Is n-acetyl-tyrosine (NALT) worth supplementing over l-tyrosine?

So I argued with people about the science and relative pharmacokinetics of NALT and L-Tyrosine before I ever even tried NALT. I thought the data clearly showed NALT was a waste of money, and that L-Tyrosine would be better and cheaper. However, then I tried NALT and changed my tune. NALT works much better for me than L-Tyrosine. I get better mood boosting effects, and it just works. There are a couple possible explanations for why.

While the studies that blog cites do show that both N-Acetyl L-Tyrosine and N-Acetyl L-Cysteine are not the best precursors for raising Tyrosine and Cysteine, when injected, we do know that NAC directly acts on multiple systems in the body. So it stands to reason that NALT does as well. This would explain why so many people react better to NALT, even though it does not raise L-Tyrosine levels as much as supplementing it directly. The effects people are getting could be from the direct actions of NALT, not due it it raising L-Tyrosine plasma levels. Also, the study referenced by the blog above, and the one most people point to about NALT's pharmacokinetics, was done with parenteral adminstation, not oral.

They do say the following statement:

The high urinary excretion of NAT shown in our paper has been previously described in rats, adult humans, and preterm neonates. Also concurring with our study is the finding of Heird et al’ that plasma NAT levels exceeded plasma tyrosine concentrations. Inasmuch as a relatively high percentage of NAT and NAC was excreted in the urine, it can be hypothesized that the deacetylation of these substrates is not optimal. This is remarkable because NAC is frequently used as a mucolytic agent and as therapy for paracetamol intoxication, and NAT has been reported to be used efficiently in rats. Several explanations are possible: the intestinal mucosa is the most potent hydrolyzing tissue and is bypassed in parenterally fed neonate; the hydrolyzing activity of hepatocytes and renal cells is probably much less, resulting in a low deacetylation rate...

So they postulate that there is a lot more deacetylation happening in the GI tract, and bypassing that with other routes of administation is not taking that into account. So while injecting NALT does not raise L-Tyrosine levels as much as injecting L-Tyrosine directly, taking it orally might. So one has to look at the studies using parenteral administration with that in mind. Furthermore, that blog does not cite any study showing NALT does not pass the blood brain barrier. They use the injection study showing NALT was not efficient at raising L-Tyrosine levels as a reasoning for it not getting L-Tyrosine to the brain. However, if NALT is acting directly on the brain, or if the GI tract is deacetylating it more than it would in plasma and the kidneys, then that reasoning doesn't really make sense. Also, that study above showed that the plasma levels of NALT were 3x higher than that of L-Tyrosine. So if it acts directly, then those high plasma levels would explain why some people get such good effects from it.

Also, this study has some good information on why different study methods see different clearance rates:

Utilization of N-acetyl-L-tyrosine and glycyl-L-tyrosine during long-term parenteral nutrition in the growing rat.

Comparing the excretion rates in this study, N-AC-TYR excretion relative to the amount infused was one-twentieth less than the peptide GLY-TYR. TYR-excretion too was one-fifth less in those rats under infusion of N-AC-TYR than under infusion with the peptide. As GLY- TYR as part of TPN has not been previously investigated, comparable data on the excretion rates for this substance are not available. Daabees and Stegink (23) infused adult rats for 24 h with the dipeptide L-alanyl-L-TYR at a rate of 0.5 mmol/kg/24 h and reported urinary losses of 7.7% which is closer to our findings. However, as urinary losses were very high during the first day ofTPN, the excretion rate ofthe peptide administered also might be altered during that period. In experiments with labeled N-AC-TYR carried out by Stegink et al (10), a urinary excretion rate of 10. 1 ± 2.5% was found at an infusion level of 0.5 mmol/ kg/24 h and an increase to 14.3 ± 2.8% was recorded during the infusion of 2.0 mmol/kg/ 24 h.

These data also differ from the values found by us. An explanation might be that during one day of infusion a negative N-balance may be expected due to the change from oral to parenteral feeding, which in fact might influence excretion rates. In a study carried out by Jonxis and Huisman (24), children were infused during 24 h with a 5% protein hydrolysate containing TYR free- and peptide-bound forms. Excretion rates of 1.7% for TYR and 11.4% for the bound AA respectively were found; these values are in the range of our results. It is noted that TYR excretion is also much less during infusion with N-AC-TYR than with GLY-TYR. In fact, TYR excretion is no more here than under infusion of the complete solution with optimal PHE content. As it was found that the kidney plays an important role for hydrolysis of both N-AC-TYR (9) and peptides (25), the increased urinary losses of GLY-TYR and TYR may be the results of different cleavage mechanisms for N-AC-TYR and GLY-TYR, resulting in different renal clearance or reabsorption. Although the excretion rate was much lower for N-AC-TYR compared to GLY-TYR, utilization was about the same when evaluated by N-balance or weight gain. Generally, for infusion solutions, a urinary loss of 10% of the given substances is tolerated and accepted. Therefore, in view of the excretion rates observed, not only N-AC-TYR but also GLY-TYR can be recommended as TYR-source in TPN.

In conclusion, the results of the present study concerning weight gain and N-balance indicate that both the dipeptide GLY-TYR and N-AC-TYR are efficiently utilized in long-term TPN and may replace either TYR or part of PHE. The lower urinary excretion may favor the use of the N-acetyl-derivative. It re- mains to be studied whether the situation is similar under various pathological conditions. It may well be for instance, that the N-acetyl-derivative, which is predominantly cleaved in the renal tubules, is less favorable than the tyrosine peptide in cases of renal insufficiency.

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NALT works better for me than L-Tyrosine, and I am not alone in that sentiment. This could either be from a direct action of NALT in the body, or favorable pharmacokinetics when passing through the GI tract and kidneys, which does not show up on studies that use injection. That blog, while citing useful information, misinterprets the implications of those studies. It is true that IV injection of NALT does not raise plasma L-Tyrosine levels as much as injecting the parent compound directly would. However, that is not really useful information to compare the relative effects of oral administration of both compounds. There is a lot of anecdotes out there showing that many people react better to NALT, and the two studies above show why that might be. We need some more human pharmacokinetic and effect studies to know for sure, though. NALT certainly does not seem to be an efficient prodrug for L-Tyrosine, especially when injected. However, that does not preclude other effects that we don't yet fully understand.