The Blueberries of Wrath
The citation links in this post are temporarily broken, but you can still find the respective numbered references at the bottom.
Eating fruit is good, right?
Let’s explore how some substances1 commonly found in plants might make someone think twice about eating another cup of berries, and how they are probably wrong to worry about it.
Then, I’ll propose a novel mechanism which if true, might strike fear into your breakfast.
In 1973, the pediatric allergist Ben Feingold proposed to the American Medical Association that dietary salicylates2 worsen ADHD symptoms in children [1]. Therefore, he promoted a salicylate elimination diet. Many plant foods contain salicylate [2,3,4]: around 1-5 mg per 100 g for fresh fruits, up to ~35 mg per 100 g for dried fruits, and a whopping ~1 g per 100 g for spices like cumin, turmeric, rosemary, and ginger. Feingold’s fruit-fearing diet would avoid them all.
And people might still be trying that, if it weren’t for a 1983 meta-analysis [5] of 23 studies of the Feingold diet that found effect sizes of 0.015 and 0.052 on scales measuring attention and disruptive behaviour. Statistically speaking this is pathetic, and afterwards the field more or less abandoned the salicylate-ADHD connection.
There’s one valid and lasting take on salicylate intolerance. This one’s inflammatory, rather than neuropsychiatric: some people with asthma or other inflammatory conditions see their symptoms worsen when they take aspirin or other non-selective NSAIDs, like ibuprofen or naproxen. In the case of asthma, this is called aspirin-exacerbated respiratory disease (AERD) [6].
The mechanism? NSAIDs inhibit the enzyme cyclooxygenase (COX).3 This reduces the conversion of arachidonic acid to prostaglandins, which have both inflammatory and anti-inflammatory effects depending on context; the inflammatory cases are the ones helped by NSAIDs. But then more arachidonic acid is available for conversion by another enzyme, arachidonate 5-lipoxygenase (5-LOX). 5-LOX is the rate-limiting step in the production of leukotrienes, which also serve as inflammatory signals; there is an extra synergy in that PGE2, one of the prostaglandins synthesized by COX-1 and blocked by NSAIDs, serves an anti-inflammatory role by putting the brakes on 5-LOX. Usually all of these concerns are clinically insignificant next to the anti-inflammatory effect of reducing prostaglandins. But for those with AERD, it’s a problem:4
Eosinophils and mast cells, which are specific types of immune cells, participate in a positive feedback loop where they are recruited and activated by leukotrienes, and also produce more of them.
The cysteinyl leukotrienes LTD4 and LTC4, downstream of 5-LOX, act on CysLT1 receptors causing airway constriction, tissue edema, and mucus production.
Through the positive feedback loop of 1, mast cells tend to activate explosively, roping in their neighbours and suddenly dumping a bunch of histamine. This can worsen lung inflammation and also cause additional allergy-like symptoms such as hives and itching. However, antihistamines alone are not sufficient to treat AERD, suggesting this is a secondary mechanism.
Why this becomes problematic in patients with AERD is not well understood, but looks like it follows from an infection-induced epigenetic shift in the baseline reactivity of immune cells, and production of prostaglandins versus leukotrienes.
Should dietary salicylates also be a problem for AERD sufferers? Clinically, the answer appears to be no. And this fits with what we know about salicylates that aren’t aspirin (which doesn’t appear in significant quantities in plants): they only weakly inhibit COX.5
So: the asthmatics probably need not fear the berries. Well, not on account of their asthma, anyway.6
I’m not going to review the entire cursed realm of internet users claiming to be sensitive to dietary salicylates, polyphenols, and whatever other Trojan berry adversaries that might be captivating their paranoia. But here’s a mugshot. In it we see people:
Attributing all kinds of symptoms to dietary salicylates including dark undereye circles and adrenal fatigue.
Fixating on a handful of studies from the 1990s (mostly in autistic children) suggesting that phenol sulfotransferase deficiency is responsible for the accumulation of dietary phenols in the body.
Failing to rigorously distinguish between polyphenols, salicylates, and phenols in general, let alone different polyphenols, instead lumping everything into “high-phenol” foods. Likewise the recommended treatments for salicylate sensitivity, phenol sensitivity, and methylation disorders more or less overlap.
Self-diagnosing with conditions in the absence of established diagnostic tests; while in principle elimination/challenge dieting can reveal things, we should expect it to be vulnerable to placebo and confirmation bias.
Following modern variants or extensions of the Feingold diet. The most structured is FAILSAFE (Free of Additives, Low in Salicylates, Amines, and Flavour Enhancers), which has a large Facebook following but no modern evidence to back up the salicylate claim.
Of course, in the proud tradition of giving the deranged more material to work with, I’m going to do a bit of my own speculation now, and suggest what I believe is a novel mechanism by which the consumption of salicylate- or polyphenol-containing foods might make someone anxious, stressed, agitated, aggressive, or otherwise affect their mood, and in fact how salicylic acid and polyphenols might be synergistic in this respect.
What I am about to propose is probably fake. Like, I’ve eaten a cup of blueberries before and become anxious afterwards. Okay, maybe there’s a connection there. But it does not need to be the one that I’m proposing. Probably the blueberries were just an easy scapegoat. And me, just someone who used to have moderate baseline anxiety yearning to be accounted for.
Now consider:
A single unreplicated study [7] in 2018 found that when mice were given 2 mg/kg/day of aspirin for 30 days, it increased the expression of tyrosine hydroxylase (TH) by 2-3x in the substantia nigra, one of the two major midbrain nuclei where dopamine is synthesized. The upstream mechanism involves the phosphorylation of CREB, one of the classic ways gene expression is regulated in animals.
Multiple studies [8,9] have shown that some common fruit polyphenols inhibit the enzyme catechol-O-methyltransferase (COMT), which metabolizes dopamine and thus controls dopamine levels. In most areas COMT isn’t the only enzyme that does this. But in prefrontal cortex (PFC), it is [12,13]. This means that, if any of those polyphenols can reach PFC in sufficient concentration, it should increase the concentration of dopamine there by reducing its degradation by COMT.
The mainline theory of the relationship of PFC dopamine levels to psychology is the inverted-U model [19]: agonism of dopamine D1 receptors on pyramidal neurons enhances NMDA (excitatory) channel currents and suppresses other inputs to the neuron. This strengthens whichever representations are currently active, while reducing updating based on new inputs. This framing says that when PFC dopamine levels are too low, you get ADHD-like poor working memory because representations are wispy and transient, and this is the major hypothesis about how psychostimulants like amphetamine improve working memory in ADHD. On the other hand, too much dopamine and you tend to become ruminative and unable to stop thinking about whatever you’re currently thinking about. Downstream of that: anxiety, agitation, and whatever else.
There are significant differences in COMT activity between individuals, due in part to the Val158Met polymorphism. Individuals with the Met/Met variant (about 25% of Europeans [10]) naturally have 3-4x lower enzymatic activity [10,11] and we might expect them to be more ruminative even prior to the addition of inhibitors.
So: if your fruit contains a COMT-inhibiting polyphenol which can make it into PFC, it could raise the dopamine levels there and shift you towards ruminative on the inattentive-ruminative axis. And if your fruit contains salicylates which upregulate TH similarly to 10 mg of aspirin (which is a very low dose) then this may synergize by increasing the dopamine supplied to PFC. And the magnitude of the effect should depend on your baseline expression of COMT, which depends on your genes.
There are a few potential problems here:
The 2018 TH study [7] is the product of a single lab and hasn’t been replicated yet, even in rodents.
Dopamine projections to PFC actually come from the ventral tegmental area (VTA), and not the substantia nigra. This is probably irrelevant as these two regions are right next to each other and identical in how CREB phosphorylation affects TH expression.
Do rodent studies translate to humans? Or even, do results from one transgenic mouse model translate to all mice? These are nagging questions in animal research. At least, the 2018 TH study tests two different mouse types: C57/BL6 mice, which are “normal”, and aged A53T mice, which are a model of Parkinson’s disease. Additionally, the CREB phosphorylation mechanism by which TH is upregulated is probably conserved across mammals, and we know that both aspirin and dietary salicylates cross into the brain, in humans [25]. But this is not definitive.
The study shows that aspirin upregulates TH. Does this apply to salicylic acid, and other dietary salicylates? We know that salicylic acid and aspirin (acetylsalicylic acid) largely share mechanisms, with a significant exception being aspirin’s direct, irreversible COX inhibition which requires the extra acetyl group. More importantly, aspirin is almost entirely metabolized to salicylic acid within an hour or two [25], with salicylic acid levels dropping ~2x slower, which makes it somewhat more likely that salicylic acid is actually the thing responsible for the upregulation anyway. The study does need to be replicated with salicylic acid, but I bet you’ll find a similar effect.
The dose makes the poison. Assuming dietary salicylates do upregulate TH, how much do I need to consume to do so? The 2018 TH study shows that the TH upregulation happens in a narrow dosage range. So 1 mg or 100 mg of aspirin might not have the same effect, which we might only observe for the dietary salicylate equivalent of around 10 mg of aspirin. The relevant studies are weak (n=20-40 per group) and produced by the same Scottish team [16,17]; one study measured urinary salicyluric acid, and the other, plasma salicylic acid. Their results suggest that vegetarians are similar to people taking 75 mg/day of aspirin, whereas non-vegetarians are perhaps a third of that. Everyone was Scottish and the vegetarians came from a monastery, and we might not expect quite the same results for an average American. But overall these studies roughly accord with expectations, and the equivalent of 10 mg/day probably accounts for a non-negligible subset of most populations.
On the off-chance that this “salicylate and/or polyphenols cause too much PFC dopamine and thus rumination” hypothesis is actually relevant, one of its strengths is that it would validate that some people do experience adverse effects from fruit, while also potentially explaining (say, because they have low COMT activity to begin with) why they are so fixated on whatever explanations they can scrounge up to clothe their miseries. Of course, other mechanisms may still contribute in parallel.7
This post was a speculative review of potential mechanisms. As we just saw, there’s plenty of uncertainty remaining around methodology, mechanisms, and dosing. I’ll finish with a couple of general issues we haven’t covered yet.
First, there are significant differences in salicylate content for each specific food source. We should assume that a blueberry will contain different levels of particular salicylates and polyphenols depending on growing conditions, cultivars, regions, and estimation methods.
Second, leaving aside concerns about mechanism and replication, probably the greatest source of variability remaining is the absorption and distribution of dietary polyphenols. Many polyphenols have low bioavailability [23]8, especially because they are actively yeeted back out of the intestinal wall by the bouncer (P-glycoprotein) right after absorption.9 Likewise, many polyphenols act as prebiotics for gut microbes, and it might be the metabolites that are actually relevant here, and which would need to be assayed in vivo if we wanted to be thorough about it.
Well, there it is. Are you afraid yet? You shouldn’t be. Fruit is probably mostly fine for you.
References
[1] Feingold BF. Why Your Child Is Hyperactive. Random House, 1975.
[2] Swain AR, Dutton SP, Truswell AS. “Salicylates in Foods.” J Am Diet Assoc 85(8):950-960, 1985. 10.1016/S0002-8223(21)03743-3
[3] Malakar S, Gibson PR, Barrett JS, Muir JG. “Naturally Occurring Dietary Salicylates: A Closer Look at Common Australian Foods.” J Food Comp Anal 57:31-39, 2017. 10.1016/j.jfca.2016.12.008
[4] Paterson JR, Srivastava R, Baxter GJ, Graham AB, Lawrence JR. “Salicylic Acid Content of Spices and Its Implications.” J Agric Food Chem 54(8):2891-2896, 2006. 10.1021/jf058158w
[5] Kavale KA, Forness SR. “Hyperactivity and Diet Treatment: A Meta-Analysis of the Feingold Hypothesis.” J Learn Disabil 16(6):324-330, 1983. 10.1177/002221948301600604
[6] Baenkler HW. “Salicylate Intolerance: Pathophysiology, Clinical Spectrum, Diagnosis and Treatment.” Dtsch Arztebl Int 105(8):137-142, 2008. 10.3238/arztebl.2008.0137
[7] Rangasamy SB, Dasarathi S, Pahan P, Jana M, Pahan K. “Low-Dose Aspirin Upregulates Tyrosine Hydroxylase and Increases Dopamine Production in Dopaminergic Neurons: Implications for Parkinson’s Disease.” J Neuroimmune Pharmacol 14(2):173-187, 2019. 10.1007/s11481-018-9808-3
[8] Chen D, Wang CY, Lambert JD, Ai N, Welsh WJ, Yang CS. “Inhibition of Human Liver Catechol-O-Methyltransferase by Tea Catechins and Their Metabolites: Structure-Activity Relationship and Molecular-Modeling Studies.” Biochem Pharmacol 69(10):1523-1531, 2005. 10.1016/j.bcp.2005.01.024
[9] Lu H, Meng X, Yang CS. “Enzymology of Methylation of Tea Catechins and Inhibition of Catechol-O-Methyltransferase by (-)-Epigallocatechin Gallate.” Drug Metab Dispos 31(5):572-579, 2003. 10.1124/dmd.31.5.572
[10] Egan MF, Goldberg TE, Kolachana BS, Callicott JH, Mazzanti CM, Straub RE, Goldman D, Weinberger DR. “Effect of COMT Val108/158Met Genotype on Frontal Lobe Function and Risk for Schizophrenia.” PNAS 98(12):6917-6922, 2001. 10.1073/pnas.111134598
[11] Karayiorgou M, Altemus M, Galke BL, Goldman D, Murphy DL, Ott J, Gogos JA. “Genotype Determining Low Catechol-O-Methyltransferase Activity as a Risk Factor for Obsessive-Compulsive Disorder.” PNAS 94(9):4572-4575, 1997. 10.1073/pnas.94.9.4572
[12] Gogos JA, Morgan M, Luine V, Santha M, Ogawa S, Pfaff D, Karayiorgou M. “Catechol-O-Methyltransferase-Deficient Mice Exhibit Sexually Dimorphic Changes in Catecholamine Levels and Behavior.” PNAS 95(17):9991-9996, 1998. 10.1073/pnas.95.17.9991
[13] Käenmäki M, Tammimäki A, Myöhänen T, Pakarinen K, Amberg C, Karayiorgou M, Männistö PT, Gogos JA. “Quantitative Role of COMT in Dopamine Clearance in the Prefrontal Cortex of Freely Moving Mice.” J Neurochem 114(6):1745-1755, 2010. 10.1111/j.1471-4159.2010.06889.x
[14] Kalhan R, Smith LJ, Nlend MC, Nair A, Hixon JL, Sporn PHS. “A Mechanism of Benefit of Soy Genistein in Asthma: Inhibition of Eosinophil p38-Dependent Leukotriene Synthesis.” Clin Exp Allergy 38(1):103-112, 2008. 10.1111/j.1365-2222.2007.02862.x
[15] Smith LJ, Kalhan R, Njoroge T, Gibeon D, Convertino M, Welti R, Holtzman MJ, Sporn PHS. “Effect of a Soy Isoflavone Supplement on Lung Function and Clinical Outcomes in Patients With Poorly Controlled Asthma: A Randomized Clinical Trial.” JAMA 313(20):2033-2043, 2015. 10.1001/jama.2015.5024
[16] Blacklock CJ, Lawrence JR, Wiles D, Malcolm EA, Gibson IH, Kelly CJ, Paterson JR. “Salicylic Acid in the Serum of Subjects Not Taking Aspirin. Comparison of Salicylic Acid Concentrations in the Serum of Vegetarians, Non-Vegetarians, and Patients Taking Low Dose Aspirin.” J Clin Pathol 54(7):553-555, 2001. 10.1136/jcp.54.7.553
[17] Lawrence JR, Peter R, Baxter GJ, Robson J, Graham AB, Paterson JR. “Urinary Excretion of Salicyluric and Salicylic Acids by Non-Vegetarians, Vegetarians, and Patients Taking Low Dose Aspirin.” J Clin Pathol 56(9):651-653, 2003. 10.1136/jcp.56.9.651
[18] Hosseini SA, Shateri Z, Abolnezhadian F, Maraghi E, Haddadzadeh Shoushtari M, Zilaee M. “Does Pomegranate Extract Supplementation Improve the Clinical Symptoms of Patients With Allergic Asthma? A Double-Blind, Randomized, Placebo-Controlled Trial.” Front Pharmacol 14:1109966, 2023. 10.3389/fphar.2023.1109966
[19] Arnsten AFT. “Catecholamine Influences on Dorsolateral Prefrontal Cortical Networks.” Biol Psychiatry 69(12):e89-e99, 2011. 10.1016/j.biopsych.2011.01.027
[20] Laidlaw TM, Boyce JA. “Aspirin-Exacerbated Respiratory Disease — New Prime Suspects.” N Engl J Med 370(1):21-32, 2014. 10.1056/NEJMra1403070
[21] Kopp E, Ghosh S. “Inhibition of NF-kappa B by Sodium Salicylate and Aspirin.” Science 265(5174):956-959, 1994. 10.1126/science.8052854
[22] Pearce FL, Befus AD, Bienenstock J. “Effect of Quercetin and Other Flavonoids on Antigen-Induced Histamine Secretion from Rat Intestinal Mast Cells.” J Allergy Clin Immunol 73(6):819-823, 1984. 10.1016/0091-6749(84)90453-6
[23] Manach C, Williamson G, Morand C, Scalbert A, Rémésy C. “Bioavailability and Bioefficacy of Polyphenols in Humans. I. Review of 97 Bioavailability Studies.” Am J Clin Nutr 81(1 Suppl):230S-242S, 2005. 10.1093/ajcn/81.1.230S
[24] Bhardwaj RK, Glaeser H, Becquemont L, Klotz U, Gupta SK, Fromm MF. “Piperine, a Major Constituent of Black Pepper, Inhibits Human P-glycoprotein and CYP3A4.” J Pharmacol Exp Ther 302(2):645-650, 2002. 10.1124/jpet.102.034728
[25] Needs CJ, Brooks PM. “Clinical Pharmacokinetics of the Salicylates.” Clin Pharmacokinet 10(2):164-177, 1985. 10.2165/00003088-198510020-00004
I won’t be covering the fructose question here, but I don’t think there’s any clear evidence against fructose intake from fruit, even though large enough boluses of plain fructose are known to be harmful to gut microbiome and liver metabolism. For sedentary individuals, anyway.
“Salicylates” includes the drug aspirin, a.k.a. acetylsalicylic acid. Aspirin in particular is dangerous to give to children, as it can cause Reye’s syndrome, but this is probably specific to aspirin and there’s no evidence to suggest it applies to dietary salicylates.
There are two active forms of COX, COX-1 and COX-2. Different NSAIDs have different selectivity for one or the other. Aspirin prefers COX-1, especially at low doses. Naproxen is about equally balanced. Ibuprofen slightly prefers COX-2. Diclofenac and all the drugs in the coxib family are COX-2 selective. COX-1 inhibition is antithrombotic (by reducing production of thromboxane A2) but is also largely responsible for negative effects of NSAIDs on the gut, which is why aspirin is the most cardioprotective but also the most stomach-melting of the bunch. COX-2 inhibition is primarily anti-inflammatory, and while the absence of COX-1 inhibition by coxibs means they are comparatively gut-safe, it is also pro-thrombotic (due to reducing production of prostacyclin while sparing thromboxane A2) and thus increases the risk of cardiovascular adverse events with chronic use.
There are several clues why [20]:
~5x elevation of LTC4 synthase expression in affected tissues, relative to asthmatic patients that tolerate aspirin. So, more production of LTC4 downstream of 5-LOX.
Reduced baseline levels of the prostaglandin PGE2 that acts as a brake on 5-LOX activity and eosinophil/mast cell recruitment.
Reduced expression of EP2 receptors, which mediate PGE2’s braking activity.
Reduced production of lipoxin A4 (LXA4) which normally counterbalances leukotriene signaling. Like leukotrienes, LXA4 is the product of lipoxygenase enzymes (5-LOX as well as 15-LOX) so this might be another situation of shunting / imbalance of sister pathways.
This all points to a pathological attractor state; a self-reinforcing equilibrium in the system dynamics. It’s uncertain which of these doors leads to the attractor in the first place. It does seem it’s not strictly congenital, but tends to arise in a patient’s 30s or 40s following a severe upper respiratory infection, suggesting an epigenetic trigger.
Salicylic acid is similarly anti-inflammatory to aspirin, but probably by a combination of different upstream mechanisms, such as inhibition of IκB kinase β → less NF-κB production [21], and less downstream upregulation of COX-2 conditional on being in an inflammatory state. But ultimately aspirin shares these mechanisms, as it’s partly metabolized to salicylic acid.
Plants contain other substances which might be relevant (but probably aren’t):
Several polyphenols inhibit 5-LOX in vitro. A very weak (n=11, uncontrolled, 4-week longitudinal) pilot study [14] showed decreased 5-LOX activation and reduced production of leukotrienes by eosinophils, in participants consuming 100 mg/day of soy isoflavones for 4 weeks. A later, stronger RCT (n=386, placebo-controlled, 24 weeks) [15] returned a negative result for asthma measures, even after verifying that the crucial isoflavone genistein was present at plasma levels sufficient to match in vitro inhibition conditions, suggesting either that the polyphenol was not entering eosinophils from plasma, or else that 5-LOX inhibition is inadequate to control asthma. And anyway, 100 mg/day of isoflavones is equivalent to about a pound of tofu, or 5-10 cups of soy milk.
Some polyphenols inhibit the enzyme COMT, which metabolizes catechols (dopamine, norepinephrine, epinephrine, and others). This could increase the half-life of circulating epinephrine → activates β2 adrenergic receptors in the lungs → dilates airways, by the same mechanism as asthma medications like salbutamol. As far as I can see this has not been tested, but I doubt it is significant as there are other mechanisms for clearing plasma epinephrine which should pick up the slack.
Quercetin, a polyphenol, is exceptionally effective at blocking the release of inflammatory cytokines from mast cells in vitro [22]. But there’s no RCT evidence for asthma. Besides, quercetin has very low bioavailability. But more about that later in the post.
There are a couple of weak RCTs (n=64, 8 weeks) [18] from a single research group, giving 500 mg/day of pomegranate extract and noting a significant reduction in eosinophils.
One example that’s close to the kind of salicylate sensitivity seen in AERD involves brain mast cells: though there are few of them, if they were in an AERD-like hypersensitive state, we might expect salicylates to cause them to activate, with downstream psychiatric effects.
P-glycoprotein serves a similar role at the blood-brain barrier, bouncing things back out. This is why loperamide, an opioid, treats diarrhea but does not get you high, and also why the antihistamine cetirizine makes you less drowsy than diphenhydramine. We expect variability here for a few reasons: 1) P-glycoprotein has different affinity for different substrates, as usual, 2) P-glycoprotein expression varies between individuals, and 3) P-glycoprotein is inhibited by certain dietary substances, such as piperine from black pepper [24].