Ketamine, NAD+, and the Kynurenine Pathway: Another Look at Depression & Inflammation
Most of us understand ketamine's NMDA receptor antagonism, and the importance of NAD+, but there's another metabolic pathway that explains why they works so uniquely—the kynurenine pathway: a biochemical highway that processes tryptophan into various pathways, some “good” (protective) and some “bad” (harmful). Here’s what’s happening…
How the Kynurenine Pathway Works
The kynurenine pathway breaks down about 95% of dietary tryptophan into molecules affecting brain health and energy.
It splits into two branches:
Protective branch: Makes NAD+ (supports mitochondria and energy), kynurenic acid (protects neurons), and anthranilic acid (reduces inflammation).
Harmful branch: Produces quinolinic acid (toxic, overstimulates NMDA receptors), 3‑hydroxykynurenine (damages neurons), and xanthurenic acid (possibly toxic).
When inflammation or immune activation occurs, enzymes like indoleamine‑2,3‑dioxygenase (IDO) accelerate the harmful side. In some patients with depression, elevated brain levels of quinolinic acid have been linked to neuroinflammation and glutamate toxicity.
What Happens When the Kynurenine Pathway Skews Negatively
When the body is under ongoing stress, infection, or inflammation, the immune system diverts how it processes tryptophan. Instead of fueling healthy repair, the pathway gets skewed toward its harmful side. This shift builds up quinolonic acid, a compound that overstimulates and damages brain cells, while reducing NAD+ production. Someone in this state may experience…
Less energy, due to lower NAD+
More brain stress from quinolinic toxicity
Neuroinflammation that continues the cycle
Mood symptoms like fatigue and depression as downstream effects
Note: altered levels of kynurenine metabolites can also correlate with suicidal behavior in some individuals (PMCID PMC5998805).
How Can Ketamine Support a Negatively Skewed Kynurenine Pathway?
Ketamine is known for blocking NMDA receptors, which is also how it can influence the kynurenine pathway directly:
It quickly shields neurons from quinolinic damage by blocking NMDA receptors.
With the toxicity blocked, the brain gets a “break” to repair, reconnect, and restore balance.
Ketamine essentially acts as a shield to the NMDA receptors, giving the brain cells protection to “ride out” the metabolic storm.
But that’s not the end of the storm…
NAD+ in a Negatively Skewed Kynurenine Pathway
Even when ketamine protects the brain from toxicity, it doesn’t refill the body’s energy stores caused by low NAD+ levels.
This is why some patients only get partial relief from ketamine therapy, especially in chronic fatigue conditions. This is where NAD+ therapy may be able to address the gap:
Ketamine = protection (blocks harmful effects)
NAD = restoration (replenishes energy supply)
How Ketamine and NAD+ Can Work Together
Inflammation shifts tryptophan metabolism toward toxic metabolites and away from NAD+.
Quinolinic acid build‑up damages neurons and reduces energy.
Ketamine steps in to shield the neurons and reduce inflammation.
NAD+ therapy restores cellular energy and supports healing.
Using both approaches can offer fuller support than ketamine alone. Clinical evidence suggests ketamine therapy often reduces depressive symptoms quickly, especially in treatment‑resistant cases with inflammatory features.
If you’re curious about pairing NAD+ with your ketamine therapy, or simply trying NAD+ alone, contact our offices today.