CRLA & QRLA review article.
http://relentlessimp...gainst_crla.pdf
Wow. That paper has some major ramifications. For starters, it doesn't make AOR look very good. They have pushed controlled release LA for a while. According to Carlson et al., the authors of this paper, CR LA is not only unnecessary, but it might even be ineffective. They go further to intimate that it may even be harmful, but I don't think they make a very good case there.
A major point they raise has to do with the mechanism of activity of LA. They say that while LA is an antioxidant in vitro, its in vivo action is very different. It is actually a pro-oxidant(!) and induces a hormetic response:
LA induces a beneficial stress response: Evidence indicates the in vivo mechanisms of action of LA involve activation of the natural environmental stress response systems which up-regulate the so-called ‘early response genes’, thus activating Phase II detoxification enzymes via Nr-f2 and the antioxidant response element (ARE) (63). Activation of these genetic systems is nature’s way of making the body more adaptable to stress and environmental insults. One physiological result of Nr-f2 and ARE activation is a significant increase of endogenous antioxidants (vitamin C, vitamin E, GSH, etc.) and antioxidant enzyme systems (64, 86) Despite its abbreviated half-life, this is how LA is able to affect the redox status of the cell, not by acting as a direct scavenger of free radicals. The theory that LA acts as a direct scavenger of free radicals, or that it acts directly as an ‘antioxidant’ in the cell has been disregarded as a valid theory by most LA experts several years ago (6) and yet is still being advanced by the advocates of CRLA. To date there is lack of evidence that LA acts this way in vivo and a large body of research demonstrating the ‘stress-response’ theory of action for therapeutic LA. Thus, the misguided or ill-conceived basis for suggesting increased efficacy of CRLA products due to their increased “free-radical scavenging” or “antioxidant properties” due to an increased MRT forms an erroneous rationale.
LA up-regulates the early response genes by inducing a mild “hormetic” or “redox stress” which paradoxically confers protection against oxidative stress but requires a threshold concentration to initiate the therapeutic response. The activation of PI3-K & MAP kinases (65, 66) and up-regulation of Nr-f2 (63) heme oxygenase [HO-1] (66-68) and heat shock proteins [HSPs] (69-70) indicate the mechanism of action of LA involves induction of a stress response that resets the cell’s homeostatic mechanisms that become disrupted; for example, during age-related diseases and diabetes. The typical range of concentrations required to induce the hormetic, Phase II (therapeutic) response is 10-20 μg/mL (~50-100 μM) and can be achieved with multiple oral doses of typical or QRLA preparations (e.g. Na-RLA) (2, 60, 71). Like the name “early response” implies, activation requires only short time periods of 15 minutes-1 hr, which coincides closely with the plasma time course of both IVLA & QRLA products (68). If this theory is correct, and all of the existing evidence indicates it is, then high concentrations, rapid plasma clearance and metabolism of LA are essential for both the safety and the efficacy in vivo (1, 2). It further suggests that CRLA preparations require more toxicity data due to their increased plasma MRT before being considered safe. Furthermore, it is not valid to utilize QRLA safety or efficacy data to claim CRLA is safe and effective (88).
If this is the case, then doesn't it call into question the use of ALA as a "mitochondrial antioxidant" that we all combine with ALCAR? The coupling of these two drugs comes from Bruce Ames' work, where ALCAR was shown to restore the function of aged mitochondria, but also to create more ROS. He showed that LA solved the ROS problem in vitro, and formed a company to market the combination under the name Juvenon. (Tory Hagen, a co-founder of Juvenon, was the PhD advisor of Anthony Smith, an author of the above paper.) Anyway, if LA is acting in this entirely different manner involving the upregulation of enzymatic antioxidant systems, is it effective in the mitochondria in vivo? Is it safe to take ALCAR?
Finally, a few caveats about this paper: The lead author, Carlson, is the designer of Geronova's supplement line, so he has a dog in the fight. This is not to impugn his work, but it's a conflict of interest. I don't know where if anywhere this manuscript has been published. The sometimes sniping tone of the paper suggests that Carlson is pretty unhappy with the parts of the supplement industry that are pushing controlled release LA. He may be entirely within his rights to feel that way (if I'm reading him right) but it isn't the kind of thing you find in a journal article.
