Man...what a fun diversion this thread was...quite a pie fight at times. Including some cow pies.
As if more studies were needed:
Antidepressants for the new millennium
by
Skolnick P
Neuroscience Discovery, Eli Lilly,
Lilly Corporate Center, Indianapolis, IN 46285, USA.
[email protected]
Eur J Pharmacol 1999 Jun 30; 375(1-3):31-40
ABSTRACT
Despite a remarkable structural diversity, most conventional antidepressants may be viewed as 'monoamine based', increasing the synaptic availability of serotonin, norepinephrine, and/or dopamine.
Both preclinical and recent clinical studies indicate that compounds which reduce transmission at N-methyl-D-aspartate (NMDA) receptors are antidepressant. Moreover, chronic administration of antidepressants to mice alters both the mRNA levels encoding N-methyl-D-aspartate receptor subunits and radioligand binding to these receptors within circumscribed areas of the central nervous system. It is hypothesized that these two different treatment strategies converge to produce an identical functional endpoint: a region-specific dampening of NMDA receptor function. The pathways leading to this convergence provide a rudimentary framework for discovering novel antidepressants.
That could explain Blueprint's positive effect on mood.
Glutamate and Depression: Clinical and Preclinical Studies
by
Paul IA, Skolnick P.
Laboratory of Neurobehavioral Pharmacology and Immunology,
Division of Neurobiology and Behavior Research,
Departments of Psychiatry and Pharmacology,
University of Mississippi Medical Center,
Jackson, Mississippi 39216, USA.
Ann N Y Acad Sci. 2003 Nov;1003:250-272
ABSTRACT
The past decade has seen a steady accumulation of evidence supporting a role for the excitatory amino acid (EAA) neurotransmitter, glutamate, and its receptors in depression and antidepressant activity. To date, evidence has emerged indicating that N-methyl-d-aspartate (NMDA) receptor antagonists, group I metabotropic glutamate receptor (mGluR(1) and mGluR(5)) antagonists, as well as positive modulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors have antidepressant-like activity in a variety of preclinical models. Moreover, antidepressant-like activity can be produced not only by drugs modulating the glutamatergic synapse, but also by agents that affect subcellular signaling systems linked to EAA receptors (e.g., nitric oxide synthase). In view of the extensive colocalization of EAA and monoamine markers in nuclei such as the locus coeruleus and dorsal raphe, it is likely that an intimate relationship exists between regulation of monoaminergic and EAA neurotransmission and antidepressant effects. Further, there is also evidence implicating disturbances in glutamate metabolism, NMDA, and mGluR(1,5) receptors in depression and suicidality. Finally, recent data indicate that a single intravenous dose of an NMDA receptor antagonist is sufficient to produce sustained relief from depressive symptoms. Taken together with the proposed role of neurotrophic factors in the neuroplastic responses to stressors and antidepressant treatments, these findings represent exciting and novel avenues to both understand depressive symptomatology and develop more effective antidepressants.
Neuroplasticity, in the flesh (but sounds like in a good way to me).
Seriously though, I have accidentally went through chronic opioid therapy withdrawal syndrome when I used to take those drugs (I stopped taking them for a while...whoops). Glutamate overactivity/toxicity plays a huge part in making you feel miserable during opioid withdrawal syndrome-general CNS overexcitation/excitotoxic neuronal effects, etc. But that doesn't seem like a point of contention here, so I'll move on.
I think one of the most critical issues with the studies suggesting NMDA antagonist neurotoxicity (NAN-and they are numerous, but not specific to the ingredients in Blueprint however) is that brain damage is evinced in rats as vacuoles/lesions/necrosis in the brain (depending on numerous factors and the antagonist in question) while psychotic symptoms are the only extent to which studies can indicate toxicity in humans (no brain donor volunteers, lol). A typical psychotic reaction in humans would be to an NMDA antagonist such as PCP or Ketamine (though the reaction is usually temporary so a hard argument to correlate that with neuronal necrosis). IOW, as far as I know, NMDA antagonist neurotoxicity has not been demonstrated in humans for ethical reasons (duh) and possibly b/c it does not occur in humans (roughly my meta-analysis-esque conclusion, lol-I am no scientist).
Here are more studies than you care to read that discuss NAN if interested. It's' hard to draw any conclusions from them regarding the supplement in question (can't really), and I don't believe that the supplement being discussed in this thread is a threat (the research on this thread says as much). But I would imagine that generalizations incorrectly applied to this supplement earlier in this thread are probably related to studies in rats with specific NMDA antagonists.
My guess is that not all NMDA antagonists are safe, but the NMDA-glutamate system is very complex (aren't they all?). So when a wealth of studies show that the supplement in question specificially is associated with unilaterally positive effects and no toxicity, I am inclined to believe that this supplement is quite safe.
Invalid Link Removed
Low SJ, Roland CL
Review of NMDA antagonist-induced neurotoxicity and implications for clinical development.
Int J Clin Pharmacol Ther. 2004 Jan;42(1):1-14.
NMDA receptor antagonists have been investigated for many years as therapeutic agents for the treatment of neurological disorders such as stroke, epilepsy, pain and Parkinson's disease. It has been discovered, however, that many of these compounds cause adverse behavioral (psychotomimetic) effects and can produce neurotoxicity characterized by neuronal vacuolization, induction of heat-shock protein, neuronal/axonal degeneration and regional brain cell death in several animal species. It is unknown whether NMDA antagonists induce neurotoxicity in humans. The mechanism of NMDA antagonist-induced neurotoxicity is not completely known, but some evidence suggests disinhibition of GABAergic inputs to the affected neurons. Several classes of compounds have been shown to prevent NMDA antagonist-induced neurotoxicity. The extent of neurotoxicity produced by NMDA antagonists is affected by many factors, including type of antagonist, dose, length of exposure, age, sex and species. While there are no published regulatory guidelines regarding how NMDA antagonist compounds should be evaluated, sponsors and investigators of these compounds should make every effort to assess the potential for neurotoxicity. NMDA receptor antagonists, as well as other CNS-active compounds need to be analyzed for neurotoxicity through careful experimental design, adequate tissue sampling and through the use of a sensitive method of detection.
There are about 50 more studies at the link above, but like I said, they are really more of a tour of how little is known about NMDA antagonist neurotoxicity in humans versus what is much better understood in rats and "several other animals". There are mechanisms by which rats would be more suceptible to NAN than humans so most attempts to apply rat study toxicity to humans has failed here as far as I can tell-many researchers have made the statement that it applies to humans only to recant it later.
Having said that, I might try a 2 bottle run of blueprint since I can get it on the cheap (which what lead me to this thread for info and a very long but education diversion). Great discussion other than the typical "I am right and you are wrong" banter, but that is expected.
