A Guide to CECDS (Clinical Endocannabinoid Deficiency Syndrome)

Imagine that you live in a country where medical and recreational marijuana has been legal for years. (I know, humor me for the moment.) This is your first checkup with your new doctor. He’s younger, bright and bushy-tailed, only fresh out of residency last year. But he knows more about the endocannabinoid (eCB) system in humans than any dozen of his elder peers. That’s because medical schools started teaching their fledglings about this remarkable organic structure several years earlier on the coat tails of the Nobel Prize laureates who painstakingly mapped out the mechanisms of disease from clinical endocannabinoid deficiencies in humans.

The endocannabinoid system is a Titan. In fact, it’s bigger than the biggest of all receptor systems found within the human body. This means that eCB ligands and their receptors are literally peppered across and among nearly every single “other” receptor arrangement known to exist in human biochemistry.

Once the “model” of disease was presented it took only another two years before teams the world over were able to replicate these prize findings. Proving to the domains of Man that dis-ease starts FIRST within the intricacies of endocannabinoid physiology.

Our fictitious doctor examines you, asks numerous questions, draws 3 tubes of your precious blood and sends it off to regions unknown within the campus orbit. After about an hour wait he comes back with promising results.

He carefully reads the computer printout and proclaims with a slight smile: “Mitch, you have a severe endocannabinoid deficiency. We need to start you out-today-on a special blend of medical cannabis. In no time you will start feeling much better. I have written for 12 refills. That should do it for the year. See me one month from now to assess how you are doing.”

Within days of starting your new medication you are sleeping better and the fibromyalgia-like symptoms are nearly gone. You notice that while your appetite has improved you are actually losing body fat-another advantage from the medication’s actions on metabolism.

The diagnosis was CECDS, the new “it” disease. The treatment?#

Phytocannabinoids from the plants Cannabis Sativa and Cannabis Indica either in a smokable form, metered inhaler, or in a tasty edible candy. Big Pharma also provides numerous synthetic cannabinoid agonists and antagonists but our imaginary doctor is a purist and believes as many do that whole-plant remedies work best.

OK, wake up everyone this has not yet happened, it’s only speculation. But it may very well turn out to be a premonition of things to come. Nobel prizes are certainly in store as the future will verify.

So let me ask you this: what if real bona fide cures for many diverse human illnesses were to be found in the sap of the marijuana plant? The search to relieve human suffering is as old as time, but some intrepid scientists think we are a step closer.

A handful of pioneering researchers are confident they have found the common ground through which many ailments manifest. Before long we may be seeing distinct prescriptions of cannabinoids being used to cure human illnesses. We could even imagine the Merck Manual adding the definition of a new disease phylum to their already burgeoning tome.

A UNIQUE AND NOVEL CONCEPT

In 2003 an enterprising doctor formulated a unique and novel concept that sought to unite seemingly unrelated disorders to a deficiency of endocannabinoids. Back then proposing such an unusual theory was as inappropriate as using your soupspoon for desert. Nobody was thinking along those lines which makes it all the more fascinating.

After careful observation of the facts, Ethan B. Russo introduced the concept of a clinical endocannabinoid deficiency (CECD) underlying the pathophysiology of migraine, fibromyalgia, irritable bowel syndrome and other functional conditions alleviated by clinical cannabis.

Investigation at that time suggested that cannabinoids can block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, irritable bowel syndrome and muscle spasm.

Five years later Russo followed up with another salvo of information from the available databases. The results were promising:

Migraine has numerous relationships to endocannabinoid function. Anandamide (AEA) potentiates 5-HT1A and inhibits 5-HT2A receptors supporting therapeutic efficacy in acute and preventive migraine treatment. Cannabinoids also demonstrate dopamine-blocking and anti-inflammatory effects. AEA [ANANDAMIDE] is tonically active in the periaqueductal gray matter, a migraine generator. THC modulates glutamatergic neurotransmission via NMDA receptors. Fibromyalgia is now conceived as a central sensitization state with secondary hyperalgesia. Cannabinoids have similarly demonstrated the ability to block spinal, peripheral and gastrointestinal mechanisms that promote pain in headache, fibromyalgia, IBS and related disorders. The past and potential clinical utility of cannabis-based medicines in their treatment is discussed, as are further suggestions for experimental investigation of CECD via CSF examination and neuro-imaging.

Let me clarify some of this discussion for you. The 5HT1 and 5HT2 receptors are serotonin receptors. AEA, which is our body’s endogenous THC-like molecule, acts specifically to stimulate 5HT1 and block 5HT2 receptors in the brain while blocking dopamine receptors.

Guess what? This arrangement is precisely the same as the activity of the new “atypical” antipsychotics which block dopamine (D2) receptors and 5HT2 receptors. The implications in the treatment of mental-emotional disorders is clear. This provides another fertile area of research and reinforces the theory of CECDS.

Also from the above paragraph: AEA in sufficient quantities helps to mitigate migraine by acting on serotonergic pathways. Imitrex, the best seller for migraine treatment, acts in a similar fashion.

Finally, THC acts on NMDA receptors. NMDA receptors are for glutamate an excitatory neurotransmitter. Here we can appreciate the enormous potential of the cannabinoids in treating hyperactive brain regions involving the excitatory glutamate pathways by attenuating their activity.

Cannabinoids act to decrease glutaminergic and other pathway activities in brain regions prone to seizure activity. That’s why CBD is so powerful in treating seizure disorders.

Twelve years later the CECD concept has gained considerable ground and is now thought to be a viable theory on the pathogenesis of numerous clinical conditions refractory to modern medical interventions.

A NEW THEORY FOR NEW DISEASES

The 21st century has evolved with a tangle of “new” disorders causing human misery and disease. These new diseases have names that we know all too well. Many of these are thought to have an autoimmune component such as fibromyalgia and Crohn’s disease, but investigators are left scratching their collective heads on what to do about them. So far little in the way of medications has worked; the ones that do perform often have serious side effects that can complicate therapeutic decisions.

Perhaps they have been wrong all along and the primary problem is NOT autoimmunity but a deficiency of endocannabinoids manifesting as an autoimmune-like disease. That’s precisely what several investigators hope to prove someday.

Not to be outdone in 2014 Smith and Wagner performed a new comprehensive literature review from the National Library of Medicine among other sources and concluded that;

…underlying endocannabinoid deficiencies indeed play a role in migraine, fibromyalgia, irritable bowel syndrome and a growing list of other medical conditions. Clinical experience is bearing this out. Further research and especially, clinical trials will further demonstrate the usefulness of medical cannabis. As legal barriers fall and scientific bias fades this will become more apparent.

STILL HAMSTRUNG

Indeed the legal barriers are legion among those who study cannabis. Still in 2015 as Dr Mechoulam, the father of cannabis research, reminds us there is virtually a freeze on the clinical study of cannabis in humans. Plenty in mice and rats but not too much on the forefront for humans except in Israel. It is however slowly changing. Moving at about the speed of glacier.

MORE HOPE
Meanwhile Storr et al was making progress on the role of the endocannabinoids and irritable bowel syndrome (IBS). In his recent publication entitled, [t]he role of the endocannabinoid system in the pathophysiology and treatment of irritable bowel syndrome, they had this to say:

We now know that the endocannabinoid system is involved in the regulation of numerous gastrointestinal functions including motility, sensation and secretion under both physiological and pathophysiological conditions. They showed that:

Activation of cannabinoid (CB) (1) and CB (2) receptors under various circumstances reduces motility, limits secretion and decreases hypersensitivity in the gut. Drugs that alter the levels of endocannabinoids in the gut also reduce motility and attenuate inflammation. In this review, we discuss the role of the endocannabinoid system in gastrointestinal physiology. We go on to consider the involvement of the endocannabinoid system in the context of symptoms associated with IBS and a possible role of this system in the pathophysiology and treatment of IBS.[ref]Neurogastroenterol Motil. 2008 Aug;20(8):857-68.[/ref]

EAT, SLEEP, RELAX, FORGET, PROTECT

Also in 2014 McPartland et al examined the literature and performed the most recent systematic review of clinical interventions that enhance the eCB system–ways to upregulate cannabinoid receptors, increase ligand (neurotransmitter) synthesis, or inhibit ligand degradation.

The “classic” endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. The eCB system’s salient homeostatic roles have been summarized as, “eat, sleep, relax, forget, and protect”.[ref]Biochimica et Biophysica Acta – Lipids and Lipid Metabolism 1392: 153–175[/ref]

Here McPartland schools us on the eCB system and its remarkable involvement in nearly all human activity and physiology. It modulates embryological development, neural plasticity, neuroprotection, immunity and inflammation, apoptosis and carcinogenesis, pain and emotional memory, and most importantly from the viewpoint of recent drug development: hunger, feeding, and metabolism.

Obese individuals seem to display an increased eCB tone, driving CB1 activation in a chronic, feed-forward dysfunction.[ref]Di Marzo V, Piscitelli F, Mechoulam R (2011) Cannabinoids and endocannabinoids in metabolic disorders with focus on diabetes. Handbook of Experimental Pharmacology 75–104[/ref] An antagonist or inverse agonist of CB1 called Rimonabant was approved for the treatment of obesity. It was subsequently withdrawn from the market due to adverse effects.[ref]Pharmacology Biochemistry and Behavior 95: 375–382[/ref]

Other diseases are associated with suboptimal functioning of the eCB system. Russo [see above] proposed that migraine, fibromyalgia, irritable bowel syndrome, and related conditions represent CEDS, “clinical endocannabinoid deficiency syndromes.” Fride [Neuroendocrinology Letters 25: 24–30] speculated that a dysfunctional eCB system in infants contributes to “failure to thrive” syndrome. Hill and Gorzalka [Behav Pharmacol 16: 333–352] hypothesized that deficient eCB signaling could be involved in the pathogenesis of depressive illnesses. In human studies, eCB system deficiencies have been implicated in uncompensated schizophrenia [Neuropsychopharmacology 29: 2108–2114] migraine [Neuropsychopharmacology 32: 1384–1390], multiple sclerosis [Journal of Neurology Neurosurgery and Psychiatry 79: 1224–1229] Huntington’s [Journal of Chemical Neuroanatomy 37: 266–281, Journal of Nuclear Medicine 51: 1413–1417], uncompensated Parkinson’s [Movement Disorders 25: 920–924] irritable bowel syndrome [Neurogastroenterology and Motility 24], uncompensated anorexia [Biological Psychiatry 70: 777–784], and chronic motion sickness [PLoS ONE 5].[ref]PLoS One. 2014; 9(3): e89566.[/ref]

FOR MOST OF THESE CONDITIONS

The goal is to increase activity of the eCB system. Another way to say this is to upregulate the structure. Upregulation in this context is to stimulate the system to make more of its neurotransmitters AEA and 2-AG, to proliferate receptors CB1 and CB2, or to inhibit the enzymes responsible for degradation of endocannabinoids.

McPartland’s search covered hundreds of animal and in vitro (test tube) studies and 36 human trials. What his team found was completely unexpected. Many of our “bread and butter” medicines act through the eCB system. Furthermore, alternative practices like acupuncture also implicate the eCB system as do our recreational substances. For example:

Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as “complementary and alternative medicine” also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances–alcohol, tobacco, coffee, cannabis) also modulate the eCB system.

They concluded:

Few clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.

Folks, we are witnessing a possible revolution in human biochemistry and medicine; it appears that the eCB system underlies many disease states. Furthermore, our familiar medicines do not work the way we thought they did. Rather, they in some unusual and unknown way, tweak the eCB matrix to ameliorate dysfunction and cure disease.

If anything were Nobel Prize material this surely is.

In a separate publication I will detail some of our common household OTC and prescription drugs that markedly affect the eCB system.

One special word of caution. The drugs I will be referring to upregulate the eCB system when used ACUTELY. The chronic use of these substances produces the opposite effect: the system downregulates as a response to these drugs. Downregulation may turn out to be a setup for disease. It may even help explain the side effects of some drugs when chronically used.