Is Bipolar Disorder Really a Diet Problem?

Kynurenic acid and quinolinic acid are neurotoxic serotonin/tryptophan pathway metabolites associated with brain inflammation.

"organic acids that we measure in functional medicine we've been doing for decades... which measure various metabolites like kynurenic acid and quinolinic acid, which are metabolites of, you know, serotonin metabolites, and and they they're neurotoxic and so they're they're often linked to inflammation." (said at 0:51:15)

The speaker's claim bundles several assertions with significant inaccuracies regarding biochemistry. First, kynurenic acid (KYNA) and quinolinic acid (QUIN) are downstream metabolites of the kynurenine pathway of tryptophan catabolism, not direct metabolites of serotonin (though both serotonin and kynurenine pathways share tryptophan as their precursor). Second, while quinolinic acid is well-established as an excitotoxic, neurotoxic NMDA receptor agonist induced by pro-inflammatory cytokines, kynurenic acid is an NMDA and alpha-7 nicotinic receptor antagonist that is generally characterized as neuroprotective rather than neurotoxic (though excessive levels may impair cognition). Because one of the metabolites (kynurenic acid) is primarily neuroprotective and both are tryptophan catabolites rather than serotonin metabolites, the assertion that both are neurotoxic serotonin metabolites is contradicted in part.

• partial: The kynurenine pathway in major depressive disorder, bipolar disorder, and schizophrenia: … (Revista brasileira de psiquiatria (Sao Paulo, Brazil : 1999) 2023) · cited 13x in the literature

  "KA, which has possibly neuroprotective effects, is increased in SZ. QA, which has neurotoxic effects, may be increased in MDD." (abstract, conclusions, passage verified)

  pubmedfull study (doi)
• partial: Modulation of the Kynurenine Pathway: A New Approach for Treating Neurodegeneration. (Life (Basel, Switzerland) 2026) · cited 1x in the literature

  "In recent years, the kynurenine pathway, which is one of the main pathways of tryptophan metabolism, responsible for the synthesis of products that act oppositely in the CNS including neurotoxic (quinolinic acid) and neuroprotective products, has gained increasing recognition as a potential therapeutic target." (abstract, background, passage verified)

  pubmedfull study (doi)
• context: Kynurenine pathway at the crossroads of neurological and psychiatric disorders: Bridging m… (Progress in neuro-psychopharmacology & biological psychiatry 2026)

  "The kynurenine pathway (KP), serving as the principal catabolic route for tryptophan metabolism, has emerged as a potential regulatory mechanism in neurological and psychiatric pathophysiology. This biochemical cascade produces functional metabolites - particularly kynurenine (KYN), kynurenic acid (KYNA), and quinolinic acid (QUIN) - that exert bidirectional neuromodulatory effects through glutamatergic transmission and nicotinic receptor signaling." (abstract, background, passage verified)

  pubmedfull study (doi)

Lamotrigine treatment typically produces reductions in brain glutamate levels over a period of approximately three months.

"And the reductions you typically see in, like, three months, for example, on lamotrigine, but we were seeing much larger reductions in six to eight weeks of a ketogenic diet." (said at 1:08:13)

Human magnetic resonance spectroscopy (MRS) studies examining the effect of lamotrigine on brain glutamate levels over 8 to 12 weeks (approximately 2 to 3 months) do not show consistent or typical reductions in overall brain glutamate. In an MRS study of depressed bipolar patients treated with lamotrigine for 10–12 weeks, lamotrigine had no significant overall effect on glutamate/glutamine (Glx) levels in the anterior cingulate cortex, and clinical responders actually exhibited an increase in Glx. Similarly, an 8-week trial in older patients with bipolar depression found no significant changes in glutamate-to-creatine ratios following lamotrigine therapy. While preclinical animal models suggest lamotrigine inhibits presynaptic glutamate release, human in vivo imaging over this timeframe does not demonstrate typical reductions in tissue glutamate concentrations.

• contradicts: Changes in brain Glx in depressed bipolar patients treated with lamotrigine: A proton MRS … (Journal of affective disorders 2019) · cited 13x in the literature

  "Overall, lamotrigine treatment had no significant effect on Glx levels in ACC. However, in patients who responded clinically to lamotrigine treatment Glx concentrations were significantly increased." (abstract, results, passage verified)

  pubmedfull study (doi)
• contradicts: Lamotrigine Therapy and Biomarkers of Cerebral Energy Metabolism in Older Age Bipolar Depr… (The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry 2019) · cited 9x in the literature

  "However, there were no associations between NAA/Cr, Glu/Cr, or Gln/Cr and either depression severity or lamotrigine treatment." (abstract, results, passage verified)

  pubmedfull study (doi)