Nootropics (Systematic Review)

Een type wetenschappelijk onderzoek in de biowetenschappen, vooral in de geneeskunde, waarbij getracht wordt de vraag te beantwoorden of een bepaalde behandeling ('interventie') werkzaam of zinvol is. Hiervoor wordt een bepaalde methode gebruikt: de te testen behandeling wordt uitgevoerd bij een interventiegroep en vergeleken met een controlegroep. Een controlegroep is een vergelijkbare groep proefpersonen of proefdieren met dezelfde klacht of hetzelfde probleem, maar die met een placebo of met een ander middel wordt behandeld.

A systematic review (also systematic literature review or structured literature review, SLR) is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine.

Abstract: The term neuroenhancement refers to improvement in the cognitive, emotional and motivational functions of healthy individuals through inter alia, the use of drugs. This popular topic attracts attention both from the general public and the scientific community.

Our objective is to summarize in a synthetic review the data of randomized placebo-controlled trials that assessed cognitive effects of administration of neuroenhancers in non-sleep-deprived healthy adults compared to placebo. The major outcomes were attention, memory, learning, executive functions, and vigilance/wakefulness. Details on the pharmacological profile, effectiveness and safety for each drug are provided. We classify them according to their recognized major primary mode of action, namely catecholaminergics (methylphenidate, modafinil, amphetamines, tolcapone, pramipexole, guanfacine, antidepressants), cholinergics (nicotine, varenicline, acetylcholine esterase inhibitors, anticholinergics), glutamatergics (ampakines, memantine, D- cycloserine), histaminergics, and non-specified (caffeine, racetams/phosphodiesterase inhibitors and glucocorticoids).

Discussion:
This synthetic, qualitative review presents evidence on cognitive enhancement effects of a number of drugs. The major findings are summarized in Table 1. (zie foto bijlage) Methylphenidate, amphetamines and modafinil (i.e. dopaminergics) showed some enhancing properties in memory and attention tasks. The same was the case for nicotine. On the contrary, no effects were found for serotoninergic, glutamatergic and cholinergic drugs. However, these substances were studied mostly in single-dose trials and it is probable that this design did not suit their pharmacological properties. Several other reasons for failing to find consistent results should also be considered. Samples in studies with healthy individuals are often much lower than in clinical trials; many of the studies reported here included less than 20 participants which is often not sufficient to detect a small effect. It is also often discussed whether cognitive tasks carried out in a neuropsychology laboratory are representative of real life [190].

The identification of cognitive enhancement effects should ideally include an optimization in terms of dose, individual genetic characteristics, baseline levels and the nature of the specific task. The effects on motivation, in addition to cognitive effects, also need to be investigated. We found that motivation was hardly evaluated in studies, although this dimension may be a particularly important modulator of the general effects of these substances when used as neuroenhancers. It is also shown that individual baseline characteristics seem to make a considerable difference to the outcomes of cognitive enhancement: positive effects seem in fact to be more prominent if the baseline performance of the individual is at the lower end of the normal distribution, which means that cognitive enhancers could potentially enable people with certain deficits to achieve a mean level of performance [191]. Some even postulate that this could be one (further) way to narrow the inequality of the “genetic lottery” [192]. However, concerns about coercion are also warranted. Regardless of their position in the normal distribution, healthy individuals might feel compelled to take cognitive enhancers because of real or perceived competitive pressure.

Very few data exist on students’ perceived effects of cognitive enhancers on their cognitive and academic performance [193,194]. Although one of the reasons for taking prescription stimulants seems to be to improve academic performance, no long-term academic benefits from their use have been reported to date. The most commonly reported effect is short-term improved alertness and energy levels. Estimation of societal benefits and harms might require more information on effectiveness and prevalence [7]. Studies should differentiate between various types of drug use purposes and record prevalence and frequency data, as well as perceived efficacy. Use should also be correlated with other factors, such as socio- demographic indicators, academic performance, and illicit drug and alcohol use habits.

A widespread use of even some of the above reviewed substances does not seem warranted, not only because of the low level of evidence for a positive effect, but also because of the potential of side effects that were not presented in this paper. Acceptance for side effects would be lower in healthy individuals than in patients. For a meaningful use-risk analysis, long-term effects on the individuals and possibly on the societies should be considered. Since the majority of the studies that were performed until now were short-term and single-dose trials, no evidence-based statement can be made on long term effects and especially on reinforcing effects, dependence development, drug tolerance and long-term toxicity of these substances when used for cognitive enhancement purposes by healthy individuals.

Finally, most of the basic modes of action of the reviewed drugs have been elucidated, although this paper does not replace standard psychopharmacology textbooks to which the interested reader is encouraged to refer to [195]. For readers with little background in pharmacology in general and pharmacological cognitive enhancement in particular, it might seem counterintuitive that so many different substances with so diverse mode of actions are being reviewed. Our goal was to provide an overview of possible interventions and especially of interventions that have been discussed in the context of cognitive enhancement. Beside this, cognition is a broad concept and different aspects of cognition can be modulated through different neurotransmitter systems and hence through different substances. We are however fully aware that although some substances, such as amphetamines and methylphenidate, might be in use already, most of the substances reviewed here are not actually being used at all for enhancement purposes in everyday life and will probably never be used for that purpose in the future. For many of them, the high rate of side effects and/or the possibility of severe adverse effects will always be a limiting factor for their use, so that it is sheer hypothetical to consider them as conceivable neuroenhancers. It is only for the sake of completeness that we report results from RCTs on these drugs.

We are especially aware that reviewing presumably enhancing effects of substances can induce a self-fulfilling prophecy, particularly if secondary literature overestimates reported positive effects. A recently published content analysis [196] of the coverage of one of the first studies of donepezil on healthy individuals [127] supports our concern: the media and bioethics literature made strong claims about donepezil being a cognitive enhancing drug. Enhancement language was used while reporting the results of the primary study and magnifying the perceived connection between these results and the cognitive enhancers debate that was alluded to in the primary study. In this review we could show to some extent the discrepancy between the high expectations, as presented mainly through the mass media, and the actual effects of these drugs as found in RCTs.

Amphetamines:
Amphetamines (dexamphetamine, (Dexedrine®) and chemically related substances) have a long history of both medical and non- medical use and abuse. Adderall® is a combination of four amphetamine salts (racemic amphetamine aspartate monohydrate, racemic amphetamine sulfate, dextroamphetamine saccharide, and dextroamphetamine sulfate) [14]. Amphetamines are sympathomimetic amines with central nervous system (CNS) stimulant activity that have both therapeutic properties and a potential for abuse. Amphetamines are considered as dopamine transporter substrates and as dopamine releasers, acting, mostly on the dopamine vesicle transporter VMAT2 and releasing dopamine in the extracellular cleft by reversing the direction of the transport of dopamine [35]. The pharmacological effects of amphetamines have been attributed to their effects on central catecholamine neurotransmission, where they block the reuptake from the synapse, inhibit the action of monoamine oxidase and facilitate the release of dopamine and norepinephrine [36,37]. Although it was thought that amphetamine use for non-medical reasons was more widespread in the US but less so in Europe, there has been a recent cross-sectional study showing that in France amphetamines were used as frequent as MPH by medicine and pharmacology students for neuroenhancement purposes [38].

The first review on the effects of amphetamine's on performance of healthy individuals was published in 1962 and concluded that 10 mg d-amphetamine may hasten conditioning, increase the rate at which subjects may acquire proficiency in a motor skill, decrease discriminative reaction time (but more in fatigued subject than in others), improve coordination performances but do not improve strictly speaking intellectual performance [39]. Since this work, more than 40 RCTs assessing cognitive performance of healthy adults after amphetamine administration have been conducted; about half of them focusing on mood enhancement. Studies assessing d-amphetamine and methamphetamine's effect on cognitive performances in non- sleep deprived healthy adults are summarized in Table 1 [40-61]. Surprisingly no meta-analysis of this data has been carried out to date. In summary, a large number of studies found a large positive effect of a d-amphetamine single dose administration in verbal memory tasks, on vigilance, learning and inhibitory control and on delayed memory rather than immediate/short term memory (Table 1) but negative results were also reported [47] and a meta-analysis is warranted to determine the effectiveness of amphetamine administration on cognitive performances in healthy adults.

Racetams:
The word “nootropic” was coined upon discovery of the effects of piracetam (pyrrolidone acetamide, Nootropil®, Nootrop®, Nootropil®), developed in the 1960s. Piracetam and piracetam-like molecules are thought to be neuroprotective agents with potential enhancement properties, possibly due to their common 2-oxopyrrolidine structure [11]. Ampakine activity has been established as one of the modes of action of the racetams, however these drugs have multiple modes of action and produce only weak AMPA receptor activation, and it is unclear how significant their ampakine actions are in producing their positive effects. Piracetam, aniracetam and oxiracetam are indicated in neurocognitive impairment and cognitive decline. Therapeutic applications of racetams are also reported [169].

Although animal studies suggest memory and wakefulness enhancement properties of several racetams [170-177], the effectiveness of piracetam or piracetam-like molecules was not explored in healthy adults to date. An explanation could be that all animal data focused on restoring age-impaired cognitive functions [11].

Levodopa (L-DOPA):
L-DOPA (L-3,4-dihydroxyphenylalanine) (Sinemet®, Parcopa®, Atamet®, Stalevo®, Madopar®, Prolopa®) is in some animals and humans a product of biosynthesis deriving from the amino acid L-tyrosine. L- DOPA is the precursor to the neurotransmitters dopamine, norepinephrine and epinephrine. As a drug, it is used in the treatment of Parkinson's disease and dopamine-responsive dystonia.

The results of the 7 studies that were found on L-DOPA effects on memory and attention are summarized in Table 1. L-DOPA seems to improve encoding but showed no effect on long-term memory and selective attention [65-71].

Nicotine:
Nicotine is a potent parasympathomimetic alkaloid found in the nightshade family of plants (Solanaceae). It acts as a nicotinic acetylcholine receptor agonist. Nicotine is named after the tobacco plant Nicotiana tabacum, which in turn is named after the French ambassador in Portugal, Jean Nicot de Villemain, who sent tobacco and seeds to Paris in 1560, and who promoted their medicinal use. The cholinergic modulation of the midbrain dopamine system has been connected to nicotine self-administration in rats and hence is thought to support drug reinforcement [113].

Nicotine is likely one of the most extensively studied drugs in humans and its effects on cognitive abilities have been extensively reviewed. A recent meta-analysis [10], including 41 RCTs on nicotine administration in healthy adults (non-smokers or not tobacco- deprived smokers) found significant positive effects of nicotine or smoking on six domains: fine motor, alerting attention-accuracy and response time (RT), orienting attention-RT, short-term episodic memory-accuracy, and working memory-RT (effect size range=0.16 to 0.44). The majority of studies (75%) administered nicotine via a medication approved by the FDA, usually nicotine gum and transdermal patch. Most studies (73%) administered single doses of nicotine. Nicotine has been also found to enhance driving [114] and flight [115] performances. For a detailed analysis of the methodologies and results of these studies see [10].

Melatonininergics:
Melatonin (N-acetyl-5-methoxytryptamine) is a naturally occurring compound found in animals, plants, and microbes. In animals, circulating levels of the hormone melatonin vary in a daily cycle, thereby allowing the entrainment of the circadian rhythms of several biological functions. In humans, melatonin is produced by the pineal gland. Melatonin receptors appear to be important in mechanisms of learning and memory in mice [155]. Melatonin can initiate offline plastic changes underlying memory consolidation, an effect similar to the effect of sleep [156]. Products containing melatonin have been available over-the-counter in the United States since the mid-1990s. In many other countries, the purchase of melatonin requires a prescription. Agomelatine (Valdoxan®, Melitor®, Thymanax®) is a melatoninergic antidepressant.

A single dose of 3 mg melatonin specifically enhanced recognition memory accuracy of objects encoded under stress in 27 young volunteers versus 23 placebo controls [157].

Caffeine:
Caffeine, a methylxanthine, is the most widely consumed psychoactive substance in history [158]. Caffeine is an adenosine receptor antagonist that reduces inhibition of neural firing through an increased turnover of noradrenaline in the brain [159]. Unlike psychostimulant drugs, caffeine apparently only triggers a dopamine release in the prefrontal cortex, whereas a dopamine release in the ventral striatum does not occur [160]. Therefore, there is a neurobiologically definable difference leading to a lower addiction potential in comparison to psychostimulants that increase dopamine release in the ventral striatum such as amphetamines.

The widespread use of caffeine may be due in part to the perception that oral ingestion of the drug enhances performance and mood. However, the validity of the belief that caffeine can enhance human performances has been questioned, giving rise to debate. Surprisingly, we found no meta-analysis on caffeine cognitive effects in healthy adults. In a review, James et al. [161] concluded that appropriately controlled studies show that its apparent beneficial effects on performance and mood are almost wholly attributable to reversal of the withdrawal effects that occur after short periods of abstinence (e.g. overnight). It appears from a minority of low/non-consumer and long- term abstinence studies that there may be some modest improvement in mood, and perhaps performance, as an acute effect of caffeine when ingested in the absence of withdrawal. However, these effects are small and inconsequential compared with the effects attributable to withdrawal reversal. Crucially, these modest acute net effects also seem to be subjected to the development of tolerance when caffeine is repeatedly consumed.

djeemen schreef:Interessant! Bedankt.

Fool schreef:Thanks, bijzonder dat alle verslavingsboeken over 'stoppen met roken' claimen dat nicotine niets met je doet.

Piracetam has a history of being used to treat cognitive impairment. According to a meta-analysis on human studies, piracetam improves general cognition when supplemented by people in a state of cognitive decline, such as the kind that comes with aging. Though piracetam may be a useful supplement for improving longevity, it offers limited benefits for healthy people.

Healthy people supplementing piracetam do experience little to no cognitive benefit. Though piracetam supplementation in healthy people is understudied, preliminary evidence suggests that piracetam is most effective for older people. Piracetam supplementation has also been found to reduce the chances of a breath-holding spell in children.

Piracetam enhances cellular membrane fluidity. This mechanism explains why piracetam is able to improve cognition, particularly in elderly people.

Piracetam is as effective as aspirin when it comes to preventing blood clotting, which makes it a useful supplemental intervention after cardiovascular trauma.

Claviceps schreef:Een andere reden waarom er niet veel over racetams bij staat is omdat de systematic review heeft gekeken naar studies in gezonde mensen en cognitieve verbetering met RCTs. Als je zelf literatuur gaat zoeken zul je erachter komen dat er vrij weinig tot geen van deze studies beschikbaar zijn over verschillende racetams.

Vraag me bij dit soort onderzoeken wel vaak af of er niet iets over het hoofd wordt gezien

[...]

Het onderzoek, hoe het hier uiteengezet staat, is in mijn ogen een interessante.

• Nature.com - Study design VII. Randomised controlled trials
• American Journal of Roentgenology - Fundamentals of Clinical Research for Radiologists, Randomized Controlled Trials

Advantages of RCT:

• Ability to make causal inferences mean that RCT provide the strongest empirical evidence of a treatment's efficacy.
• Randomisation of participants to the test and control arms and concealment of their allocation ensures that allocation bias and confounding of unknown variables are minimized.
• The study can be tailored to answer a specific research question.

Disadvantages of RCT:

• High dropout when the intervention has undesirable side-effects or there is little incentive to stay in the control arm.
• Ethical considerations may mean that a research question cannot be investigated using the RCT design.
• For a descriptive overview it may be cheaper and easier to use an observational design.
• Prior knowledge is required about the level of improvement that is clinically meaningful and the expected variation of improvement in the sample in order to calculate the RCT sample size. These facts are often not known.

frozentoast schreef:RCT's hebben vaak ook wel lage ecologische validiteit (labonderzoek), dus de resultaten generaliseren slecht naar een setting in het dagelijks leven.

Ecological validity is often confused with external validity (which deals with the ability of a study's results to generalize). While these forms of validity are closely related, they are independent—a study may possess external validity but not ecological validity, and vice versa.

frozentoast schreef:Plus wat vaak (in de psychologie in ieder geval) lijkt te gebeuren is het weglaten van controle voor aantal meetvariabelen en covariaten, waardoor er al snel een significant effect uit rolt.