Academy of Medical Sciences and Cognition-Enhancing Drugs
James recently forwarded me an article entitled "Academy of Medical Sciences suggests urine tests to detect smart drugs"
that discusses widespread use of cognition-enhancing drugs and putative legislation to curb their use.
"Sir Gabriel Horn, a neuroscientist at Cambridge University who chaired the [academy's expert] panel, said: “The Government should work with interested bodies to consider local regulation around the workplace, schools and universities, and other places of that kind...When this [the use of cognition-enhancing drugs] becomes serious for education authorities, they may need to take steps. They could examine urine samples, for example.”
While we're at it, why don't we be sure to screen students' urine for dietary micronutrients that might give them an advantage. Or perhaps also for genetic polymorphisms associated with intelligence in order to reduce students' grades to handicap their "innate abilities". Or even better, the government could just perform video surveillance on the students 24/7 to ensure they're not acquiring any "unfair advantages," pharmacological or otherwise. Maybe we should enforce laws that allow students to study no more than a certain number of hours per week, just to make sure to avoid any unfair advantages.
Despite the provocative title of the article, it appears as though urine tests are not specifically recommended in the actual primary source article ("Brain science, addiction and drugs", article accessible here
, portal and description accessible here
) released by the Academy of Medical Sciences (searching for "urine" in the article reveals only hits relating to addiction and detection of drugs during pregnancy). However, given the above comment is from the chairperson of the expert committee, these suggestions are worryingly indicative of these academics drunkenly toeing the line between preservation of the public's safety and respect of individual liberties.
An interesting clip from the primary article:
"Most participants reported using caffeine regularly: tea, coffee, cola or 'Red Bull'. However, despite evidence that caffeine has a significant effect on cognition, most participants argued that the long history of using these drinks and their social context put them in a different category to other forms of cognition enhancers."
The phrase "long history of using these drinks and their social context" reminds me of man's inhalation of carcinogenic compounds for thousands of years before the pathogenic effects of smoke were realized. These sentiments, and the willingness of an Academy of Medical Sciences member to sacrifice personal liberties for them, reflect how fear of new technologies can profoundly cloud the judgment of those evaluating them.
"another point that I always make when this gets brought up is that we have to be realistic about the status of current cognitive enhancers. For example, ritalin and amphetamine might help you burn the midnight oil and study longer than usual, but there will quickly come a point when sleep deprivation and catecholamine depletion start to make it backfire. And of course any advantage that cholinergic drugs as well as the other gray market nootropics (like piracetam) are likely to be pretty damn subtle. These drugs have their most potent effects when there's a 'deficit' involved, like ADHD or dementia. In that case, the individual should likely be taking them anyway!
"I still want to see some research in healthy humans showing that these drugs have demonstrable positive effects on relevant cognitive tasks like standardized tests or longitudinal GPA performance."
When James and I were undergraduates, people who were not us set out to try and administer standardized tests for cognitive indices in a double-blind placebo-controlled fashion with piracetam. Perhaps surprisingly, they found that the tests were costlier and harder to come by than the volunteers and pharmaceuticals.
Hopefully those sitting in ivory towers with stacks of grant applications on their desks will have better opportunity before this generation is dust to let safety and science guide their thinking, instead of fickle social mores and flickers of totalitarianism. This is underscored by how little contemporary cognitive enhancers offer us, as Andy points out. Until then, all together now: War is Peace, Freedom is Slavery, Ignorance is Strength.
Moving towards the Genetics of Resiliance and Happiness
In my lab we work with a particular rat strain called the Wistar-Kyoto. These poor guys and gals are essentially the 'emo-kids' of rodents. They're anxious, overly suceptible to stress, and tend to fall into depressive ruts of immobility, weight loss, and decreased seeking of reward. In the past few years, there's been some good research on identifying the genetic basis of their condition. Even in humans we know that a common genetic mutation in the serotonin transporter can make people more neurotic and prone to depression (this gene has been appropriately dubbed the "Woody Allen Gene").
But with all the research on the genetics of poor mental health, what about the flip side? Are there any genes that tend to make people, to use our favorite Peter Kramer phrase, "better than well"?
Well sort of...
A collaboration of researchers from Canada, France, and China recently discovered that by deleting the Trek-1
gene, mice become depression resistant. They show less exaggerated hormonal responses to stress and are overall happier rodents. Interestingly, Prozac seems to work on inhibiting the protein made by Trek-1, allowing more efficient serotonin transmission.
Even if a future of genetically engineered humans without the Trek-1 gene isn't on the horizon, such a finding will hopefully lead to more specific and effective therapies.
PMID: 16906152 and 15685212
Modafinil: Not so novel a mechanism
Modafinil, the relatively new stimulant drug for treating narcolepsy has gained popularity in the "cosmetic pharmacology" realm as a wakefulness agent in normal people. Basically, people have been experimenting with it as an alternative to caffeine and amphetamines to feel more alert and counteract the effects of sleep deprivation. Most of the studies and feedback I've come across have demonstrated that it doesn't have many benefits over plain old caffeine. This most recent study demonstrates that the mechanism of modafinil might be more similar to something like amphetamine or ritalin rather than something particularly elusive and novel. Yet, if it the below study is true and modafinil does show good occupancy of the dopamine transporters during treatment, it woudln't explain the supposed lack of abuse potential that modafanil has:
J Pharmacol Exp Ther. 2006 Aug 2
Modafinil Occupies Dopamine and Norepinephrine Transporters in vivo and Modulates the Transporters and Trace Amine Activity in vitro.Madras BK, Xie Z, Lin Z, Jassen AJ, Panas H, Lynch L, Johnson RS, Livni E, Spencer TJ, Bonab AA, Miller GM, Fischman AJ.
Harvard Medical School.
Objectives: Modafinil (2-[(diphenylmethyl) sulphinyl]acetamide), prescribed principally to treat narcolepsy, is undergoing assessment for other neuropsychiatric disorders and medical conditions. The neurochemical substrates of modafinil are unresolved. We postulated that modafinil enhances wakefulness by modulating dopamine (DAT), norepinephrine (NET), or serotonin (SERT) transporter activities. In vivo, we determined DAT and NET occupancy by modafinil by PET imaging, and in vitro, modafinil activity at the DAT, NET, SERT and rhesus monkey trace amine receptor 1 (TA1). Methods: In rhesus monkey, modafinil occupancy of striatal DAT was detected by [(11)C]CFT and of thalamic NET by [(11)C]MeNER. In vitro, modafinil effects in DAT-HEK, NET-HEK and SERT-HEK cells were investigated alone or combined with the TA1 receptor, a Gs-linked receptor that responds to monoamines, including PEA. Results: Modafinil (i.v.) occupied striatal DAT sites (5 mg/kg: 35 +/- 12%; n = 4; 8 mg/kg: 54 +/- 3%; n = 3). In thalamus, modafinil occupied NET sites (5 mg/kg: 16 +/- 7.6%, n = 6; 8 mg/kg: 56% n = 1). In vitro, modafinil inhibited [(3)H]dopamine (IC50: 6.4 microM), [(3)H]norepinephrine (IC50: 35.6 microM), and [(3)H]serotonin (IC50:> 500 microM) transport via the human DAT, NET, SERT. Modafinil did not activate the TA1 receptor in TA1-HEK cells, but augmented a monoamine transporter-dependent enhancement of PEA activation of TA1 in TA1-DAT or TA1-NET cells, but not TA1-SERT cells. Conclusion: The present data provide compelling evidence that modafinil occupies the DAT and NET in living brain of rhesus monkeys and raise the possibility that modafinil affects wakefulness by interacting with catecholamine transporters in brain.
Finally, some insight on how antipsychotics cause weight gain and metabolic syndrome
Second Generation Antipsychotics (such as olanzapine, quetiapine, etc) are a mixed bag. On one hand, some physicians view them as a god-send for the treatment of schizophrenia, bipolar disorder, and even as augmentation strategies for antidepressants. Quite a few studies show that they can upregulate neurogenesis in key areas of the brain similar to antidepressants. Their main selling point over the older antipsychotic drugs is a lower prevalence of extrapyrmidal side-effects (parkinson symptoms). But the big issue with these drugs is their ability to cause massive weight gain and insulin resistance. And in our overweight society of fast food, drugs that cause weight gain is possibly the last thing we need. This can be a particular draw back for mental health patients who probably already have issues with self-esteem (and overall health).
The following abstract provides some ideas on how these drugs might cause such weight gain. It looks like they directly affect fat cells, decreasing fat breakdown and favoring fat cell growth in addition to making the fat cells insulin resistant:
Neuropsychopharmacology. 2006 Jun 28; [Epub ahead of print]
Atypical Antipsychotic Drugs Directly Impair Insulin Action in Adipocytes: Effects on Glucose Transport, Lipogenesis, and Antilipolysis.
Vestri HS, Maianu L, Moellering DR, Garvey WT.
Department of Nutrition Sciences, University of Alabama at Birmingham, Birmingham, AL, USA.
Treatment with second-generation antipsychotics (SGAs) has been associated with weight gain and the development of diabetes mellitus, although the mechanisms are unknown. We tested the hypothesis that SGAs exert direct cellular effects on insulin action and substrate metabolism in adipocytes. We utilized two cultured cell models including 3T3-L1 adipocytes and primary cultured rat adipocytes, and tested for effects of SGAs risperidone (RISP), clozapine (CLZ), olanzapine (OLZ), and quetiapine (QUE), together with conventional antipsychotic drugs butyrophenone (BUTY), and trifluoperazine (TFP), over a wide concentration range from 1 to 500 muM. The effects of antipsychotic drugs on basal and insulin-stimulated rates of glucose transport were studied at 3 h, 15 h, and 3 days. Both CLZ and OLZ (but not RISP) at doses as low as 5 muM were able to significantly decrease the maximal insulin-stimulated glucose transport rate by approximately 40% in 3T3-L1 cells, whereas CLZ and RISP reduced insulin-stimulated glucose transport rates in primary cultured rat adipocytes by approximately 50-70%. Conventional drugs (BUTY and TFP) did not affect glucose transport rates. Regarding intracellular glucose metabolism, both SGAs (OLZ, QUE, RISP) and conventional drugs (BUTY and TFP) increased basal and/or insulin-stimulated glucose oxidation rates, whereas rates of lipogenesis were increased by CLZ, OLZ, QUE, and BUTY. Finally, rates of lipolysis in response to isoproterenol were reduced by the SGAs (CLZ, OLZ, QUE, RISP), but not by BUTY or TFP. These experiments demonstrate that antipsychotic drugs can differentially affect insulin action and metabolism through direct cellular effects in adipocytes. However, only SGAs were able to impair the insulin-responsive glucose transport system and to impair lipolysis in adipocytes. Thus, SGAs directly induce insulin resistance and alter lipogenesis and lipolysis in favor of progressive lipid accumulation and adipocyte enlargement. These effects of SGAs on adipocytes could explain, in part, the association of SGAs with weight gain and diabetes.Neuropsychopharmacology advance online publication, 28 June 2006; doi:10.1038/sj.npp.1301142.
PMID: 16823387 [PubMed - as supplied by publisher]
Effexor Confusion in the healthy vs. depressed
I've always seen effexor as a controversial drug. With chemical and pharmacological properties distinct from the SSRI's, there's no doubt that it's effective. Much of the research even demonstrates that it's more effective and faster acting than many other antidepressants. However, a foggy mechanism of action and withdrawal complications have surrounded effexor with a sketchy veil.
Perhaps the biggest controversy regarding Effexor's mechanism of action is its capability to inhibit norepinephrine re-uptake. There's quite a gap in effexor's affinity for the serotonin and norepinephrine re-uptake pump, so its been commonly believed that its norepineprhine action doesn't kick in until the higher dosages. Clinically, most psychiatrists agree with this assessment, citing increased clinical responses as the dose gets above 150mg. Rat studies seem to support effexor's ability to inhibit NE uptake at higher dosages, but the human studies have been lacking.
Just recently a group at McGill published two seperate studies, one on healthy individuals and one on depressed individuals. In depressed individuals, doses of effexor above 225mg showed clear NE uptake inhibition by means of the tyramine pressor test. But in normal individuals, neither a 150mg nor a 300mg dose demonstrated NE uptake inhibition. On the other hand, the relatively selective NE uptake inhibitor desipramine had potent effects in healthy individuals.
So what's going on? Why can high doses of effexor act as an NE re-uptake inhibitor in depressed but not in healthy individuals? Does it have to do with actual physical differences/genetic differences in the NE transporter? Could it have to do with the testing method used and differential blood pressure regulation in the healthy vs. depressed?
Perhaps only time will tell. Until then, the nature of effexor remains quite curious.
Pubmed references: 16690005 and 16690006
The Human Condition and Selective Serotonin Reuptake Accelerators
Thanks to Chris' and Andy's previous posts, I have the luxury of entering into this dialog with the majority of our premises already defined. We believe that modern society has now reached the point where neuroscience is on the cusp of understanding the brain in previously unimaginable detail. Future discoveries in drug design and neurobiology will allow us a fine grained control over the mind itself. The time for pubic policy debate is now, while we are at this frontier of possibilities.
Unfortunately, contemporary society has a rather large problem with mind altering substances – by this I refer not only to the cornucopia of scheduled drugs of which possession alone is often a federal offense, but also to the state and corporate sanctioned GDP-boosting kind. Depression, for instance, has now been targeted by big pharma, and thanks in part to many advertisements it is now rightly looked upon as a disease rather than an indication of “weak will or character”. Pfizer's Zoloft alone generated over $3 billion in US sales in 2004. Yet there is a large divergence between these advertisements and current scientific literature.
It has never been shown that depression is a result a serotonin deficiency, as is now commonly believed. This is in part due to the fact that there is no easy way to even measure serotonin levels in living humans.
“I spent the first several years of my career doing full-time research on brain serotonin metabolism, but I never saw any convincing evidence that any psychiatric disorder, including depression, results from a deficiency of brain serotonin. In fact, we cannot measure brain serotonin levels in living human beings so there is no way to test this theory.”
-David Burns, MD, Stanford University
“A serotonin deficiency for depression has not been found.”
-Joseph Glenmullen, MD, Harvard University
To blame mental illnesses such as depression on chemical imbalances is to sidestep important problems – both philosophical and biological. Ignoring these questions leave us personally and societally at a disadvantage. Being depressed at times and even committing suicide is part of being human. This is what it means to live in a world which was created by selfish replication molecules, copying themselves for the sake of copying themselves. Individual happiness does not come into play; it has never been, nor will it ever be, a goal of natural selection. Our feelings and cognitive abilities are evolutionary byproducts, built upon selfish genes.
As such, we can postulate possible causes for depression actually being an adaptive evolutionary condition – “...rank theory proposes that depression is an adaptive response to losing rank and conceiving of oneself as a loser. The adaptive function of the depression...is to facilitate losing and to promote accommodation to the fact that one has lost. In other words, the depressive state evolved to promote the acceptance of the subordinate role and the loss of resources which can only be secured by holding higher rank in the dominance hierarchy. The function of this depressive adaptation is to prevent the loser in a status conflict from suffering further injury....” (Evolutionary Psychology, Stevens and Price) Mother nature does not care how you feel, as long as you manage to reproduce.
This line of thought brings us closer to the root of the problem. We must recognize that these diseases are not based on the individual level, but stem from the very nature of our existence. Through this, we can then understand the rational need for cosmetic pharmacology. Humanity was not created perfect, and society has spent many thousands of years bringing us to our current point. There was a time in history when humans had not even developed written language. It is now time to open our eyes and realize what human engineered chemicals can do for us, both emotionally and cognitively. The science and technologies are coming, we need only make the decision of how to use them.
It is possibly for this reason that depression is currently disguised as a chemical imbalance. People have an easier time imagining “chemical imbalances” than the idea that prehistoric history influences the way in which their minds work. SSRIs are not so much curing their depression as relieving them from worry. (http://psychiatrictimes.com/p990423.html) This would also explain the great successes SSRIs have in treating other mental disorders, ranging from Post-Traumatic Stress Disorder to Obsessive-Compulsive Disorder. One secret of anti-depressive drugs is the fact the selective serotonin reptake *accelerators* are just as effective at treating depression as selective serotonin reuptake *inhibitors*, despite the two having completely opposite effects. This is not widely discussed, as there is only one SSRA on the market, Tianeptine, and it is not currently marketed in the United States.
Tianeptine (brand names: Stablon, Coaxil, Tatinol) is as efficacious in treating depression as Prozac, with fewer side effects. For instance, sexual dysfunction or anorgasmia, is a frequently reported side-effect of SSRIs, yet it has been shown to occur with much less frequency during Tianeptine usage. (Switching to tianeptine in patients with antidepressant-induced sexual dysfunction. Human Psychopharmacology, 2003 Jun;18(4):277-80) Tianeptine also has a mood-brightening effect, in contrast to the emotion flattening caused by SSRIs. Later posts will detail tianeptine in more depth, but pubmed currently contains a wealth of information.
The general human condition itself can be much improved upon, without even entering into the realm of diseases currently standardized in the DSM-IV. Mental diseases when defined in this manner seem to often be an essentialist attempt by society to categorize and classify different behaviors which are rooted in the human condition itself and are quite often unrelated to any one chemical disorder or imbalance. (ie. Rosenhan - “If sanity and insanity exist, how shall we know them?”) Society does this not only for financial gain, but also because it does not know any better. The ontological framework which is evolutionary biology is only currently being deployed, often to vigorous debate and violence by the current Luddite or bioconservative class. It is our goal to help usher in a era where all individuals are free to safely modify their neurochemical makeup to allow them happier and more productive lives.
Thought Experiments in Cosmetic Pharmacology
In order to draw attention to some ethical concepts regarding cosmetic pharmacology, here are a couple thought experiments regarding hypothetical drugs and philosophical issues they bring up. Consider the following drugs while asking yourself the following questions: Should any of the above drugs be able to be acquired by anyone over the counter? With a prescription? Should any of them never be used by anyone?
1) A drug that makes people extremely productive, happy, not "emotionally-flattened" without any side effects, except for once every two years at an unexpected time, send user into a fit of violent rage. It cures a subset of dementias completely.
2) Consider a drug that completely suppresses sexual desire without any side effects, with long-term safety established.
3) Consider a drug that completely flattens all emotions with no side effects and established long-term safety.
The first case I think brings up the issue of giving someone a drug that could, due specifically to the drugs action, endanger the health and well-being of others in society. SSRIs have been accused of this in the past due to such things as association with school shootings and violent criminal acts. Even if a drug has a massive benefit, with such great risks should it be completely suppressed? Should the drug be allowed to circulate but only under intense supervision such that the negative effects could be negated? Could such purported violence be curbed? Where do you draw the line with regard to negative side effects? If it simply makes people verbally aggressive, would it be an infringment upon their rights to refuse them its other benefits? What if it cures the dementia but makes them not want to integrate into society or work at all? Would you let the individual decide how much a drug alters their personality by simply drawing the line at risk of violence toward others? Should the individual, medical establishment, or government have the last say in the usage of such a drug or similar drugs that lie across the spectrum of possessing side effects? I'd argue that unless a drug has a proven risk of making an individual significantly more of a direct risk to society or themselves (direct and significant here indicating interpersonal violence or suicidal tendencies), then the individual should ultimately have the decision of whether to use the drug. A possible counter-example to this argument would be: what about heroin addicts? Can a caveat be defined where disallow blatantly self-destructive tendencies without infringing upon individual rights? This seems to tap into existing drug debates involving the DEA/FDA with regard to the use of such recreational drugs as marijuana. More on these ideas later.... (in subsequent posts)
The latter two examples bring up the idea that was is natural is good and what is unnatural is necessarily bad. Much debate against emerging technologies has revolved around the technologies being "unnatural" and that their use is therefore unethical. Possibly some of the most "unnatural" side effects of drugs could be an abolishment of sexual drive or flattening of emotions, two purported side effects of SSRIs. Personally, I see these concerns as asinine knee-jerk reactions, but they seem deep seated in the contemporary status quo. Traditional counter-responses to the "unnatural is bad" mentality include the fact that pacemakers, much of contemporary medicine, antibiotics, contraception, are all unnatural. Any form of technology is likewise as unnatural from telephones to calculators, from preachers via tv to orbital satellites. What cosmetic pharmacology brings to the table as new in this regard revolves around the fact that it could much more blatantly alter who we are. I believe that the modulation of the substrate of cognition and the direct alteration of personality coming into the purvey of scientific analysis constitutes a significant paradigm shift.
How should all these concerns guide drug development and evaluation of purpoted cosmetic pharmaceutics?
Apologies for the stream of consciousness writing style, trying to get as many ideas on the table as possible for greater cohesion on this site later on.... More soon.