Loneliness, Depression & Our "Inner Cannabis"

The number of ailments, conditions, and states of mind in which the endocannabinoid system’s role is being investigated grows ever larger. There’s addiction, Alzheimer’s, autism, endocrine disruption, gut dysbiosis, headaches, inflammation … and that’s not even half the alphabet. As two new studies highlighted below suggest, depression, loneliness, and grief – mental health conditions that have taken a prominent place in public discourse lately – should be included on the list, as well.

On its face the vast scope of endocannabinoid system (ECS) involvement in human health isn’t surprising, given what we already know about the distribution and function of the cannabinoid receptors CB1 and CB2, the endocannabinoids anandamide and 2-AG (our “inner cannabis”), and all of the other receptors, signaling molecules, and biological systems with which they interact.

But generating evidence of such effects through the scientific process is another matter. Then there’s the task of translating this data into practical information and potentially therapeutic interventions. This is the end goal of most modern cannabinoid science published on a daily basis in the scientific literature, but there’s still a long way to go before cannabis is tested, proven, and approved for the vast majority of these indications.

The two papers discussed below illustrate this situation well. While they represent some progress toward – or at least lend support to the idea of – cannabinoid-based treatments for mental health, they’re still many steps removed from formal clinical practice.

Depression

Though depression is a complex and diverse disorder with many possible causes, “all the currently hypothesized etiologies for major depressive disorder, whether they are genetic, neuroendocrine, immunological, or cytogenetic, seem to rely on the correct functioning of endocannabinoid signaling,” writes a team of Spanish researchers in a December 2021 paper in the journal Frontiers in Pharmacology.1

As if that alone weren’t enough to warrant a comprehensive review of this relationship, they also present in their introduction an additional news hook: COVID-19. Depression and anxiety were major drivers of increased cannabis consumption during the first months of the pandemic, as Project CBD recently reported.

But what the authors also make clear is that researchers have been proposing a potential role for the endocannabinoid system in the pathophysiology of major depressive disorder since the early 2000s.2,3

Beyond the fact that proper balance of the ECS “is essential for the homeostatic maintenance of a number of physiological, cognitive, behavioral, and emotional processes,” and “when dysregulation of the ECS occurs, cognitive deficits might arise,” the authors point to more specific findings about the actual molecular mechanisms involved. In particular they highlight:

the role of the CB1 receptor, which is believed to play a major part in regulation of the hypothalamic-pituitary-adrenal (HPA) axis, a system linking the brain and adrenal glands (located just above the kidneys) that mediates the stress response;
the role of both CB1 and CB2 in modulating neuroinflammation, also implicated in depression;
and the relationship between cannabinoids and neurogenesis.

Finally, they identify additional avenues that should be explored and other future research directions and needs. To their earlier point about COVID, this includes generating solid evidence about whether or not cannabis use actually helps treat depression.

Loneliness and grief

Researchers with the Medical College of Wisconsin and the University of Pittsburgh School of Medicine took the link between the ECS and depression one step further by measuring circulating endocannabinoid levels in the blood of bereaved older adults experiencing loneliness and grief.

As described in a December 2021 paper in the journal Frontiers in Psychiatry,4 the study population included 44 individuals who had experienced the loss of a loved one in recent months, as well as 20 similarly aged “healthy controls.” All participants also completed baseline clinical assessments of loneliness.

Then, two, four, and six months after the blood draw, the researchers had the 44 bereaved participants complete additional follow-up clinical assessments on anxiety, depression, dementia, grief, and suicidal ideation.

In lonely, bereaved elders, increased circulating endocannabinoids are associated with better adaptation to bereavement.

By tabulating this purely observational data (meaning no interventions took place), the researchers uncovered two key endocannabinoid associations. First, in the cross-sectional analysis comparing baseline data across all participants, circulating anandamide concentrations were higher in severely lonely grieving elders than in healthy controls.

And second, in the longitudinal analysis accounting for six months of follow-up among lonely and grieving individuals, those with higher concentrations of 2-AG in their blood at baseline subsequently experienced faster resolution of grief symptoms within the six-month study window.

“An efficient ECS system is stress-responsive, which in turn leads to less physical and emotional distress,” the authors explain. “Our cross-sectional findings thus lead us to hypothesize that increased circulating endocannnabinoids seen in lonely grieving individuals are reflective of an efficient and normal functioning ‘stress-responsive’ ECS system.”

They continue: “Our novel longitudinal findings suggest that an activated ECS system in response to bereavement may be crucial for better adaptation to attachment loss and to ease the transition to integrated grief in bereaved elders who report high loneliness.”

The researchers conclude that in lonely, bereaved elders, increased circulating endocannabinoids, a reflection of a well-functioning ECS system, are associated with better adaptation to bereavement. Much like in the paper on depression, however, they don’t go so far as to suggest any ECS-tuning therapy or treatment, including cannabis itself. In fact, even though older adults are increasingly comfortable medicating with cannabis, the word doesn’t appear once in the paper.

Nate Seltenrich, an independent science journalist based in the San Francisco Bay Area, covers a wide range of subjects including environmental health, neuroscience, and pharmacology.