COGNITIVE ENHANCERS

Virtually everyone has occasionally wished that he or she could think faster, had a better memory, or was simply smarter. It is possible to improve these facets of cognitive function through practice, but most people are looking for an easier solution. At the beginning of the twenty-first century, the answer is usually imagined to be in the form of a pill.

Cognition has many elements. Key aspects of cognition include sensory perception, attention and concentration, immediate (or working) memory, and long-term memory. More complex and integrated facets of cognition include abstract reasoning and planning. Thus, there are a number of ways for pharmacological treatments to enhance cognition. However, for most people cognitive enhancement is synonymous with having a better long-term memory, so this topic is the primary focus of this entry.

Memory itself is a complex phenomenon that is still not completely understood by the medical and scientific community. Much of the research into understanding memory mechanisms is motivated by the need to develop treatments for memory impairments caused by diseases such as Alzheimer's disease. An important question in the present context is whether treatments that correct memory deficits can also enhance memory in normal healthy individuals. Virtually all drugs that improve memory show an "inverted-U" dose-response relationship: Doses of a compound up to a certain level enhance performance, but at still higher doses the enhancing effect is lost. The argument has been made that cognitive function in normal healthy subjects is at the crest of the inverted-U, while in aged, diseased, or otherwise impaired subjects cognitive function has slipped back onto the rising phase of the dose-response function. In this case, treatments to facilitate cognition in impaired subjects act to restore optimal performance, but the same treatments in normal subjects drive them past the optimal level, resulting in impairment. The inverted-U hypothesis suggests that it is easier to treat memory deficits than to improve normal memory. The results of many studies in animals and humans support this idea.

Still, the possibility of memory enhancement in normal healthy people remains very attractive. A casual search of the Internet leads to hundreds of sites offering memory-boosting aids. In some cases the agents are described only as herbal mixtures, while in others a single compound, or one or more specific components of the blend, is touted. The major constituents of these products are discussed in detail later in this entry. First, this entry reviews some drugs that are known to be able to enhance cognition and memory but are not generally available or usually sold for this purpose.

CNS Stimulants

The common feature of these agents is that they stimulate the central nervous system. Picrotoxin, bicuculline, and strychnine are drugs that block inhibitory systems in the brain, leading to a generalized increase in excitability. Picrotoxin was one of the first agents recognized to be a memory enhancer. All three drugs have been shown in animal studies to improve memory at low doses, but higher doses cause seizures and death. These drugs are too dangerous for experimentation in humans.

Another stimulant drug, amphetamine, has reliably been shown to improve memory in both animals and humans. Amphetamine causes the release of neurotransmitters that promote arousal, including epinephrine and norepinephrine. The resulting increase in attention plays a major role in the memory-enhancing properties of amphetamine. In addition, amphetamine improves memory consolidation, the process that leads to long-term memory storage. The major problems with this drug are that tolerance to its beneficial effects develops quickly, along with side effects that include physical dependence and addiction. These liabilities greatly outweigh amphetamine's utility as a memory enhancer.

Caffeine is the world's most widely used stimulant. It also increases alertness and attention, thereby enhancing cognitive performance. However, caffeine's effects on memory appear to be small. Vasopressin is a pituitary hormone that plays an important role in the body's regulation of water. In addition, vasopressin has been shown to enhance memory in both humans and experimental animals. The precise mechanism is unknown, but since vasopressin affects norepinephrine utilization in the brain researchers believe that increased arousal plays a role.

Cholinergic Agents

The neurotransmitter acetylcholine is known to play an important role in learning and memory. Neurons that contain acetylcholine degenerate in patients with Alzheimer's disease, an illness that is characterized by profound cognitive impairments. In addition, drugs that block the action of acetylcholine in the brain impair cognition in healthy humans and in experimental animals. Researchers have long hypothesized that improving cholinergic system function would be a good way to treat the symptoms of Alzheimer's disease, and this is the primary mechanism of action of drugs that are marketed for this purpose.

Cholinergic function can be enhanced either by preventing the breakdown of the acetylcholine to prolong its action or by directly activating the receptors for neurotransmitter. Physostigmine is an inhibitor of acetylcholinesterase, the enzyme that degrades acetylcholine. Physostigmine and related compounds have been shown to improve memory in normal humans and animals as well as in Alzheimer's disease patients. Activators of either the muscarinic or nicotinic receptor subtypes of cholinergic receptors also improve memory. Nicotine is well recognized as a cognition enhancer, although it is debated whether its effect is mediated by increasing attention or through another mechanism. Drugs that act at muscarinic receptors have also been shown to be effective cognitive enhancers in animal studies. Unfortunately, several muscarinic receptor activators have failed in clinical trials with Alzheimer patients because of side effects. No compound in this class has yet been developed that is safe enough for human use.

Components of "Smart Drugs"

The vast number of concoctions sold over-the-counter to improve memory provides an excellent indication of both the demand and the perceived need for these products. Many of these compounds are extracted from plants or animal tissues and consist of mixtures of ingredients. A major problem with such products is that claims concerning amounts and purity of the supposedly active elements have unusually not been verified by an independent agency. While this lack of oversight could lead to safety problems due to contaminants in the products, a more likely concern is that dosages may not be accurate or consistent. Such unreliability, coupled with the phenomenon of the inverted-U dosing effect, could explain the inconsistent results of the few formal tests of these agents that have been performed.

Five compounds seem to be most frequently sold as cognition/memory enhancers: huperzine A, vinpocetine, Ginkgo biloba, ginseng, and pregnenolone. Huperzine A, an extract derived from a particular type of club moss, is an acetylcholinesterase inhibitor that is far more potent than physostigmine. The acetylcholine plays an important role in the brain circuitry that encodes memories and is used as a neurotransmitter in the peripheral nervous system. Overactivation of these peripheral cholinergic connections can have profound and potentially dangerous consequences. Because of this problem, huperzine A is not a safe drug and should not be used without a physician's supervision.

Vinpocetine is derived from the periwinkle plant, Cricoceras longiflorus. It is widely used as a memory enhancer, and has been found to improve memory in healthy people as well as those with impairments caused by aging or disease. It is not clear how vinpocetine works, but there is evidence that vinpocetine enhances blood flow in the brain, which, in turn, provides the basis for observations of increased glucose utilization, a sign of generally increased cerebral activity. In addition, studies have shown that vinpocetine increases the production of norephinephrine, which mediates arousal, and acetylcholine. Vinpocetine is a very safe compound at therapeutic doses.

Extracts from the leaves of the Ginkgo biloba tree have been used in traditional Chinese medicine for thousands of years. These extracts consist of many compounds, the behavioral effects of which have yet to be individually characterized. Ginkgo extracts have been widely used as memory enhancers, particularly in the elderly, but studies have shown that ginkgo also improves memory in healthy young people. The primary effect of ginkgo appears to be increased cerebral circulation.

The ginseng plant, Panax ginseng, also has a long history of use in traditional Chinese medicine. Extracts from the roots or the entire plant contain over a dozen chemical compounds, collectively termed ginsenosides. Ginsenosides have been used to treat a number of diseases ranging from diabetes to insomnia, and to enhance physical and mental performance. While the memory-enhancing activity of ginseng is not as well documented as that of ginkgo, studies have shown beneficial effects in both young and elderly subjects. Like ginkgo, ginseng also promotes cerebral blood flow, but it also may enhance specific neurotransmitter systems. There is evidence that the combination of ginseng and ginkgo synergistically enhance memory. There are no known major health risks associated with either agent.

Pregnenolone is a neurosteroid, a hormone that is synthesized in the brain from cholesterol. Studies have shown pregnenolone levels decline with aging and are correlated with impaired cognitive performance. In addition, an injection of pregnenolone directly into the brains of aged animals improves memory. Pregnenolone has also been shown to enhance acetylcholine release in the brain. Taken together, these findings have been used to promote the value of taking pregnenolone supplements. While pregnenolone is safe, studies of the compound in humans have yet to provide consistent support for the idea that it is an effective cognitive enhancer.

Conclusion

Enhancing cognitive function remains both a dream and a challenge. There are a number of agents that appear to at least improve memory to some degree, but none of these compounds is so effective that it can be distinguished from the others. What is clear is that some degree of cognitive enhancement is possible even in young healthy people. Maximizing this effect will require systematic research to better understand how pharmacological treatments affect the basic neurobiological mechanisms that are responsible for particular aspects of cognition. A more immediate goal, and probably one that will be more quickly achieved, is to develop treatments to improve the cognitive impairments in aged or diseased individuals.

See also:DRUGS AND MEMORY; PHARMACOLOGICAL TREATMENT OF MEMORY DEFICITS

Bibliography

Born, J., Pietrowsky, R., and Fehm, H. L. (1998). Neuropsychological effects of vasopressin in healthy humans. Progressive Brain Research 119, 619-643.

Furey, M. L., Pietrini, P., and Haxby, J. V. (2000). Cholinergic enhancement and increased selectivity of perceptual processing during working memory. Science 290 (5,500), 2,315-2,319.

Izquierdo, I., and Medina, J. H. (1991). GABAA receptor modulation of memory: The role of endogenous benzodiazepines. Trends in Pharmacological Science 12 (7), 260-265.

Kennedy, D. O., Scholey, A. B., and Wesnes, K. A. (2000). The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers. Psychopharmacology, 151 (4), 416-423.

—— (2001). Dose dependent changes in cognitive performance and mood following acute administration of Ginseng to healthy young volunteers. Nutritional Neuroscience 4 (5), 295-310.

Kidd, P. M. (1999). A review of nutrients and botanicals in the integrative management of cognitive dysfunction. Alternative Medicine Review 4 (3), 144-161.

Mattay, V. S. et al. (2000). Effects of dextroamphetamine on cognitive performance and cortical activation. Neuroimage 12 (3), 268-275.

McGaugh, J. L., and Izquierdo, I. (2000). The contribution of pharmacology to research on the mechanisms of memory formation. Trends in Pharmacological Science 21 (6), 208-210.

Rees, K., Allen, D., and Lader, M. (1999). The influences of age and caffeine on psychomotor and cognitive function. Psychopharmacology 145 (2), 181-188.

Soetens, E., Casaer, S., D'Hooge, R., and Hueting, J. E. (1995). Effect of amphetamine on long-term retention of verbal material. Psychopharmacology 119 (2), 155-162.

Vallee, M., Mayo, W., and Le Moal, M. (2001). Role of pregnenolone, dehydroepiandrosterone and their sulfate esters on learning and memory in cognitive aging. Brain Resolution Review 37 (1-3), 301-312.

Warburton, D. M. (1995). Effects of caffeine on cognition and mood without caffeine abstinence. Psychopharmacology 119 (1), 66-70.

Gregory M.Rose