From Cod to Cannabis

In Alice’s Adventures in Wonderland, the Mad Hatter (an alleged victim of mercury poisoning) asks the koan ‘Why is a raven like a writing desk?’ The best answer I’ve seen (better than Carroll’s own) is that Poe wrote on both of them. My question is, why are cod like cannabis?

To begin with, there is more to fish than PUFAs and polyphenols.

They also contain lesser-known omega 3-polyphenol conjugates termed lipophenols, which play a critical role in mediating the anti-inflammatory effects of a fish-based diet. I will return to these important molecules in a pending post (1). The removal of lipophenols and polyphenols from those refined fish oils which currently dominate the supplement market renders these products borderline ineffective and, for some vulnerable groups, harmful (2).

That is a substantial missed opportunity, because if fish and/or algal oil were to be appropriately chaperoned, pro-inflammatory breakdown products (2) would no longer neutralise or overshadow the positive ones. The potential health benefits of fish oil would then come to the fore, and match those of consuming oily fish/

It is a matter of downstream chemistry, and metabolic modulation

Once fish oil has been ingested, even if it is the usual refined / degraded stuff, a metabolic cascade then produces a host of bioactive compounds. These include the Specialised Pro-resolving Mediators (resolvins, protectins and maresins), which have complementary anti-inflammatory and analgesic effects (ie 3-5). But these are just the hors d’oeuvres.

Those Omega-3 PUFAs not used as fuel in mitochondrial beta-oxidation or stored in adipose tissue, are incorporated into the phosphatidyl phospholipids which make up the basic cell membrane. Once in place they are able to form conjugates with other moieties in those phospholipids, specifically ethanolamine and glycerol. They also form complexes with the neurotransmitters 5HT and dopamine (DA), which localise within those membranes.

When EPA and DHA are linked to ethanolamine they form omega-3 ethanolamides, fatty acid amides which are analogues of the better-known PEA and OEA (6). These EPA and DHA conjugates encourage synapse formation and neurite growth in the brain (7, 8), processes central to learning and intelligence, and to warding off dementia. By a happy coincidence there is clinical evidence that a diet rich in oily fish promotes connectivity in the brain (9), and various aspects of intelligence (9, 10).

The importance of these particular metabolites is evidenced by the fact that even basic fish oil supplements improve brain function and structure in elderly subjects (14).

Caveat: Age is an important variable, and these results might not be repeatable in younger subjects.  Dietary changes linked to subjective feelings about the importance of eating a good diet can actually favour the elderly in at least some nations (15), resulting in better antioxidant status than in younger people (15). Elderly subjects would thus be expected to produce a more favourable spectrum of omega-3 metabolites, with less pro-inflammatory and toxic oxidation products.

This last study (15) was carried out in Greece in 2012, and is probably no longer valid. The immiseration of Europe, which accelerated after the CIA-sponsored coup in Ukraine in 2014 and again after the same bad actors blew up the North Sea gas pipelines in 2022 (16), is swelling the numbers of Europeans suffering from food poverty (ie 17-20). The elderly are particularly hard-hit in countries with poor social networks (ie 21), and the pending financial crash will remove many of them from the board.

Back to the science.

When EPA and DHA conjugate with glycerol they form EPA- and DHA-glycerols.

These compounds are not quite as well characterised as the ethanolamine compounds, but there is tantalising evidence that they may offer an entirely new approach to pulmonary hypertension (22). This serious condition is increasing (23), and while survival times have been extended it is not particularly well managed. Eating more oily fish seems a prudent preventative strategy or add-on to current therapy (24, 25).

EPA and DHA also form conjugates with the neurotransmitters serotonin (5HT) and dopamine (DA). 5HT conjugates occur naturally; DHA-5HT, for example, is formed in the gut and displays anti-inflammatory / immune-modulatory functions (ie 26, 27). DA conjugates have not been found in situ, but are being synthesised for possible use as pharmaceuticals.

Collectively, these newly recognised compounds have potentially important anti-cancer effects (28-30). They also modify neurotransmitter activity in the brain (31-33) and hence, in all likelihood, impact on mood and other aspects of brain function ranging from impulse and appetite control to creativity and social engagement.

And here is where cod and cannabis collide; in the endocannabinoidome.

The arachidonic acid conjugates anandamide and 2-arachidonoylglycerol, which act primarily at CB1 and CB2 receptors, are categorized as primary endocannabinoids (31). These, together with the enzymes that form and degrade the primary endocannabinoids, form the classical endocannabinoid system (ECS). This is part of a much larger whole, which includes:

The omega-3 analogues and their natural and synthetic DA and 5HT conjugates, which could be regarded as secondary endocannabinoids, act at different receptors (TRPV1, GPR55, the PPARs,) and add a wide range of different functionalities. PEA and OEA (6) are not considered to be endocannabinoids, but they modify the effects of endocannabinoids by increasing CB2 receptors and slowing endocannabinoid catabolism (AKA the ‘entourage effect’).

Add on other signalling molecules including various hormones and neurotransmitters, and a range of nutrients which modify ECS activity (see below), and you have the endocannabinoidome (eCBome), a complex and fundamental homeostatic system which buffers most and perhaps all bodily functions from a wide range of internal and external stressors.

The ECS gets its name from cannabis, a treasure chest of biological actives that far outstrip ergot in their chemical, pharmacological and medical diversity, and act on a range of ECS components. Cannabis compounds such as THC work mostly (but not exclusively) on CB1 and CB2 receptors. Fish oil conjugates act at these same receptors and like THC exert neuro-protective, vasodilator, anti-platelet, anti-inflammatory and anti-nociceptive effects (31, 34); but without psychoactivity.

Some fish are genuinely hallucinogenic (35), but you cannot get high on hake because the effects of 3-PUFA conjugates at the CB1 and 2 receptors are subtly different from those of THC. This is not classic lock and key pharmacology, not by a long way.

The complexity of the eCBome, fundamentally a stress-buffering system designed to promote active adaptive responses (36), is breath-taking. When an agonist such as THC attaches to a receptor, that receptor may adapt by up- or down-regulating its response to THC, or to a set of entirely different agonists. It may recruit or damp other receptors, which may modify the activity of many other parts of the ECS (the ‘entourage’ effect again). This profoundly non-linear, reflexive and stochastic system gets even more complicated when you consider that it has wide-ranging epigenetic effects (37); likely involving, inter alia, the omega-3 conjugates.

The fact that these omega-3 compounds act at CB1 and CB2 receptors but do not exert psychoactive effects raises the possibility of using docosahexaenoyl-ethanolamide (DHAEA) and other omega-3 conjugates to gain analgesia and neuroprotection, without destroying the work ethic (29-32, 34). The analogous fatty acid amides palmitoyl- and oleoyl-ethanolamide have similar profiles (6, 38), making this is a promising area for the development of novel analgesics, anxiolytics, neuro-protectants and gerosuppressants.

The fact that people suffering from chronic pain often self-medicate with alcohol provides another interesting angle. DHAEA reverses the deleterious effects of alcohol on neuronal energy sensing and production (39), and micro-structure (40). There is not yet quite enough evidence to justify mixing vodka with fish oil but it is starting to look like a good idea (41), though a terrible cocktail.

The complexity of the endocannabinoidome and its interaction with the machinery of inflammation is highlighted by the fact that conjugates of the omega 6 PUFA arachidonic acid, long demonised as a pro-inflammatory molecule, possess significant anti-inflammatory properties. Anandamide, 2-arachidonoylglycerol and AA-5HT all demonstrate anti-inflammatory and/ or analgesic properties (42-45).

eCBome chemistry suggests that the old model of pro-inflammatory omega 6’s and anti-inflammatory omega 3’s will have to be substantially revised – and there is further evidence for this. Recent large-scale analyses failed to find convincing relationships between LA intakes (46), and omega 6 and 3 blood levels (47), and any of the measured inflammatory markers (47).

This doesn’t necessarily prove that the old model was wrong. The subjects sampled in the 6:3 ratio paper (47) almost certainly included many who consumed primitive (simple) fish oils, and were producing pro-inflammatory breakdown products as a result (2, 48).

However, these findings imply that the old model is incomplete, and that factors other than the 6:3 ratio and 3 index influence the drive to observed clinical endpoints.

The results of another recent study (49) support the same conclusion. According to the authors, “The results highlight the importance of individual metabolism in the prevention of cardiovascular disease. The effects of EPA varied more between individuals than we expected.”

This last study did not use fish oil but the drug icosapent ethyl, a strategy which reflects the interests of the pharma industry rather than good nutrition. Nevertheless, I applaud the researchers’ honesty and agree with their findings. The fact that many of us previously believed in a single-order system reveals us as reductionist and rationalising rather than rational beings.

I previously cited a wide range of dietary factors which modify the inflammatory cascade at different points in the sequence (50). Now the cloud of nutrients and metabolites that modify the ECS, up- and down-regulate inflammatory sequences, and influence the degree and rate of tissue damage, must be expanded again. For example …

Cocoa contains small amounts of anandamide and related compounds (51), as do black truffles (52). Echinacea contains alkylamides (53) and hops terpenes (54) which modify ECS activity indirectly (the ‘entourage effect’ again), by altering the bioavailability and distribution of endocannabinoids.

Black pepper is a good source of piperine, an alkaloid which acts at the TRPV1 receptor (55), a key component in the ECS; as does the capsaicin in hot chillies (56). Cloves and basil contain the sesquiterpene beta-caryophyllene, which binds directly to CB2 receptors (57). Cruciferous vegetables contain kaempferol and related compounds which, by inhibiting the enzyme FAAH, boost anandamide synthesis and so modify ECS activity in a different way again (58).

All of these compounds, derived from food and medicinal plants with a rich history in folk lore, act mechanistically in ways that parallel their traditional uses. Many of their effects are mediated by an ability to reduce inflammatory, neuro-inflammatory and other stress.

In other words, a significant portion of the medical and folkloric history of these plants appears to be rooted in ECS modulation.  The pharmacological actions of their constituent compounds within the eCBome explain how and why they are able to induce relaxation and mood enhancement, reduce inflammation, enhance libido, energy and multiple aspects of cognitive and affective function, regulate appetite and sensitivity to pain, support maternal bonding … (55, 59-61).

This has wide-ranging implications for our individual and collective health.

Each time you eat you re-initiate a complex, nuanced and metabolically buffered conversation with the outside world, which is further buffered by your epigenome and microbiota (see below). It is a conversation that will last until your death, and will likely affect how and when you consume the last supper.

Many of the plant foods described above have been systematically abstracted from today’s industrial foods, removing ECS modulators from the diet. The extraordinary increase in our omega 6:3 ratio over the last century (62) has likely impacted the ECS rather more directly (63, 64), likely causing ECS over-activation (65) and an increased risk of cardiometabolic and neoplastic disease (66, 67).

The ECS is an extremely effective buffering system and is – among other things – designed to smooth out the metabolic perturbations caused by ingesting complex combinations of chemicals, AKA eating. This explains why omnivores like us have more complex ECS systems (see table, below); but the industrial diet is toxic enough to swamp even our extra-wide safety margins.

Physical activity plays into this. During and after exercise, the body produces primary and secondary cannabinoids which act on the ECS to regulate mood, pain, stress, and inflammation. This mediates many of the benefits of exercise, including the ‘runner’s high’ (68, 69), and the anti-depressant effects noted by Hippocrates and those who came after him (70).

And our microbes are involved, of course. The ECS plays a key role in regulating the gut microbial population, and is profoundly influenced by it (71). Dysbiosis damages the colonic epithelial barrier, and this damage is partly mediated by local changes in the ECS (71). The profound lack of prebiotic fiber in the modern diet reduces the formation of short chain fatty acids in the gut and promotes excessive inflammation, skewing the ECS very unfavourably.

This ECS skew is not only involved in fuelling the ongoing tides of obesity and metabolic syndrome (72), but also – via the gut-brain axis – the increasing numbers of humans suffering from anhedonia and pathetic passivity (73, 74), poor impulse control and addictive behaviour (75), and depression and anxiety (76). In short, the industrial diet has created Generation Z, a gift to the comprador politicians and sociopathic families who rule over us.

Never in the history of our species have we consumed more sugars, starches and omega 6 lipids, and less fiber and phytochemicals than we do today. Never in human history have our lives been less physical, dysbiosis more prevalent, our ECS more damaged and our psyches more fragile (77).

No wonder we are so sick, with sell-by dates looming ever closer (78, 79). Our endocannabinoid systems are out of joint. O curse Speise!

End Note: The following graphic overview and the evolutionary table were developed by Stefan Broselid at ECS.Education, to whom I am most grateful; also for his valuable feedback while writing this post.

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