Practical Considerations of Hypotheses and Evidence in Cannabis Pharmacotherapy: Refining Expectations of Clinical Endocannabinoid Deficiency

Abstract

An Industry founded on the promotion of presumed health and wellness benefits of cannabis use continues to grow in the United States, despite the lack of substantial evidence in support of the many claims being made. Several hypotheses exist regarding the role of endocannabinoids in human health and the pertinence of phytocannabinoids as pharmacotherapies for addressing their dysregulation. An opinion is offered regarding the tenuous nature of these assumptions and questions are raised regarding how best to interpret the complex metabolic interplay of the still vaguely defined endocannabinoid system.

Keywords:

• antioxidant
• cannabis
• cannabidiol
• clinical endocannabinoid deficiency
• dietary supplement
• deficient
• endocannabinoid system
• human studies

Introduction

As the state-sanctioned cannabis industry continues to grow on the fringes of federal regulation, a variety of enduring disinformation likewise continues to define the market, manipulate consumer choice, and threaten consumer safety. Not least of these problems is the ongoing overestimation and misrepresentation of preliminary scientific findings and hypothetical musings regarding the therapeutic value of the cannabis plant and its derivatives. To be sure, there is no shortage of intriguing reports regarding the pharmacologic versatility of the common cannabinoids; and still more are doubtless to come in the wake of the 2018 federal descheduling of hemp (Commissioner of the FDA Regulation of Cannabis and Cannabis-Derived Products and Including Cannabidiol (CBD), 2020). Encouraging findings of its antinociceptive, neuroprotective, antineoplastic, and anxiolytic effects alone are example enough to prioritize study of the cannabis plant as a promising source of potential therapeutics (Barnes 2006; Nurmikko et al. 2007; No Brainer: CBD and THC for Head Injuries 2020; CBD and Parkinson’s Disease, 2020; Shi et al. 2019; How Cannabis oil works to kill cancer 2018; Skelley et al. 2020).

But caution is necessary when forging expectations from preclinical and pilot studies as the effects observed in such investigations more often than not go unrealized in advanced clinical trials (DiMasi et al. 2016; Leon et al. 2011). And while that disparity no doubt brings a disappointing end to any pharmaceutical development campaign, it appears to be borne with no great discomfort by the cannabis industry wherein marketed claims promote hypotheses to fact and trade on the misrepresentation of unsubstantial and equivocal evidence. The industry is verily defined by its willingness to extrapolate therapeutic claims from preliminary findings and to employ such claims toward the enticement of consumers into a purchase (Luc et al. 2020; Ayers et al. 2019; Ishida et al. 2020; Cavazos-Rehg et al. 2019). It is worth noting here that the FDA has taken action, in some instances, against manufacturer and retailer claims, suggesting that regulation has not been completely abandoned (Commissioner of the Public Health Focus 2018). However, the existence of a popular advocacy literature dedicated to the promotion and advertising – but not direct sale - of cannabis products provides a convenient workaround for the industry (Conditions | Project CBD 2020; Medical Marijuana Archives • High Times, 2020). Unfortunately, virtually none of the research currently being leveraged toward the sale of cannabis for therapeutic purposes meets the long accepted (and FDA mandated) touchstone of compelling clinical evidence for pharmacotherapy: the large randomized controlled trial (RCT) (Jakobsen and Gluud 2013; Commissioner of the Drug Study Designs 2019). Even if criticisms and limitations of RCTs are taken into consideration (most of which do not pertain to trials of pharmacotherapeutic efficacy), the evidence base for cannabis derived medications still comes up short as we move down the rungs of most commonly referenced evidence hierarchies (Bothwell et al. 2016; Berlin and Golub 2014; Burns et al. 2011; Grossman and Mackenzie 2005). This presents a considerable problem, epistemically speaking; for the further removed our evidence base is from the “gold standard” of clinical investigation, the less warrant we hold for any claim of knowledge regarding cause and effect in therapeutic applications. Anecdote, pilot studies, case studies, animal studies, and in vitro data all serve the function of justifying progression through the drug development process. But they are entirely inappropriate for founding claims of therapeutic value, particularly in a greatly unregulated direct-to-consumer market of pronounced popular appeal (Sink et al. 2010; Harrison 2016; Perel et al. 2007). In answer to the question of why such resources command so little faith, and in addition to the aforementioned ranks of clinical trial failures, we may point to a long history of therapies that were known to work wonders up until the time when anyone bothered to go looking for evidence of their touted effects (Commissioner of the A Brief History of the Center for Drug Evaluation and Research 2019; Kuszak et al. 2016; Parapia 2008).

It must be stressed that what follows is not an indictment of any particular authors, as excitement about technological developments in one’s field often leads to overly optimistic discussions about their potential; there is no inherent problem here. The intent is rather to point out that caution is necessary when discussing preliminary hypotheses in the context of a growing industry that is happy to spin to a market that is eager to consume (ltd R and M. Legal Marijuana 2019). Multiple questions are raised throughout, beginning with observations pertaining to several of the common therapeutic claims made of cannabis products, most particularly Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). Broader questions of commonly promoted hypothetical phenomena will then be explored. A brief summary of concerns regarding claims of therapeutic benefit arising from an “entourage effect” (treated in greater detail elsewhere) will be followed by a discussion of the role of exogenous cannabinoids in the treatment of the purported “clinical endocannabinoid deficiency” syndrome (Cogan 2020). The effort will conclude with an exploration of the current fluid definition of the endocannabinoid system and will further raise questions regarding the relationship between therapeutic expectations and the artifacts of nomenclature.

More questions than evidence?

Each of the proposed applications of cannabinoid therapy listed above comes with caveats and questions as to how preliminary findings might translate into clinical outcomes. For instance, systematic reviews and meta-analyses of cannabis based interventions in the treatment of pain have reported that evidence of a therapeutic effect is limited and inconsistent or inconclusive for multiple pain varieties (Häuser et al. 2018; Aviram and Samuelly-Leichtag 2018; Mücke et al. 2018). With regards to the putative neuroprotective effects of cannabinoids, the authors of one prominent study determined that the antioxidant activity of 10 µM CBD accounts for these. But they also achieved comparable (though statistically inferior) activity from 10 µM media supplementation with either vitamins C or E - concentrations corresponding to plasma levels that satisfy the definition of “deficiency” in each (Maxfield and Crane 2019; Kemnic and Coleman 2019). Such findings raise an obvious question: though clearly a potent antioxidant, what purpose is there in developing a high dose CBD intervention when its utility is only identified in the experimental context of gross antioxidant deficiency? Might we not expect comparable results to be achieved through an appropriate diet (Arigony et al. 2013)? More generally, how many discoveries of cannabinoid therapeutic potential are restricted to the experimental models employed in their identification and how often are these offered to consumers as proof of cannabinoid value (The Antioxidant Properties of CBD, 2020)?

Reports of the antineoplastic effects of the common cannabinoids are still more problematic. One might wonder how practical THC is as a cancer therapeutic when it seems unlikely that patients would be able to tolerate the doses necessary to achieve its proposed inhibitory effects on tumor growth. As an example of this concern, Baram et al. have demonstrated that the most potent of twelve tested whole-plant extracts yielded an IC₅₀ value corresponding to 24 h treatment with 2,000 - 3,900 ng/mL THC (Baram et al. 2019). This contrasts with the clinical findings of Sellers et al. who have reported that mean transient C_max plasma concentrations of just 9.2 ± 6.3 ng/mL THC correlated to 25% of subjects discontinuing the study on account of intolerable adverse events (AEs) after oralmucosal nabiximols dosing (2.7 mg THC and 2.5 mg CBD per spray) (Sellers et al. 2013). More problematic are observations in mouse and in vitro models of THC exposure enhancing tumor growth at lower doses (Hart et al. 2004; McKallip et al. 2005; Zhu et al. 2000). These frame some particularly disturbing questions: how many people experimenting with cannabis extracts as a treatment for cancer or its associated effects are achieving high enough tissue THC concentrations to approximate published IC₅₀ values (Pergam et al. 2017)? Conversely, how many partaking for any reason at all are consistently exposing themselves to doses that might be expected to promote tumor growth? It might at first be tempting to dismiss this question in accordance with the lack of clear evidence of cannabis induced carcinogenicity throughout millennia of human exposure. However, the cannabinoid composition of products available today is substantially different than that offered by historical chemovars (ElSohly et al. 2016; Smart et al. 2017; Stuyt 2018). Moreover, the popularization of ingestion as a route of delivery has likewise changed the expected exposure to a variety of metabolites (Ujváry and Hanuš 2016; Azcarate et al. 2020). Furthermore, rare yet statistically significant adverse events (AEs) aren’t always obvious in the absence of investigations specifically designed to identify them (Cogan 2019; Jüni et al. 2004; Frank et al. 2014).

But THC is not alone in these concerns, as intriguing discrepancies are also observed in reports of CBD’s effects. As an example, Lukhele and Motadi report an IC₅₀ (and significant apoptotic cell death) of ∼ 10 µM CBD after 24 h treatment of HeLa cervical cancer cells, a concentration and duration that is consistent with the growth inhibitory effects reported for CBD in other cancer cell lines (Lukhele and Motadi 2016). But Ramer et al. report that 10 µM CBD has no significant effect on the viability of HeLa cells after 72 hr treatment (Ramer et al. 2010). More concerning are the findings of Deng et al. who report that CBD is cytotoxic to normal neural progenitor cells in the common 1 – 10 µM range associated with its putative in vitro antineoplastic activity (Deng et al. 2017). This is not only contrary to other findings of relative selectivity for cancerous cells, but also further challenges the reliability of those commonly claimed neuroprotective effects addressed above (Ligresti et al. 2006; Massi et al. 2006).

The entourage effect

Less obvious than explicit claims of therapeutic benefit, though no less prone to abuse, are the invention and popularization of hypothetical phenomena and buzz words that manage to skirt regulatory oversight. Perhaps the most well-known of these is the notion of an “entourage effect” (EE) – the vague proposition that various components of the cannabis plant enhance the therapeutic value of the primary active cannabinoid of interest (most commonly THC or CBD) (Russo 2011; Russo 2018; McPartland and Russo 2001). While there is nothing remarkable about suggestions of polypharmacy affecting the activity of any single drug, what is rather spectacular is the common suggestion that such interactions give reliable effects as a matter of general principle and that they should always be expected to be beneficial. That is to say, the generic notion of an “entourage effect” is commonly pitched as necessary for benefit without bothering to state precisely which entourage should be expected to provide the desired outcome. More problematic is the fact that, while these assumptions are refuted by common sense, basic pharmacological theory, and empirical evidence to the contrary, their hypothetical discussion in speculative scientific reviews strangely blossoms into their treatment as matters of fact in trade publications, popular press outlets, and retail websites (Skelley et al. 2020; DiMasi et al. 2016; Leon et al. 2011; Luc et al. 2020). Not unexpectedly, the term has also come to be invoked as an ad hoc excuse for the failings of purified cannabinoids in clinical studies, and as such speaks to a presumed benefit just waiting to be found (Is CBD Toxic to the Liver? , 2020; Russo 2001).

Unfortunately, such expectations of benefit appear to arise more from ideological supposition than from the sorts of proper scientific investigation that are being eschewed in favor of the direct to market approach. For example, in their 2019 screen of twelve different whole plant extracts, Baram et al. have discovered not only differences in the ability of the various chemovars to kill cancer cells in culture (with several being ineffective), but also in their toxicity to normal cell lines (Baram et al. 2019). Such observations raise the obvious question: how can blanket statements of the benefit of an “entourage effect” be made when it is not known which combinations might deliver superior effects or which ones are even safe? This is not to say that no meaningful research is being conducted on the polypharmacy of cannabis – to the contrary, the innovative work of Baram and many others is generating invaluable data that are setting the stage for meaningful clinical investigation. Nevertheless, the problem remains that some authors and the cannabis industry at large aren’t bothering to wait for the results. In any event, given the potentially infinite combinations of cannabis composition and the inconvenient observation that not all entourages are created equal, if we are going to assume that such benefits of polypharmacy perhaps do exist, there is a clear and appropriate course of action to pursue: clinical testing of well-defined, reproducible mixtures (Cogan 2020; Baram et al. 2019; Solowij et al. 2019). In the interim, pointing to the concept of cannabis polypharmacy and suggesting that an entourage is needed to render maximum benefit is no more informative than pointing to the concept of pharmacology and suggesting that chemicals are needed to treat disease. In either instance, we are left with an unavoidable question: which ones?

Clinical endocannabinoid deficiency

Author’s note: Shortly after being invited to submit an article for this special edition, I found myself speaking with a “budtender” (though not at her place of employment) who informed me that humans have an endocannabinoid system which needs to be supplemented with phytocannabinoids when it becomes deficient, so as to mitigate or forestall all sorts of illness. Intrigued, I conducted a quick web search and found that other retailers are indeed trading on similar claims (Staff 2020; The Endocannabinoid System | Learn More, 2020). This discovery framed an interesting question: why would someone believe such a thing? As it turns out, these claims are not too far removed from suggestions in the scientific literature.

Much as is found with the entourage effect, the concept of a “clinical endocannabinoid deficiency” (CED) has been posited as an intriguing hypothesis in multiple reviews and is described by cannabis trade publications and retailers both in purely optimistic terms and as if it were an established fact (Russo 2008; Russo 2016; Smith and Wagner 2014; Dr. Ethan Russo on CBD & Clinical Endocannabinoid Deficiency, 2020; Endocannabinoid Deficiency Syndrome, 2020; Are You EndoCannabinoid Deficient?, 2020; Does endocannabinoid deficiency play a role in these common illnesses?, 2019). What’s more, a treatment for this as of yet unconfirmed malady has quite miraculously already been discovered to be, unsurprisingly, dosing of phytocannabinoids (Are You Endocannabinoid Deficient?, 2017; Russo 2015; Team HBT 2018; Lindsey 2018). There is even at least one cannabis extract masquerading as a prescription medication for CED – with online prescribing instructions directing physicians to “simply write Idrasil™ 12.5 mg, 25 mg, or 100 mg PRN/Q6H on your prescription pad” (Human Receptor Information, 2020; Idrasil Launches as First Standardized Form of Prescription Medical Cannabis in a Pill, 2018; Prescribing Idrasil®, 2020). This product is not only marketed as an “Rx” treatment for CED, but also implies that it is as effective as hourly doses of up to 100 µg of fentanyl for pain, a remarkable suggestion given the mixed outcomes reported in those systematic reviews and meta-analyses cited above.

CED is most often invoked in the case of “functional” maladies of unclear etiology and pathophysiology such as migraine, irritable bowel syndrome (IBS), and fibromyalgia (Russo 2008; Russo 2016; Smith and Wagner 2014). One of the more recent observations championed as evidence of the putative CED phenomenon is that of decreased concentrations of endocannabinoid ligand molecules (ECs) in the cerebrospinal fluid (CSF) of patients suffering from migraine (Russo 2016; Sarchielli et al. 2007). However, a brief assessment of the cannabinoid literature gives some insight into just how complex and unclear the issue of endocannabinoid deficiency is, particularly regarding the suggestion that cannabis should have some therapeutic value in treating it. For instance, and confounding to the notion of a cannabis treatable deficiency, ECs are found to actually be elevated in fibromyalgia patients (Kaufmann et al. 2008; Stensson et al. 2018). Moreover, heavy cannabis use correlates with hospitalization for symptoms of IBS (Patel et al. 2020; Adejumo et al. 2019). Though a causative relationship between the two has not been established (e.g. do people with aggravated IBS tend to treat it with cannabis?), the correlation should perhaps not come as a surprise given that GI disturbances are often noted as among the more prevalent AEs in cannabinoid clinical trials (Aviram and Samuelly-Leichtag 2018).

In terms of the proposed migraine correlation, CSF or serum levels of endocannabinoids presumably represent average residuals resulting from the sum of EC release over time. Deficiency may therefore be expected to result from the dysregulation of any number of processes in the many neurons and other cells contributing to this total EC pool. For instance, given the retrograde inhibitory nature of EC signaling in several tissues, we can expect that low levels of ECs would result from reduced primary neurotransmitter activity (e.g. glutamate, GABA, serotonin, acetylcholine are not being released and thus are not triggering the release of ECs) (Ohno-Shosaku and Kano 2014). Might we not then expect supplementation with cannabinoid agonists to further down-regulate the release of these same primary neurotransmitters that are already lacking, potentially exacerbating the underlying problem and leading to the sorts of IBS outcomes correlated with cannabis exposure? More broadly, how does saturation of the CNS with phytocannabinoids – which are characterized by whole body distribution, lack of target specificity, and both up and down regulation of excitatory (e.g. glutamate) and inhibitory (e.g. GABA) pathways alike – yield an expectation of fixing the deficiency at any given location or cell type without causing cannabinoid excess or imbalance elsewhere (Laaris et al. 2010; Colizzi et al. 2019; Colizzi et al. 2016; Pretzsch et al. 2019)? After all, the one thing that can be said with reasonable certainty about the pharmacology of cannabinoids is that excess activity (e.g. THC agonism of CBR1) is associated with an assortment of adverse outcomes. It might be countered that CED must be treated with the appropriate exogenous cannabinoid or entourage. But such a distinction is notably missing from discussions of the issue in popular outlets, which is perfectly in step with the fact that there is no clear data regarding what that appropriate species might be.

Even more intriguing is the prospect of EC deficiency resulting from excessive metabolism through any number of pathways. In this case, not only would a net decrease in EC levels be expected, but the pursuant increasing concentration of pharmacologically active metabolites would need to be considered as well. In a word, it is certainly plausible that lower concentrations of ECs are not the cause but rather a result of or marker for some other underlying pathology. For example, the utility of NSAIDs in the treatment of migraine frames an interesting question regarding the role of cyclooxygenase (COX) enzymes and how they might affect EC concentrations (Pardutz and Schoenen 2010). To begin with, Bishay et al. have found that increased COX-1 expression correlates with deficiency of the endocannabinoid anandamide (AEA) in aged mice (Bishay et al. 2013). The authors further report that upregulation of fatty acid amide hydrolase (FAAH) – also expected to result in decreased AEA levels – specifically did not correlate with nociceptive hypersensitivity in these same mice while upregulation of COX-1 did. These findings suggest that excessive cyclooxygenase activity may indeed lead to measurable/functional decreases in EC concentrations. More to the point, they suggest that it is not deficiency in AEA per se that is causing the pathology (Bishay et al. 2013).

In the case of migraine pain signaling, COX-2 may play a more pertinent role as its activity has been reported to be upregulated in migraineurs (Li et al. 2017; Tassorelli et al. 2020). Further implicating cyclooxygenase metabolism of ECs is the fact that COX-2 efficiently transforms both AEA and the other main endocannabinoid, 2-arachidonoylglycerol (2-AG), into pro-nociceptive prostaglandins (PMF_2α and PGE₂ – glycerol ester, respectively) (Gatta et al. 2012; Hu et al. 2008). Of interest here is the suggestion by some that the observed decreased expression of EC catabolic enzymes (e.g. FAAH) in migraineurs might serve as a corrective response to low EC levels (Russo 2016; Cupini et al. 2008). But multiple other authors have conversely suggested that COX-2 (and other alternative pathways of EC metabolism) may take over when normal EC deactivating enzymes (e.g. FAAH and MAGL) are underactive (Bishay et al. 2013; Cupini et al. 2008; Greco et al. 2018). This suggests a mechanism for pain and hyperalgesia that is not the result of EC deficiency but rather of their metabolic repurposing. Perhaps the most intriguing finding pertinent to the role of cannabinoids in the pathophysiology of migraine (and pain in general) is that, while 2-AG has been observed to suppress COX-2 expression, THC actually induces it (Chen et al. 2013; Zhang and Chen 2008). When such findings are considered along with the fact that chronic THC or cannabis exposure have been associated with 1) a decreased response to NSAID analgesia, 2) possible tolerance to the analgesic effects of cannabinoids on migraine, and 3) reports of worse pain or hyperalgesia, it’s hard not to wonder if a common mechanism is at play (Anikwue et al. 2002; Boehnke et al. 2019; Salottolo et al. 2018; Walter et al. 2015).

Moving beyond animal models, Beckmann et al. have reported that earlier initiation and longer use of cannabis were causative of increased headache incidence in patients being treated for dependence or addiction (Beckmann et al. 2012). Analysis of the presented data is complicated by the fact that while 80.5% of the studied subjects were being treated for cannabis abuse, many were using multiple illicit substances. Still, the authors also found that only 5.5% of subjects had experienced headaches before their addiction to the various studied substances. These correlations were not described as particular to migraine, but migraine was the most common specific headache type reported by cannabis users in the study (25%). Furthermore, 49.1% of cannabis users reporting headaches (type not specified) indicated an association with drug withdrawal. This may be an important observation, as others have noted cannabis withdrawal as a precipitant of migraine (el-Mallakh 1987; Crippa et al. 2013; Adorjan et al. 2020). Caution is warranted in the interpretation of these data as most are derived from case studies or reports of mixed substance abuse. It can also certainly be argued that the observed migraine activity would be expected from cessation of a medication that is preventing migraine attacks. However, given the rarity of pre-abuse headache incidence noted by Beckmann, such migraine data can also be interpreted as suggesting migraine as a withdrawal symptom resulting from long term cannabis use creating/worsening an underlying pathology that is merely masked by ongoing exposure.

Finally, it is worth noting that, while anecdotes are often offered as evidence of the therapeutic utility of cannabis, anecdotal reports can vary greatly depending on where one goes looking. To wit, Andersson et al. have performed a qualitative search of online illicit substance forum discussions regarding migraine and cluster headaches and found that the correlation between cannabis use and headache outcomes was unpredictable (Andersson et al. 2017). More particularly, while cannabis use was associated with improvement of symptoms in some users, others reported that it reliably exacerbated headaches or precipitated their onset. Thus, while exogenous cannabinoids may deliver relief from migraine attacks and other manifestations of pain, there seems as much reason to believe that chronic exposure to these agents may in fact exacerbate the pain for some or even perpetuate/worsen the underlying pathology over time. Indeed, the feasibility of such contradictory effects developing as a function of the time course of cannabinoid exposure can be seen in the recent findings of Ogunbiyi et al. with regards to the effects of THC on cerebral blood flow (Ogunbiyi et al. 2020). Further observations of anxiogenic and hyperemesis outcomes pursuant to high dose or long term THC exposure likewise appear almost paradoxical to the often claimed anxiolytic and well documented antiemetic properties of the drug (Sorensen et al. 2017; Crippa et al. 2009).

Still more questions

The above discussion of the role of cannabinoids in migraine is by no means a thoroughly developed hypothesis and should not be promoted as such. Admittedly, most of the noted correlations regarding COX activity are derived from small preliminary studies. Likewise, outcomes such as hyperalgesia and tolerance have not been universally observed across clinical trials but rather are noted as potential concerns based on limited data. What is important to recognize here is that the evidence base for expectations of entourage benefit or the therapeutic potential of treating “endocannabinoid deficiency” are based on the same sorts of hypothetical interpretations of limited and often equivocal or contradictory preliminary data. Ultimately, the role of EC deficiency in the etiology of migraine and other disorders is not entirely clear. Indeed, the haze in this regard should come as no surprise once it is noted that the endocannabinoid system itself is not, as of yet, well defined.

What’s in a name?

The term “cannabinoid” first came into common use in the chemical literature of the late 1960s (Mechoulam et al. 1967). It originally described a group of aromatic substituted monoterpene-derived structures first approximated in the description of cannabinol by Adams in 1940 (Structure of Cannabinol 2020). But it wasn’t until Mechoulam and Gaoni identified THC as the primary psychoactive component of cannabis in 1969 that efforts to describe the molecular mechanisms of its profound pharmacological effects were finally enabled. What followed were roughly two decades of in vitro, animal, and small human studies that discovered multiple potential therapeutic applications of THC and directed development of numerous synthetic derivatives. This work ultimately led to the nexus at which the definition of a “cannabinoid” broadened from merely chemical to functional. In 1988, Devane et al. described a novel G-protein coupled receptor (ultimately designated as the first cannabinoid receptor, CBR1) characterized by its specific binding of THC and other known cannabinoid species (Devane et al. 1988). A second cannabinoid receptor (CBR2) was subsequently identified by Munro et al in 1993 based on its homology to CBR1 and its binding of multiple synthetic and plant derived cannabinoids (Munro et al. 1993). Rounding out the original core of the endocannabinoid system were the two previously mentioned endogenous ligands: AEA, identified in 1992 by Devane et al., and 2-AG, identified in 1995 by Sugiura et al. (Devane et al. 1992; Sugiura et al. 1995).

But the endocannabinoid system, as it is currently envisioned, is no more inherently cannabinoid in nature than the opioid system is opioid in nature. What’s more, the familiar endogenous hormones and receptors commonly invoked to define it may be more aptly considered as components of an “arachidonoid” system, if any weight is going to be given to human biochemistry in its classification. It is further worth recognizing that many of the known cannabinoids (both endogenous and otherwise) have been found to affect the function of a wide variety of enzymes, receptors, transporters, channels, and transcription factors throughout the body (Pertwee et al. 2010; Alhouayek and Muccioli 2017; Ibeas Bih et al. 2015). Indeed, these molecules are apparently such promiscuous actors that one can’t help but wonder if any single signaling system can rightly claim them at all through any appeal beyond that of chronological serendipity (i.e. someone else hadn’t already named the targets before they were found to interact with a “cannabinoid”). Adding to this complexity is the fact that the most commonly recognized modern cannabinoid receptors and enzymes (e.g. CBR1, CBR2, TRPV1, FAAH) appear to have multiple endogenous ligands and substrates, respectively (Di Marzo and De Petrocellis 2012; Bisogno et al. 2002; Suh and Oh 2005). Moreover, as is seen above with the EC derived prostaglandins, if we further consider the pharmacological activity of the many EC analogs derived from a variety of metabolic pathways, the regulatory domain of these molecules is discovered to be truly vast (Guindon and Hohmann 2008; Kantae et al. 2017).

Surely, there is no reason to hold the endocannabinoid system in contempt for its appellation as those who identify novel systems retain the right to name them as deemed appropriate and, in this case, have done so in congruence with long held convention (e.g. opioid receptors, muscarinic receptors). However, it is important that our expectations of pharmacological pertinence not be guided by the artifacts of nomenclature. That is to say, there is no particular reason to expect that phytocannabinoids should deliver any particular therapeutic effect through interaction with the endocannabinoid system. This is made particularly clear when one takes into account the confounding clinical observations noted above. It is furthermore difficult to define what a “clinical endocannabinoid deficiency” might entail when it is unclear what exactly constitutes the endocannabinoid system it is proposed to affect. It thus seems premature to suggest that dysregulation of so complex and still nebulous a web of interactions can be broadly considered as a simple “deficiency”. All that can be said with certainty is that some of the known phytocannabinoids have been shown to affect the activity of several human proteins and that some of these are recognized as part of the quite arbitrarily named “endocannabinoid system”.

In all, suggestions of treating CED with phytocannabinoids, given the current evidence base, make about as much sense as advocating for the supplemental consumption of Inocybe mushrooms to address “muscarinic deficiencies” or P. somniferum to remedy “opioid deficiencies”. Pharmacotherapy is a bit more nuanced than hitting receptors with their chemical namesake; a lesson learned in part from traveling this presumptive road before (Haller 1989). That is not to imply that cannabis is as dangerous as opium (or any given alkaloid) but rather that we are still grossly ignorant as to the clinical effects of the plant and its many constituents. This is particularly true of modern mega-dosing trends and relatively novel routes of administration as noted above. It will certainly be argued that the therapeutic claims made of cannabis are based on empirical observation and not merely expectations directed by hypotheses and the artifacts of nomenclature. But in the absence of appropriate clinical evidence, such suggestions remain uncompelling. No doubt it is the long-standing prohibition of cannabis that is to blame for this failing, but regardless of how we arrived, here we are nonetheless.

Conclusion

As is the case with the presumed “entourage effect”, claims of clinical endocannabinoid deficiency would be of little concern if it were not for the fact that they are already being brought directly to market. And while the complexity and diverse nature of available evidence does not preclude the reality of CED nor the utility of cannabinoids in pain management of any kind, it certainly calls into question the appropriateness of bringing such claims to popular outlets and retailers as if they were established facts. There would at first appear to be a rather simple answer to this mess: fund and conduct large, well designed, sufficiently powered, and properly blinded RCTs. That is the most reliable way to lay these questions to rest, deficiency or no. Unfortunately, until legislation and regulation manage to catch up with the industry, there will remain little incentive to perform such trials.