of THC ratios, and mapping of risk/benefit based on drug-drug interactions.


In this article, we have provided some background on the prevalence of mental health disorders and identified the endocannabinoid system as a prominent therapeutic avenue in the treatment of conditions such as depression, anxiety, and schizophrenia.

We also explored the mechanistic underpinnings of the endocannabinoid system in mental health disorders, and the prominent role of cannabinoid receptors as a likely genetic component of schizophrenia resulting from cannabis use.

Lastly, we briefly reviewed the emerging technologies that characterize the endocannabinoid genotype, assisting decision-making processes and managing the mental health risks/benefits when selecting cannabinoid-containing products.



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Matthew Lees earned his PhD in exercise physiology, nutrition and aging from Leeds Beckett University in the United Kingdom in 2020. To date he has published over 35 peer-reviewed academic publications and has presented his work at national and international conferences. His passions lie in communicating research findings to lay audiences and finding the answers to the most challenging questions in nutrition, health, and disease.

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