ABSTRACT

Humans consume a wide range of foods, drugs, and dietary supplements that are derived from plants and which modify the functioning of the central nervous system (CNS). The psychoactive properties of these substances are attributable to the presence of plant secondary metabolites, chemicals that are not required for the immediate survival of the plant but which are synthesized to increase the fitness of the plant to survive by allowing it to interact with its environment, including pathogens and herbivorous and symbiotic insects. In many cases, the effects of these phytochemicals on the human CNS might be linked either to their ecological roles in the life of the plant or to molecular and biochemical similarities in the biology of plants and higher animals. This review assesses the current evidence for the efficacy of a range of readily available plant-based extracts and chemicals that may improve brain function and which have attracted sufficient research in this regard to reach a conclusion as to their potential effectiveness as nootropics. Many of these candidate phytochemicals/extracts can be grouped by the chemical nature of their potentially active secondary metabolite constituents into alkaloids (caffeine, nicotine), terpenes (ginkgo, ginseng, valerian, Melissa officinalis, sage), and phenolic compounds (curcumin, resveratrol, epigallocatechin-3-gallate, Hypericum perforatum, soy isoflavones). They are discussed in terms of how an increased understanding of the relationship between their ecological roles and CNS effects might further the field of natural, phytochemical drug discovery.

Introduction

Approximately one-half of all licensed drugs that were registered worldwide in the 25 y period prior to 2007 were natural products or their synthetic derivatives. However, only 3 of a total of 84 psychotropics registered in this period fell within this class (1). Although the contemporary medical pharmacological arsenal includes an array of synthetic psychotropic medications designed to modify aspects of brain function in specific pathological groups, to date there are few mainstream options in terms of improving brain function for cognitively intact populations. These groups include the growing segments of our aging societies that suffer from natural, age-related declines in brain function. Even sufferers from dementia are offered few treatment options for their more severe cognitive deficits. Those that are available are generally potentially toxic cholinesterase inhibitors that were initially derived from alkaloid phytochemicals (2). These chemicals generally have a less than favorable efficacy/side effect profile (3). Contrast this with the multitude of off-the-shelf herbal supplements that purport to improve aspects of brain function and are commonly used in developed societies. As an example, ~20% of the population of the US takes herbal products, often in the absence of any good evidence of their effectiveness, with 6 of the 10 most popular products being consumed in the belief that they will beneficially modify aspects of brain function (4).

A huge scientific literature focusing on psychoactive herbal extracts and their phytochemicals, encompassing hundreds of thousands of scientific papers, has emerged over recent decades. The vast majority of these papers describe in vitro investigations of the potential mechanisms of action of putatively psychoactive phytochemicals, whereas a much smaller proportion explores their effects in vivo in animals and only a tiny minority investigate their efficacy in humans.

The following comprises a review concentrating on those few nonprescription plant extracts and phytochemicals that have garnered enough evidence in human trials to arrive at some sort of indication of their efficacy in terms of improved brain function. Several polyphenols that are attracting huge scientific interest and that are in the first stages of the human trial process are included for completeness.

Curiously, one question that is almost completely ignored in the vast literature surrounding the effects of natural psychotropics is why plant chemicals affect human brain function. The answer to this fundamental question is not only of academic interest but also has a number of practical implications for future research and product development. This review therefore includes a consideration of why the plant chemicals that affect brain function, almost all of which can be classified as secondary metabolites, have their effects and how an exploration of this subject might help move this field of research forward.

The role of secondary metabolites in plants

Plants, and the evolutionarily more recent subdivision of flowering plants (angiosperms), have colonized the vast majority of the terrestrial surface, courtesy of rich levels of specialization and intricate relationships with other organisms. They make an exponentially larger contribution to terrestrial biomass by volume and weight than all other forms of life combined (5). However, as stationary autotrophs, plants have to cope with a number of challenges, including engineering their own pollination and seed dispersal, local fluctuations in the supply of the simple nutrients that they require to synthesize their food, and the coexistence of herbivores and pathogens in their immediate environment. Plants have therefore evolved secondary biochemical pathways that allow them to synthesize a raft of chemicals, often in response to specific environmental stimuli, such as herbivore-induced damage, pathogen attacks, or nutrient depravation (6, 7). These secondary metabolites can be unique to specific species or genera and do not play any role in the plants' primary metabolic requirements, but rather they increase their overall ability to survive and overcome local challenges by allowing them to interact with their environment (8). An indication of how essential these secondary metabolites are to plants' survival can be seen in the energy invested in their synthesis, which is usually far in excess of that required to synthesize primary metabolites (9). Some of the roles of secondary metabolites are relatively straightforward; for instance, they play a host of general, protective roles (e.g. as antioxidant, free radical-scavenging, UV light-absorbing, and antiproliferative agents) and defend the plant against microorganisms such as bacteria, fungi, and viruses. They also manage inter-plant relationships, acting as allelopathic defenders of the plant's growing space against competitor plants. More complex roles include dictating or modifying the plant's relationship with more complex organisms (8, 10, 11). Their primary role here is often viewed as being one of feeding deterrence, and to this end many phytochemicals are bitter and/or toxic to potential herbivores, with this toxicity often extending to direct interactions with the herbivore's central and peripheral nervous systems (12). In this regard, secondary metabolites often act as agonists or antagonists of neurotransmitter systems (11, 13) or form structural analogs of endogenous hormones (14). However, equally importantly, plants also have to foster a number of symbiotic relationships in order to survive. The most obvious role here is attraction of pollinators and other symbiotes via colors and scents or the provision of indirect defenses for the plant by attracting the natural enemies of their herbivorous attackers. This may take the form of providing an attractive chemical milieu for the predator or, alternatively, may be in direct response to tissue damage by the herbivore, which results in the synthesis and release of a cocktail of phytochemicals that attract the natural predators of the herbivore (8, 10, 11).

In terms of the evolutionary forces that have shaped the plant's selection of phytochemicals, it is notable that plants live within their own microenvironment, replete with a comparatively warm and humid microclimate rich in chemical emissions (15). Their interactions with animals are most often with the rich palette of invertebrates that coexist alongside them, and in particular with the arthropod, or insect, subgroup. The insect group itself comprises more than one-half of all of the species of multi-cellular life identified on earth thus far (16). Nearly one-half of all of these insect species are herbivorous, with the feeding habits of most species restricted to a small number of plant species (17). Many of the remainder live courtesy of either direct symbiotic relationships with plants or predation on other herbivorous insects. On the other side of the coin, two-thirds of flowering plants are entirely reliant on symbiotic insect interactions for pollination (15). Not surprisingly, plants and insects have coevolved in terms of physical and chemical diversity over their 400 million year common history (15, 18).

In contrast to the pivotal role of insects in the life of plants, it is notable that vertebrates make up a mere 4% of species on earth and are physically outweighed by insects by a factor of 10 to 1 across temperate areas of the earth (5). Although there are many examples of plant secondary metabolites interacting with vertebrates, the evolutionary imperative underlying these instances naturally become less prevalent to the majority of plants as the size of the animal increases and frequency of contact decreases. In these terms, humans have been inconsequential to the plant kingdom until the very recent past (in evolutionary terms) and the advent of agriculture some 12,000 y ago, with the ensuing deforestation and transformation of the earth's surface.

I might buy some flavonoids and see if it helps me.

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