Depression, and the related disorder anxiety, are pathologies that affect human beings across many aspects of their life; social interactions, professional productivity, and overall health and well-being. The impact of depression can range from a general feeling of "the blues" to the most severe manifestation, where a depressed person may consider taking their own life or the life of others. The continuum of depressive disorder is wide.
To additionally complicate matters, depression may exhibit as a side effect of other illnesses or their associated treatments. For example, those undergoing chemotherapy are often observed for depression.
The endocannabinoid signaling system (ECS) is an extremely important mechanism for the regulation of long and short term synaptic plasticity. Synaptic plasticity is a major determinant in how the brain processes reward, fear, memory extinction and stress. As all of these fundamental processes are dysregulated in major depression, a better understanding of ECS and exploration of viable treatment options holds great potential for the improved understanding of the biology of depression. (1)
The central endocannabinoid system (ECS) is a neuroactive lipid signaling system in the brain which acts to control neurotransmitter release. The expression patterns of this system throughout limbic regions of the brain ideally situate it to exert regulatory control over emotional behavior, mood and stress responsivity.
A growing body of evidence unequivocally demonstrates that deficits in endocannabinoid signaling may result in depressive and anxiogenic behavioral responses, while pharmacological augmentation of endocannabinoid signaling can produce both antidepressive and anxiolytic behavioral responses. Collectively, both clinical and preclinical data argue that cannabinoid receptor signaling may be a realistic target in the development of a novel class of agent for the pharmacotherapy of mood and anxiety disorders. (2)
Anxiety-related disorders affect a huge segment of our population - 40 million adults (18%) in the United States age 18 and older. In response, Big Pharma has developed numerous drugs to treat anxiety-related disorders, from selective serotonin reuptake inhibitors (SSRIs) like Prozac and Zoloft to tranquilizers (the most popular class being benzodiazepines such as Valium and Xanax). (3)
While some have experienced a positive response from these drugs, for many they are problematic. New information shows is that there may be some help using SSRIs if there is a severe shortage of serotonin within the patient's brain, but the average person's depression cannot simply be related to a "chemical imbalance." The human brain is too complicated to have a simple, quick explanation related to serotonin alone, particularly when depression is often linked to both biological and environmental factors.
Moreover, the negative impacts of using SSRIs are well-documented. In an article appearing in Everyday Health, Dr. Chris Iliades notes 7 antidepressant side effects:
There is no way of measuring the serotonin in the brain of a living person, short of cutting open the skull. There is no standard measure of what a normal level of serotonin should be and below which researchers can say with certainty that depression kicks in. People with high serotonin levels can be depressed and those with low levels can be happy. Serotonin inducing drugs like ecstasy can make you feel very happy, but so can alcohol and heroin.
Due to the side effects of these commonly-prescribed anti-depressants, many are seeking other treatments that are more effective and less risky.
For many, CBD holds the answers to treating depression. CBD works within the ECS system in multiple ways, not singularly targeting serotonin levels.
Researchers found that chronic stress reduces the production of endocannabinoids, which affect our cognition, emotion and behavior, and have been linked to reduced feelings of pain and anxiety, increases in appetite and overall feelings of well-being. The body naturally produces these compounds, which bear similarity to the chemical compounds of CBD. Reduction of endocannabinoid production may be one reason that chronic stress is a major risk factor in the development of depression. CBD is able to mimic these ECS compounds and fill in the gaps where the patient's own body is unable to do so. (4)
CBD's treatment of depression is so revolutionary that its application is noted in significant publications, like this study in The Huffington Post. Neuroscientists from the University of Buffalo's Research Institute on Addictions found that activating endocannabinoid chemical compounds in the brain activates receptors that may be helpful in treating depression that results from chronic stress. (5)
There are three relevant applications of CBD for those suffering from depression, presented in this 2014 article, Endocannabinoid Signaling in the Etiology and Treatment of Major Depressive Illness. In their study, Drs. Hilliard and Liu explored three relevant theories they believe feed into individuals exhibiting chronic depression. (6)
The first hypothesis is that deficient CB1R-mediated signaling results in symptoms that mimic those seen in depression. The second hypothesis is that activation of CB1R-mediated signaling results in behavioral, endocrine and other effects that are similar to those produced by currently used antidepressants. The third hypothesis is that conventional antidepressant therapies act through enhanced CB1R mediated signaling. Together the available data indicate that activators of CB1R signaling, particularly inhibitors of fatty acid amide hydrolase, has been so effective it should be considered for more widespread clinical trials for the treatment of depression.
Although there are more than 60 unique chemicals in the parent plant for CBD, only one has been shown to produce psychoactive effects in humans in each of the three theories presented above. CBD exerts its effects on the body because it is a partial agonist of two G protein coupled receptors (GPCRs), cannabinoid receptors types 1 and 2 (CB1R and CB2R, respectively). (7)
The psychoactive effects of CBD are the result of activation of CB1R.(8) Both CB1R and CB2R couple to G proteins and their cellular effects are blocked by pertussis toxin treatment. CB2R couple to Gi but not Go proteins and exert their cellular effects via inhibition of adenylyl cyclase and regulation of transcription factors. (9)
CB1R regulate the activities of adenylyl cyclase, ERK, glycogen synthase kinase 3; and the open probability of calcium and potassium channels. In addition, CB1R can increase intracellular calcium concentrations through Gq/11 proteins. CB1R are very highly expressed in the brain, particularly in regions involved in motivated behavior and emotional processing, which highly impacts the reactions to depression. (10)
Depression is a complicated and delicately interconnected illness of the brain. In a general sense, the delicate interconnections within the brain seem to have missing communication links when depression is in place. CBD is a very broad treatment options that targets multiple symptoms and ranges present with depression.
Specifically, a deficiency in endocannabinoid signaling is sufficient to produce a "depressive-like" phenotype at the preclinical level, including changes in rewarding, emotional and cognitive behavior and biological changes such as increased HPA axis activity, impaired stress adaptation, reduced neurogenesis and altered serotonin negative feedback. This combination is capable of inducing symptoms of depression in humans at a clinical level. (11) SSRIs, which are the most commonly prescribed treatments for depression, target only the serotonin levels in the brain, which is not thought to be singularly responsible for the onset of depression, as referenced earlier in this article.
In line with these findings, clinical populations diagnosed with depression are found to have reduced levels of circulating endocannabinoids and preclinical models of depression reveal a deficit in central endocannabinoid signaling. Moreover, facilitation of endocannabinoid signaling is sufficient to produce all of the behavioral and biochemical effects of conventional antidepressant treatments. Further, many forms of antidepressant treatments significantly alter endocannabinoid signaling, and in some of these cases this recruitment of endocannabinoid signaling is involved in the neuroadaptive effects of these treatments. Ultimately, these data present a compelling picture of the putative role of the endocannabinoid system in the processes subserving both the development and treatment of depression.
Without a doubt, the brain is the most mysterious and least understood system within the human body. The use of CBD to manage neurological responses is an emerging area of science showing great promise. Research like animal studies and clinical data, is revealing that use of CBD is having a positive impact on the delicate inner workings of the human brain. The positive impacts are documented for stress relief, anxiety management, and the full range of depressive disorders.
Depression is a multi-factorial disorder that can manifest with different symptoms. It is very likely a disorder with both genetic and environmental causes. Better understanding of the roles of all candidate systems in the etiology of depression is the only way to inform treatment approaches that are evidence-based and personalized. Clearly thus far, utilizing CBD as part of a treatment protocol for depression has proven to be an essential for those individuals battling the disease. Evidence-based and personalized treatment plans, many of which include CBD, will undoubtedly lead to better outcomes for people with this debilitating disease.
1 - Hill, MN, Goralka, BB, "The Endocannabinoid System and the Treatment of Mood and Anxiety Disorders," NCBI National Institutes of Health, (December 2009).
2 - Hill, MN, Goralka, BB, "The Endocannabinoid System and the Treatment of Mood and Anxiety Disorders," NCBI National Institutes of Health, (December 2009).
3 - Davis, Lennard, "Five Reasons Not to Take SSRIs," Psychology Today, (Dec 2009)
4 - Gregoire, C, "New Study Finds CBD to be Effective Against Depression," The Huffington Post, (Feb 2015).
5 - Gregoire, C, "New Study Finds CBD to be Effective Against Depression," The Huffington Post, (Feb 2015).
6 - Hilliard, CJ, Liu Q, "Endocannabinoid Signaling in the Etiology and Treatment of Major Depressive Illness," NCBI National Institutes of Health, (2014).
7 - Waskow IE, Olsson JE, Salzman C, et al. "Psychological effects of tetrahydrocannabinol," Arch Gen Psychiatry, (1970).
8 - Huestis MA, Gorelick DA, Heishman SJ, et al. "Blockade Effects CB1-selective cannabinoid receptor antagonist SR141716," Arch Gen Psychiatry (2001).
9 - Howlett AC, Blume LC, Dalton GD, "CB(1) Cannabinoid Receptors and their Associated Proteins," Curr Med Chem. (2010).
10 - Hilliard, CJ, Liu Q, "Endocannabinoid Signaling in the Etiology and Treatment of Major Depressive Illness," NCBI National Institutes of Health, (2014).
11 - Gorzalka, BB, Hill, MN, "The Putative Role of Endocannabinoidal Signaling in the Etiology of Depression," NCBI National Institutes of Health, (August 2010).
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