Introduction
The Endocannabinoid System (eCBS) runs throughout our bodies and brains, and, as we will see, seems to have many of the functions we currently ascribe to the Autonomic Nervous System and the Vagus Nerve, or at least is a parallel system for these functions. This includes having a vital role in regulating stress and dopamine, indicating this system is likely to be highly relevant to Parkinson’s Disease.
Here, we review the literature on the eCBS, especially in regards to its relevance to PD. However, much of the literature on this is motivated by the medical use of cannabis, or by creating new drugs which activate/de-activate the receptors of this system. The problem with such exogeneous chemical hacking is that the functions of the eCBS are so varied, widespread and profound, that unintended consequences of non-targeted chemical interventions abound, and indeed are inevitable. An example of this is the withdrawal from the market of the anti-obesity drug, Rimonabant, that acted on the eCBS, but which caused severe mental health issues.
For myself, then, the motivation for writing this review is to learn about what the eCBS does for us, and then how to self-regulate it, in order to call on it for healing purposes. So to be clear at the outset, this article is not about the uses of cannabis, CBD or other opioids for PD.
To introduce the concepts, here is an excerpt from a journal article entitled Getting High on the Endocannabinoid System:
“The endogenous cannabinoid system… is one of the most important physiologic systems involved in establishing and maintaining human health. Endocannabinoids and their receptors are found throughout the body: in the brain, organs, connective tissues, glands, and immune cells. With its complex actions in our immune system, nervous system, and virtually all of the body’s organs, the endocannabinoids are literally a bridge between body and mind. By understanding this system, we begin to see a mechanism that could connect brain activity and states of physical health and disease.”
The Basics
A good primer to the eCBS is the following excerpt from the journal article The Endocannabinoid System: Essential and Mysterious.
“The eCBS regulates and controls many of our most critical bodily functions such as learning and memory, emotional processing, sleep, temperature control, pain control, inflammatory and immune responses, and eating… comprises a vast network of chemical signals and cellular receptors that are densely packed throughout our brains and bodies. The "cannabinoid" receptors in the brain… outnumber many of the other receptor types of the brain… They (the eCBS receptors) [also]… control the levels and activity of most of the other neurotransmitters. This is how they regulate, by immediate feedback, turning up or down the activity of whichever system needs to be adjusted, whether that is hunger, temperature, or alertness.”
It is worth noting that sense of hunger, regulation of body temperature, and alertness/awareness can all be seriously disrupted in folks with PD. The article continues:
“a second type of cannabinoid receptor, exists mostly in our immune tissues and is critical to helping control our immune functioning, and it plays a role in modulating intestinal inflammation, contraction, and pain in inflammatory bowel conditions.”
Again, it is worth noting that weakened immune function, inflammatory bowel issues, and especially constipation, are often strongly associated with PD too. Next is a further excerpt from the article.
"... if we didn’t forget, we wouldn’t function, and [the eCBS] helps us do this. The role that the eCBS plays in forgetting also opens up opportunities for the treatment of PTSD, a condition in which there are unpleasant, intrusive memories that people can’t help but remember, and that cause a whole syndrome of troublesome and dangerous symptoms related to the pathological remembering.”
So here we begin to see a direct link between trauma/chronic stress and the eCBS, which we will explore in more depth below.
The Endocannabinoid System and Dopamine
Of primary interest to people with PD are the connections of the eCBS with dopamine production and regulation. Indeed, the eCBS seems to act as a master regulator of many of the important neurotransmitters, and can excite or inhibit their activity. Below are some more relevant findings from journal papers I found.
Firstly, according to the article Modulation of the Serotonin System by Endocannabinoid Signaling, the eCBS plays a key role in the Central Nervous System, in particular, in the regulation of the activity of neurons, and hence in a myriad of physiological and psychological functions. There is a lot of evidence from behavioural studies that the eCBS is an important regulator of stress responses, and also that problems with the eCBS can impact stress related disorders like anxiety and depression. This link between eCBs [dys]regulation and stress is a vital part of the story, especially for folks with PD. It is mediated by the interactions of the eCBS with the serotoninergic systems.
According to the article Endocannabinoid Modulation of Dopamine Neurotransmission, the eCBS has a role in exciting, inhibiting, and modulating the dopaminergic circuits of the CNS, responsible for cognitive, emotional, motor, and goal-directed aspects. Here is an excerpt:
"influences behavior[s]… a crucial regulatory role for the endocannabinoid (eCB) system… Notably, many behaviors and disease states that have traditionally been conceptualized as ‘dopamiine-dependent’ are now understood to arise from interactions between the eCB and dopamine systems, including motor control or motor disorders… and reward seeking or addiction…suggests these two systems are even more unified than previously thought.”
So this suggests that the old narrative of PD, which was created long before the eBCS was even discovered, as being “caused” by the death of dopamine producing cells in the substantia nigra part of the brain may be too simplistic, and we need to look at other parts of the system, including the role of the eCBS, to understand why people with PD aren’t producing sufficient dopamine. It might not be because cells have died.
Also, according to the article To Act or Not to Act: Endocannabinoid/Dopamine Interactions in Decision-Making:
“Decision-making is… impaired in multiple psychiatric disorders. Activity within the… dopamine system has been traditionally associated with decision-making. The endocannabinoid system through its actions on inhibitory and excitatory synapses modulates dopamine activity and decision-making.”
Difficulty making descisions is another common feature of PD.
Social Engagement
The eCBS roles include participating in Social Engagement, which is significantly downregulated in people with PD. According to the journal article Endocannabinoid Signaling Mediates Oxytocin-Driven Social Reward, oxytocin-dependent eCBS functions contribute to rewarding “feel-good” factors of social behaviour. Indeed, they find that these social reward circuits involve the activation of eCBS receptors.
The article Social Neuroscience: Staying Bonded Over Oxytocin and Endocannabinoids also confirms that oxytocin is critical for the formulation of social relationships, and the eCBS is recruited for this purpose. Another article in the same vein is Endocannabinoid Signalling in Social Functioning.
The Endocannabinoid System and Fascia
Receptors of the eCBS are widespread in the fascia, or connective tissue, of the body. According to Sensitivity of the Fasciae to the Endocannabinoid System: Production of Hyaluronan-Rich Vesicles and Potential Peripheral Effects of Cannabinoids in Fascial Tissue:
“The demonstrated expression of endocannabinoid receptors in myofascial tissue suggest the role of fascia as a source and modulator of pain. Fibroblasts [a special type of cell] can modulate the production of the various components of the extracellular matrix, according to type of stimuli: physical, mechanical, hormonal, and pharmacological”
The authors found that the stimulation of the eCBS receptors of the fibroblasts led to the production of lubricating fluid filled vesicles being rapidly released into the extracellular environment.
“These results may show how fascial cells respond to the endocannabinoid system by regulating and remodeling the formation of the extracellular matrix. This is a first step in our understanding of how therapeutic applications of cannabinoids to treat pain may also have a peripheral effect, altering the biosynthesis of the extracellular matrix in fasciae and, consequently, remodeling the tissue and its properties”.
The fascia in folks with PD tends to be very stiff and dehydrated.
The Endocannabinoid System, Stress and Trauma
Returning to the role of the eCBS in stress responses and trauma, the article The Endocannabinoid System in Guarding Against Fear, Anxiety and Stress delves into this more deeply. Accordingly, the eCBS has a central role in linking the perception of external and internal stimuli, to neurophysiological reactions and behaviours, including fear reactions, anxiety and stress-coping, and adaptive changes to the environment. Again, people with PD tend to be anxious, fearful, and cope poorly with stressors. The article goes on to say that the eCBS has a role in determining the level of threat from fear-evoking stimuli (or Neuroception, which is again dysregulated in folks with PD), and to generate appropriate behavioural responses. Dysregulation of these features of the eCBS can lead to psychiatric disorders.
“In a similar manner to anxiety, fear perception, elaboration and response involves neuronal, autonomic and hormonal responses. The behavioural reactions to specific threats can be passive in nature (that is, aimed at hiding from or passively avoiding the source of threat; for example, by freezing) or active in nature (that is, aimed at escaping and actively avoiding the danger)."
In my view, people with PD are stuck in the freeze stress response, requiring exogeneous dopamine supplementation to temporarily alleviate the freeze.
"Fear can be innate (such as human fear of snakes and/or other animals) or acquired (when the individual learns that a certain stimulus represent a specific threat to well-being or life). All these modalities of fear and fear responses have been studied in experimental settings, and there is scientific literature linking these aspects to the eCBS system. The eCBS system is also centrally involved in the crosstalk between central and peripheral processes regulating behaviour. “
Also, according to the article Endocannabinoid System in Trauma and Psychosis: Distant Guardian of Mental Stability, the eCBS is neuro-modulatory system that inhibits potential harmful and excessive neuronal activity, and is involved in preventing psychosis, and dealing with trauma.
"Moreover, here we explore eCBS as a guard against hypothalamic-pituitary-adrenal axis over-activation... eCBS function in creating adaptive behavioral patterns… involvement in the memory formation process, extinction learning and emotional response… eCBS in the context of possible biomarkers of trauma.”
How Can We Use This information?
We have seen that the eCBS has critical and vital roles in regulating stress states, and that dysregulation of this system is heavily implicated in PD. So what can we do to ensure a well functioning eCBS, apart from supplementing with exogenous opioids? From what I can gather, as well as diet and exercise, the usual things which calm the Nervous System can also help keep the eCBS in good order. See my master list of suggestions, all of which I believe will help restore and regulate good eCBS function.
Indeed, chronic stress seems to be the thing which most negatively impacts the eCBS, and this is backed up by the article Neurobiological Interactions Between Stress and the Endocannabinoid System:
“in almost every brain region examined, exposure to chronic stress reliably causes a downregulation or loss of [eCB] receptors…
So, in summary, our study into the endocannaboid system points us once more towards chronic stress being the root cause of PD, and that addressing chronic stress is absolutely key to progressive symptom reduction.