Thursday, April 17, 2014

'Smart Drugs' Are Stupid

Smart drugs, or “nootropics,” are a topic I’ve stayed cleared of until now because, well, the idea of using them was stupid.  Not only is the research on those so-called smart drugs severely deficient and inadequate; but also the evidence on which people make their decision to use them or not derive largely from anecdotes found on Internet forums, which are fishy to me and notoriously unreliable. 

There are a few problems as to why the situation on the topic of smart drugs is in disarray.  The first is that a distinction between simple arousal and stimulation versus true learning is often sloppily made or passed over.  The second is that there is too much emphasis placed on manipulating neurotransmitters, namely choline, serotonin, histamine, dopamine, and norepinephrine.  And the third is that there is a tendency to deemphasize (or to gloss over altogether) the availability and metabolism of glucose, as well as the hormones that govern and interact with these processes, such as insulin, thyroid hormone, and cortisol.

Mitochondria, the sites where the oxidative metabolism of glucose occur, are found in abundance in and nearly everywhere in brain cells – from cell bodies to all the way down to the tip of axons.   The positive effects of glucose on memory and cognition are now fairly well established.  So I think it would be reasonable to suppose that investigations in to substances to improve cognition should probably start there – with metabolic support, the degree of which will probably vary depending on a person’s age, insulin sensitivity, stress levels, among other related factors.

In addition to its role in regulating glucose levels in the body, insulin, which I touched on in my diabetes post last year, is important for the process of forming memories in an area of the brain called the hippocampus, via the same signaling pathways insulin acts through in the body.  Insulin also happens to increase the metabolic intensity in the hippocampus, and this is probably the reason why cognition worsens in diabetes.  Generally, mentally draining tasks quickly deplete extracellular glucose, and artificially replacing that glucose – either systemically or by way of microinjections directly into the brain – restores the capacity of the brain to form memories, for instance. 

Derivatives of thiamine, a critical nutrient involved in the oxidative metabolism of glucose, such as benfotiamine and sulbutiamine, are being used to improve cognition, and pyrithiamine, an anti-metabolite of thiamine (that inhibits the synthesis in the brain of thiamin triphosphate) leads to degenerative changes in the brain.

Compared to other organs, in the brain, with the exception of probably certain fats and amino acids, every substance needed is made from glucose.  For instance, consider that when glucose is incubated in flasks containing brain cortical slices, the amino acids aspartate and glutamate appear in mere minutes.  So glucose is not only important for generating energy, but also for acting as a starting material to make other substances needed by the brain.

I’ve written some of my thoughts about ketogenic diets a few months ago, and why I think they are effective – which isn’t often.  I wouldn’t recommend such a diet to the masses for a myriad of reasons, but even chronic low-carbohydrate diet adherents could probably follow the diet (why I don’t know) without perceivable cognitive effects because a variety of systems kick in to maintain a normal supply of glucose to the brain.  But over time, the brain becomes flooded with cortisol, whose higher-than-average levels already correlate with (sub-clinical) cognitive deficits in the elderly, as well as Alzheimer’s disease.  It turns out that cortisol interrupts the provision of glucose to the hippocampus and to the rest of the brain so as to impair learning and memories from being laid down effectively.  Chronic, elevated levels of cortisol also destroy the hippocampus.

Taming stress is critical in keeping cortisol suppressed, and this entails avoiding missed meals, under-eating, and severe carbohydrate restriction.  Han Selye said that activities as unrelated as possible to the activity causing stress at the moment was the most effective means of reducing stress – in particular, exercise; I think light aerobic exercise and simple stretching routines are probably the most effective forms (they have been for me).  Extra amounts of the antioxidant vitamins – A, C, and E – are probably protective, too, against the oxidative stress produced by the excessive cortisol exposure; thyroid hormone prevents oxidative stress.

Thyroid hormone ‘lights up’ the brain like caffeine does, and one of the most basic ways it does this is by increasing the supply of glucose.  Thyroid hormone, acting by way of the hypothalamus and the sympathetic nervous system and therefore the brain, stimulates the release of glucose by the liver and synergizes with insulin to intensify the uptake and oxidative metabolism of glucose in the brain and in the body.  In fact, thyroid hormone directly stimulates the transcription of the glucose transport proteins (GLUT) in the body, and probably the brain, too – just like insulin does.  Cortisol, on the other hand, interferes with these transport proteins, antagonizing insulin and thyroid hormone in effect; cortisol also indirectly inhibits the release of thyroid hormone from the thyroid gland. (The low metabolic rate seen in Alzheimer’s disease I think is indicative of hypothyroidism and helps to explain the impaired glucose uptake and oxidation measured in Alzheimer’s brains, including the hippocampus.)

Valproic acid was recently in the news because it was shown to aid in the ability to acquire perfect pitch, or the ability to perfectly discriminate musical notes, an ability generally thought to only be capable of being acquired during critical periods of hearing development.  Actually, the ability of valproic acid to improve the plasticity of the brain has been known for several years now; but the doors are now open to use the drug to aid in the development of other skills as effortlessly as is seen in very young children, such as in the acquisition of languages.

Valproic acid is structurally similar to a neurotransmitter called GABA, which is derived from glucose by way of glutamate, and enhances the action of GABA that is already present.  Therefore, valproic acid would probably stand to benefit the most those in whom the availability or metabolism of glucose has become impaired or reduced.  GABA turns over faster than any other neurotransmitter in the brain, indicating its rapid use and importance therein.  It’s no surprise that defects in glucose metabolism leads to seizures, epilepsy, and other degenerative brain disorders, and that valproic acid is used and is effective for those conditions.  Ditto for ketone bodies, which are also similar to GABA.

A few people I’ve had the chance to talk to have told me that they’ve had negative experiences using synthetic thyroid hormone products.  Finding the right dosage takes time, on the order of months, and the right dosage varies from person to person and within the same person based on other factors.  Bear in mind that having too much thyroid hormone can be as equally as bad as not having enough regarding all of the things discussed above. (Broda Barnes said that most of the adults he worked with could get away with a daily dosage of 2 grains of a desiccated thyroid product, which is about 1/2 of a synthetic combination product; only rarely did his patients need more than that.)


References for this post will be added shorty; I apologize for the inconvenience.