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Sunday, 16 May 2021

Is cannabis protective against an adverse effect of the modern diet? Cannabinoid signaling in the omega 3/6 hypothesis of obesity and mood disorders.

(this post originally appeared for subscribers on my Patreon blog in Dec 2020, and is now unlocked. If you want to support my blogging habit and see these posts before they happen, subscribe here!
The rest of you, enjoy.)

It’s pretty well accepted that cannabis is an appetite stimulant in the normal dose range. In fact, it’s pretty much been the unofficial standard-of-care drug for the treatment of appetite loss during illness or chemotherapy for a long time.
So we’d expect people smoking cannabis to have higher rates of obesity and type 2 diabetes, because of the munchies.
Yet it’s been a consistent epidemiological finding that the opposite is true – and the explanation that’s been proposed may give us an insight into why cannabis has become the modern panacea, a drug that has been proposed to treat almost everything and why its legalisation, especially for medical use, is being welcomed by such a large chunk of the population.

How consistent is the association between cannabis use and obesity? In a meta-analysis of BMI data:
“Nine studies were included that reported BMI of users and nonusers and met selection criteria, and an additional two studies were identified that reported lower BMI in Cannabis users, but did not provide numerical data. Of these studies, all reported lower values of BMI in Cannabis users, and only one of these did not reach statistical significance. A second study did not report statistical analysis of the BMI data. Of those studies reporting significant negative correlations, two reported that longer duration of Cannabis use was associated with reduced BMI.”(Clark 2018)

That’s a convincing association as far as it goes, but is there a mechanism that explains it?

In another paper, we read that “Suppressing hyperactive endocannabinoid tone is a critical target for reducing obesity.”(Alvheim 2012) The endocannabinoids, 2-arachidonoylglycerol (2-AG) and anandamide (AEA), promote both appetite and the growth and expansion of fat cells.(Naughton 2013, Banni 2010, Madsen 2012) This is a useful adaptation to store energy after a meal (or in the autumn, when linoleic acid, like sugar, is most easily found in nature) - but if it becomes a constant state can lead to obesity; with higher food (and especially carbohydrate) intake insulin levels also rise, ensuring more synthesis and storage of fat. When this fat exceeds the capacity of the body to store it, type 2 diabetes is one possible outcome, and at this stage it is very difficult to get the appetite to normalise; at which point removing carbohydrate from the diet seems to be the most effective way to reduce food intake without hunger.(van Zuuren 2018)

A drug that antagonises 2-AG and AEA, Rimbonabant, looked promising in animal studies but turned out to cause depression in humans.

Cannabis, of course, has similar effects to 2-AG and AEA, but the body’s response differs in an important way; we respond to the stimulation of endocannabinoid tone from THC and CBD by downregulating it, and this inhibition lasts longer than the effect of the drug does. In a sense, smoking pot inoculates us against excessive endocannabinoid signalling. This counter effect means that our cells burn more energy, rather than store it, and our appetite decreases, for quite a while after a session, even if we did have the munchies at some point.(Clark 2018) In a recent epidemiological study even historical cannabis use was associated with lower BMI and better insulin sensitivity. The rebound effect seems to last. Users probably don’t want to be saturated in cannabis all the time, but be using it intermittently to benefit.

But where does this excess endocannabinoid tone come from in the first place? 2-AG and AEA are made in the body from arachidonic acid, an omega-6 (ω-6 or n-6) fatty acid only found in animal foods – but the amount of AA in these foods is very low. Most AA in the body is synthesised from linoleic acid, the main polyunsaturated fatty acid in cheap vegetable oils (corn oil and soy oil, for example, are around 60% LA).

(Pathways for anandamide synthesis, from Naughton et al 2013)

So, what counters the obesogenic effect of anandamide and 2-AG naturally? The action of omega-6 endocannabinoids is opposed by omega 3 (ω-3, n-3) endocannabinoids, docosahexanoyl ethanolamide (DHEA) and eicosapentaenoyl ethanolamide (EPEA), which have a weaker binding affinity to CB1 and CB2 receptors.(Naughton 2013, Watkins 2014) The omega-3 cannabinoids are synthesized from DHA and EPA, the fatty acids in oily fish (pastured lamb or mutton is also a pretty good source). EPA and DHA can also be synthesized from alpha-linolenic acid (ALA), the omega-3 fatty acid found in flaxseed, canola oil and hemp oil (and present in small amounts in most green veges). However, it looks as if too high an intake of ALA also suppresses blood levels of EPA and DHA.(Gibson 2018)
(There is also an omega-9 cannabinoid, made from the main monounsaturated fat oleic acid, which counters the effects of the omega-6 series, decreasing appetite and increasing fat-burning, but this does not seem to depend on dietary intake. Oleic acid is produced in the body as well as an item of diet; it is synthesised after meals from carbohydrate and other fats, so its cannabinoid probably acts as a fullness signal).

It’s been known for a while that a higher intake of LA drives synthesis of AA and inhibits the conversion of ALA to EPA and DHA.(Gibson 2018) This is probably why fish oil became popular as a supplement, but fish oil has had relatively disappointing results in human trials. The only fish oil product approved as a drug (for cardiovascular disease) is VASCEPA, a synthetic variant of EPA which is reliably able to raise the EPA level in the bloodstream.

However, research out of Australia and France shows that saturated fat, especially dairy fat, increases the level of EPA or DHA in the bloodstream, in people fed omega 3 fatty acids from fish oil or canola oil respectively, compared with people instructed to use vegetable oils as per common governmental health advice.(Dias 2016, Dabadie 2005)  The Australians achieved a doubling of the EPA level when the other fat in the diet was more saturated. Yet the LDL (so-called “bad cholesterol”) level also increased.(Dias 2016)

Why would this be? EPA and DHA trigger the burning of fat in the liver – this is a good thing, lowering triglycerides, but it means these omega-3 fatty acids are destroyed in the process so less will reach the bloodstream in the lipoprotein (“cholesterol”) particles. Some saturated fats, especially the longer medium-chain fatty acids in dairy and coconut, also trigger fat burning and lower triglycerides – and this tends to spare some of the EPA and DHA present, so that other cells in your body can use it.(Drouin 2018)  But removing triglycerides from lipoproteins in the liver means they come out with less fat, and therefore more cholesterol. This raises your LDL-cholesterol, yet these cholesterol-rich LDL particles are less likely to harm your blood vessels than cholesterol-depleted ones.(Hirayami 2012)

It’s noticeable that the true relationship between dietary saturated fat and omega-3 is thus the opposite of that described in influential early books about omega-3 fatty acids, such as Horrobin’s “The Madness of Adam and Eve” and Allport’s “The Queen of Fats”, which painted them as enemies, based on a priori assumptions.

Our diets used to be very low in omega 6 LA. This changed for two reasons – first we were told to replace animal fat with polyunsaturated vegetable oil for cooking because this would lower cholesterol and so reduce the risk of heart disease. But human experiments have never supported this idea. In particular, a meta-analysis of those trials replacing saturated fat with oils and foods high in LA (rather than omega 3 fats) found that the risk of heart disease and death was non-significantly increased in those trials that were properly controlled.(Hamley 2017)
The second reason is that more of our animal-based food today comes from animals fattened on grains. The fat of chickens and pigs fed on corn and soy waste can be very high in LA and higher in AA compared with the fat of the same animals in the past, and even ruminant fat gets higher in LA and AA, and lower in EPA and DHA, when sheep and cattle are fattened on grains.

Guyenet and Carlson analysed all the different studies done over the years measuring the fatty acid percentages of fat stores in samples from people in the USA and found “that adipose tissue LA has increased by 136% over the last half century and that this increase is highly correlated with an increase in dietary LA intake over the same period of time”.(Guyenet 2015)

Adipose LA in Sweden, for example, is significantly lower than in the USA – Scandinavians still eat plenty of meat and dairy fat, and when they do use plant oils prefer canola, which has 1/3 the LA content of soy or corn oil, or olive oil with 1/6 as much; they are also more likely to eat oily fish than Americans. The official recommended limit of saturated intake in some Scandinavian countries is significantly higher than the 10% of energy limit recommended in the USA, UK or NZ. The Swedes enjoy lower rates of obesity, type 2 diabetes, and heart disease than we do with a saturated fat limit which they seem to ignore.

As Clark et al stated in their hypothesis paper,

“…populations with diets characterized by a high omega-6/omega-3 ratio will see significantly larger health improvements from Cannabis use than those eating diets with more moderate ratios of omega-6/omega-3 FAs. This may explain some of the inconsistencies in the data on the metabolic impact of Cannabis use; for example, Cannabis use by Swedish populations may not have the same health impacts as Cannabis use by Americans due to the different dietary backgrounds and obesity rates of these populations.
Cannabis use in the United States appears to provide significant public health benefits due to partial or complete reversal of the metabolic dysregulation caused by the strongly elevated omega-6/omega-3 ratio of the American diet

(Note: If “cannabis use… appears to provide significant public health benefits” in a preventive sense, then the distinction between medicinal and recreational uses of the drug becomes a little blurred, as some medications, such as aspirin or statins, can be legally be prescribed to perfectly healthy people for their purported preventive effects, despite there not being strong evidence for such effects outweighing harms.)

Are governments blind to the possible harms of a high omega-6 intake? The New Zealand MOH is still recommending that high-omega 6 seed oils replace animal fats and coconut oil. Why?

Some public health experts still want us to have low cholesterol levels, despite a lack of evidence that the cholesterol effect of food (as opposed to genes or drugs) has any effect on disease risk.
Some also point to epidemiology in which higher linoleic acid intakes appear to be associated with benefit.
Unfortunately, this isn’t as reliable as it might be – the only foods that supply zero LA are sugar, alcohol, and highly refined flour. The less of these foods you consume, the better – and the higher your LA intake will be. None of these studies separates out the LA consumed from seed oils, as opposed to chicken or nuts and seeds, foods which might reasonably be expected to keep you healthy for other reasons than the type of fat they contain – there is no epidemiology of seed oils. How do you even measure cooking oil accurately in a questionnaire? Those takeaway chips you ate last week – do you remember what they were fried in?

But despite only weak evidence for benefit, plenty of negative evidence, and growing evidence of harm, the push continues. In 1987 the government of Mauritius introduced a raft of health measures, most of which were sensible (smoking, exercise, blood pressure control) but also ordered that soy oil replace palm oil in the cheap “ration” oil used for cooking by most people. 5 years later public health experts applauded a decrease in saturated fat intake, a large increase in polyunsaturated fat, and lower cholesterol levels.(Uusitalo 1996) But what was the outcome 10, 20 years later? Cardiovascular mortality increased a bit, BMI increased– and the prevalence of type 2 diabetes increased from 12.8% in 1987, to 15.2% in 1992, and 17.9% in 1998.(Morrell 2019, Söderberg 2005) Mauritius is now fighting the same type 2 diabetes epidemic seen in most other countries after seed oils were introduced. Yet the government of Fiji imposed a tax on palm oil in 2015 to try to get the same outcome, citing the Mauritius experiment as if it had been successful – because no-one involved had published anything suggesting that it wasn’t.(Coriakula 2018)
But while governments and establishment public health experts may appear to be blind to this problem, behind the scenes efforts to lower the amount of omega-6 in the food supply have been going on for decades. These initiatives include the development of canola and more recently the breeding of “high-oleic” oil seeds that are much lower in omega-6. For example, recently Pic’s peanut butter and peanut oil switched to using a high-oleic peanut, and these products now contain a far lower dose of linoleic acid than most other brands.
At present high-oleic oils and nut butters cost a bit more. The linoleic acid in the food supply, found in cheap oils, margarines and mayonnaise, and deep fried food, especially chicken (the cheapest meat), is tilted towards the diets of the poor, and alongside the similarly cheap refined carbohydrates is doing them no favours, whatever diet epidemiology, which is generally done in more privileged populations, might say.

Is this theory relevant to the psychotropic uses of cannabis in modern society?
I haven’t researched this question deeply, but here are some pointers -

The omega-3/6 balance also influences inflammation and pain perception; a high omega-3 and low omega-6 diet in people with chronic headache reduced pain. The control group restricting omega-6 alone, with no extra omega 3, had a lesser reduction in pain and saw some raising of EPA in the blood, but did not experience the drop in AA that was seen in the omega-3 arm.(Ramsden 2013, Taha 2014) Of course, pain relief is an important use of cannabis.

Omega-3 fatty acids supress some effects of PTSD in animals, and Hibbeln and Gow, writing in the journal of Military Medicine, proposed that improving the omega-3/6 ratio in military rations would reduce depression, suicide, and impulsive aggression among US troops.(Hibbeln 2014) In a case-control study, low DHA status was more strongly associated with suicide in US troops than having witnessed the death or wounding of colleagues in combat (OR 1.62 vs 1.54).(Lewis 2011)

There’s an interesting study on the effect of cannabis use during CBT therapy for PTSD and substance use disorders – “results revealed a crossover lagged effect, whereby higher cannabis use was associated with greater PTSD symptom severity early in treatment, but lower weekly PTSD symptom severity later in treatment. Cross-lagged models revealed that as cannabis use increased, subsequent primary substance use decreased and vice versa”.(Ruglass 2017)

A high-dose EPA supplement in children with ADHD aged 6-18 significantly improved measures of attention and vigilance in those subjects with low EPA at baseline.(Chang) A trial of Sativex in adults with ADHD found “nominally significant” improvement in some measures tested, not contradicting the anecdotal reports from this population of cannabis users.(Cooper)

Acetaminophen (paracetamol) is a painkiller that enhances cannabinoid signalling through CB1 receptors in the pain centre of the brain.(Klinger-Gratz 2018) Paracetamol also reduces the pain of social rejection, empathy for the pain of others, and the experience of existential angst after exposure to material that provokes what psychologists call a “meaning threat”, defined as “whenever one is assaulted by thoughts and experiences that are at odds with one’s expectations and values” - represented in the experiment by the films of David Lynch played to people who hadn’t seen them before!(Mischkowski 2016, Slavich 2019, Randles 2013)

And now we’re getting into deep psychological and sociological territory indeed. Has the remodelling of diets (and reformulation of infant formulas) since the 1970s altered our social functioning? Should it join the long queue of factors proposed to account for our current malaise? Or has David Lynch just made too many films?

More research is needed.
But one thing does seem clear – for good or bad, cannabis probably is an appropriate medication for our times, and the widespread modern awareness of its efficacy may have complex roots in the recent history of our society.


Alvheim, A. R., Malde, M. K., Osei‐Hyiaman, D. , Hong, Y. H., Pawlosky, R. J., Madsen, L. , Kristiansen, K. , Frøyland, L. and Hibbeln, J. R. (2012), Dietary Linoleic Acid Elevates Endogenous 2‐AG and Anandamide and Induces Obesity. Obesity, 20: 1984-1994. doi:10.1038/oby.2012.38

Banni, S. and Di Marzo, V. (2010), Effect of dietary fat on endocannabinoids and related mediators: Consequences on energy homeostasis, inflammation and mood. Mol. Nutr. Food Res., 54: 82-92. doi:10.1002/mnfr.200900516

Chang, J.P., Su, K., Mondelli, V. et al. High-dose eicosapentaenoic acid (EPA) improves attention and vigilance in children and adolescents with attention deficit hyperactivity disorder (ADHD) and low endogenous EPA levels. Transl Psychiatry 9, 303 (2019) doi:10.1038/s41398-019-0633-0

Clark TM, Jones JM, Hall AG, Tabner SA, Kmiec RL. Theoretical Explanation for Reduced Body Mass Index and Obesity Rates in Cannabis Users. Cannabis Cannabinoid Res. 2018;3(1):259–271. Published 2018 Dec 21. doi:10.1089/can.2018.0045

Cooper RE, Williams E, Seegobin S, Tye C, Kuntsi J, Asherson P. Cannabinoids in attention-deficit/hyperactivity disorder: A randomised-controlled trial. Eur Neuropsychopharmacol. 2017 Aug;27(8):795-808. doi: 10.1016/j.euroneuro.2017.05.005. Epub 2017 May 30.

Coriakula J, Moodie M, Waqa G, Latu C, Snowdon W, Bell C. The development and implementation of a new import duty on palm oil to reduce non-communicable disease in Fiji. Global Health. 2018;14(1):91. Published 2018 Aug 29. doi:10.1186/s12992-018-0407-0

Dabadie H, Peuchant E, Bernard M, LeRuyet P, Mendy F. Moderate intake of myristic acid in sn-2 position has beneficial lipidic effects and enhances DHA of cholesteryl esters in an interventional study. J Nutr Biochem. 2005 Jun;16(6):375-82

Dias, C., Wood, L. & Garg, M. Effects of dietary saturated and n-6 polyunsaturated fatty acids on the incorporation of long-chain n-3 polyunsaturated fatty acids into blood lipids. Eur J Clin Nutr 70, 812–818 (2016) doi:10.1038/ejcn.2015.213

Drouin G, Catheline D, Sinquin A, et al. Incorporation of Dairy Lipids in the Diet Increased Long-Chain Omega-3 Fatty Acids Status in Post-weaning Rats. Front Nutr. 2018;5:42. Published 2018 May 23. doi:10.3389/fnut.2018.00042

Garg ML, Wierzbicki AA, Thomson ABR, Clandinin MT. Dietary saturated fat level alters the competition between α-linolenic and linoleic acid. Lipids 1989; 24: 334–339

Gibson RA, Musings about the role dietary fats after 40 years of fatty acid research. Prostaglandins Leukot Essent Fatty Acids. 2018 Apr;131:1-5. doi: 10.1016/j.plefa.2018.01.003. Epub 2018 Jan 6.

Guyenet SJ, Carlson SE. Increase in adipose tissue linoleic acid of US adults in the last half century. Adv Nutr. 2015;6(6):660–664. Published 2015 Nov 13. doi:10.3945/an.115.009944

Hamley, S. The effect of replacing saturated fat with mostly n-6 polyunsaturated fat on coronary heart disease: a meta-analysis of randomised controlled trials. Nutr J 16, 30 (2017) doi:10.1186/s12937-017-0254-5

Hibbeln JR, Gow RV. The Potential for Military Diets to Reduce Depression, Suicide, and Impulsive Aggression: A Review of Current Evidence for Omega-3 and Omega-6 Fatty Acids, Military Medicine, Volume 179, Issue suppl_11, November 2014, Pages 117–128,

Hirayama S, Miida T. Small dense LDL: an emerging risk factor for cardiovascular disease. Clin Chim Acta 2012; 414: 215–224.

Klinger-Gratz PP, Ralvenius WT, Neumann E, et al. Acetaminophen Relieves Inflammatory Pain through CB1 Cannabinoid Receptors in the Rostral Ventromedial Medulla. J Neurosci. 2018;38(2):322–334. doi:10.1523/JNEUROSCI.1945-17.2017

Lewis MD, Hibbeln JR, Johnson JE, Lin YH, Hyun DY, Loewke JD. Suicide deaths of active-duty US military and omega-3 fatty-acid status: a case-control comparison. J Clin Psychiatry. 2011;72(12):1585–1590. doi:10.4088/JCP.11m06879

Madsen L, Kristiansen K. Of mice and men: Factors abrogating the antiobesity effect of omega-3 fatty acids. Adipocyte. 2012;1(3):173–176. doi:10.4161/adip.20689

Mischkowski D, Crocker J, Way BM. From painkiller to empathy killer: acetaminophen (paracetamol) reduces empathy for pain. Soc Cogn Affect Neurosci. 2016;11(9):1345–1353. doi:10.1093/scan/nsw057

Morrell, S., Taylor, R., Nand, D. et al. Changes in proportional mortality from diabetes and circulatory disease in Mauritius and Fiji: possible effects of coding and certification. BMC Public Health 19, 481 (2019) doi:10.1186/s12889-019-6748-7

Naughton SS, Mathai ML, Hryciw DH, McAinch AJ. Fatty Acid modulation of the endocannabinoid system and the effect on food intake and metabolism. Int J Endocrinol. 2013; 2013:361895. doi:10.1155/2013/361895

Ramsden CE, Faurot KR, Zamora D, et al. Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial. Pain. 2013;154(11):2441–2451. doi:10.1016/j.pain.2013.07.028

Randles D, Heine SJ, Santos N. The common pain of surrealism and death: acetaminophen reduces compensatory affirmation following meaning threats. Psychol Sci. 2013 Jun;24(6):966-73. doi: 10.1177/0956797612464786. Epub 2013 Apr 11.

Ruglass LM, Shevorykin A, Radoncic V, et al. Impact of Cannabis Use on Treatment Outcomes among Adults Receiving Cognitive-Behavioral Treatment for PTSD and Substance Use Disorders. J Clin Med. 2017;6(2):14. Published 2017 Feb 7. doi:10.3390/jcm6020014

Simopoulos AP. Dietary omega-3 fatty acid deficiency and high fructose intake in the development of metabolic syndrome, brain metabolic abnormalities, and non-alcoholic fatty liver disease. Nutrients. 2013;5(8):2901–2923. Published 2013 Jul 26. doi:10.3390/nu5082901

Slavich GM, Shields GS, Deal BD et al. Alleviating Social Pain: A Double-Blind, Randomized, Placebo-Controlled Trial of Forgiveness and Acetaminophen. Ann Behav Med. 2019 Dec; 53(12): 1045–1054.

Söderberg S, Zimmet P, Tuomilehto J, de Courten M, Dowse GK, Chitson P, Gareeboo H, Alberti KG, Shaw JE. Increasing prevalence of Type 2 diabetes mellitus in all ethnic groups in Mauritius. Diabet Med. 2005 Jan;22(1):61-8.

Taha AY, Cheon Y, Faurot KF, et al. Dietary omega-6 fatty acid lowering increases bioavailability of omega-3 polyunsaturated fatty acids in human plasma lipid pools. Prostaglandins Leukot Essent Fatty Acids. 2014;90(5):151–157. doi:10.1016/j.plefa.2014.02.003

Uusitalo U, Feskens EJM, Tuomilehto J, Dowse G, Haw U, Fareed D, et al. Fall in total cholesterol concentration over five years in association with changes in fatty acid composition of cooking oil in Mauritius: cross sectional survey. BMJ 1996;313:1044­6.

van Zuuren EJ, Fedorowicz Z, Kuijpers T, Pijl H, Effects of low-carbohydrate- compared with low-fat-diet interventions on metabolic control in people with type 2 diabetes: a systematic review including GRADE assessments, The American Journal of Clinical Nutrition, Volume 108, Issue 2, August 2018, Pages 300–331

Watkins BA, Kim J. The endocannabinoid system: directing eating behavior and macronutrient metabolism. Front Psychol. 2015;5:1506. Published 2015 Jan 6. doi:10.3389/fpsyg.2014.01506


1 comment:

Passthecream said...

Very interesting George. That's an impressive list of references to read through which will keep me busy for a while. Here's another one to add to your list:

You wrote:

"behind the scenes efforts to lower the amount of omega-6 in the food supply have been going on for decades. These initiatives include the development of canola and more recently the breeding of “high-oleic” oil seeds that are much lower in omega-6."

I think this is a situation where the profit motive coincides with a genuine positive outcome for public well being - foods containing the high linoleic oils go rancid very quickly, high oleic foods have a much longer shelf life therefore less wastage, later use-by dates.