Why are side effects to cannabis mild? Homeostasis and the ECS

Bias in cannabis science has a problem, the endocannabinoid system (ECS) induces homeostasis. This means the system that cannabis responds to will provide balance and harmony to many other systems in the body. But to do this, cannabinoids often have to pit multiple functions against each other. Otherwise, most side effects to cannabis are countered by a positive benefit which makes it easy to cherry-pick good or bad data.

A negative-feedback loop occurs when an effect blocks the function and this is required for a homeostatic system. In the case of appetite and energy, the CB1 receptor releases ghrelin which causes hunger. But food intake releases another hormone known as leptin which competes with the endocannabinoid system (ECS). (1)

Cancer and requiring the full-spectrum

ECS therapy is sometimes best achieved by the whole cannabis plant, though. This is because the ECS comprises a system of receptors and signaling molecules, each uniquely affected by a wide variety of substances in the plant. For example, synergistic effects from terpenes such as caryophyllene and cannabinoids like CBG help to maintain homeostasis. That said, the perfect spectrum of constituents to induce homeostasis through the ECS usually depends on the person, the desired outcome, and a lot of factors science has yet to figure out.

Cancer is an example where homeostasis is critical during recovery, and where the full spectrum of cannabis can be utilized. That is, different cultivars (strains) will provide different effects. For example, a high THC variety will help turn off a switch that (non-hormonal) cancers rely on, whereas a CBD:THC blend will instead aid with the growth of healthy tissue.

Self-moderated tolerance

The cannabinoid receptors keep themselves in check, too. An abundance of THC can still cause excessive activity across the CB1 receptor even though it is only a partial agonist. To compensate for any overactivity, CB1 receptors are temporarily shut down and CB2 receptors morph into place for further maintenance. 

Inflammation on-demand by the ECS

As it turns out, CBD can help protect from CB1 receptor desensitization by acting on the signaling protein, beta-arrestin. Whereas alcohol destroys certain receptors and that damage can be long-lasting if not permanent. (2)

Homeostasis is sometimes maintained on-demand, which is a complex facet of endocannabinoid therapy. More often than not, anti-inflammatory properties are characteristic of the plant. This is so well documented that it might be perplexing to explain how the ECS can provide inflammation when necessary. Yet, endocannabinoids degrade into inflammatory metabolites that the body uses in emergencies, like when you break a bone. 

Blood pressure side effects and cannabis greenouts

Blood pressure, however, is one mechanism that an overloaded endocannabinoid system cannot keep in a homeostatic state. This is why hypotension is considered one of the few side effects of cannabis, the root cause for green outs. But this concern, alongside interactions with other drugs, is more problematic for minor cannabinoids that have not yet been documented in phase I clinical trials. And yet, well-run trials face the burden of bias in the cannabis space according to a study by the Consortium for Medical Marijuana Clinical Outcomes Research.

So, it seems that cannabis and endocannabinoid therapy sustain physiological balance more efficiently than humans can document science. 

Show your work

  • The CB1 is biphasic, with early ERK 1/2 inhibition via beta-arrestin, and late-stage activation via the adenylate cyclase path.
  • Chronic exposure to THC causes CB1 receptor desensitization. But THC also interacts with b-arrestin, a signaling protein that can limit receptor desensitization. CBD and possibly limonene have the potential to lower the need for tolerance breaks via b-arrestin.
  • CB2R and GPR55 cross-talk negatively.
  • Neuro-morphology after chronic cannabis use includes new CB2 receptors on microglial cells.
  • Memory and focus: CB1 agonists and linalool inhibit acetylcholine, whereas pinene acts as an acetylcholinesterase inhibitor.


  1. Miralpeix, C., Reguera, A.C., Fosch, A. et al. Hypothalamic endocannabinoids in obesity: an old story with new challenges. Cell. Mol. Life Sci. (2021).
  2. Nguyen, P. T., Schmid, C. L., Raehal, K. M., Selley, D. E., Bohn, L. M., & Sim-Selley, L. J. (2012). β-arrestin2 regulates cannabinoid CB1 receptor signaling and adaptation in a central nervous system region-dependent manner. Biological psychiatry71(8), 714–724.