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The concept adaptogen was originally created by the pharmacologist A.V. Lazarev in 1947 to describe novel effects of dibazol 12-benzyl benzimidazol, an arterial dilator developed in France [1]. This concept was later (in the former Soviet Union) applied to describe remedies that increase the resistance of organisms to stress in experimental andclinical studies . According to the original definition adaptogens are non-specific remedies that increase resistance to a broad spectrum of harmful factors “stressors” of different physical, chemical and biological natures . An adaptogen must have a normalizing effect i.e. counteracting or preventing disturbances brought about by stressors. (The term stress is here used in the classic sense as defined by Hans Seyle as a state of threatened homeostasis.)

Moreover, it must be innocuous with a broad range of therapeutic effects without causing any major side effects.

This definition has been updated and today adaptogens are defined as a new class of metabolic regulators which increase the ability of an organism to adapt to environmental factors and to avoid damage from such factors [2, 3] .

In spite of an extensive amount of research in the USSR, (by 1984, more than 1,500 pharmacological and clinical published studies) , the concept is not generally recognized in Western countries as it seemed to be in contrast to some of the key-concepts of modern pharmacology: potency, selectivity and with efficacy balanced by and accepted level of toxicity . In 1998, however, the term adaptogen was allowed as a functional claim for certain products by US Food and Drug Administration and it is now a generally accepted concept , also by the European Medicines Agency and EFSA . Crude drugs that meet the criteria of being adaptogens are Eleutherococcus, Rhodiola, Schisandra and Ginseng .

The mechanism of action has been hard to rationalize. However, already by 1965 it was demonstrated that the adaptogenic effect was dependent on the DNA-dependant synthesis of RNA .

A series of recent pharmacological studies have provided a rationale for the effects at the cellular molecular level. The stress-protective activity of adaptogens has been found to be associated on the cellular level via activation molecular chaperons Hsp70 and other key mediators of the stress response such as cortisol, nitric oxide, stress-activated protein kinase JNK , DAF-16 . [[Heat-shock factor 1 (HSF1) and Neuropeptide Y (NPY) might be primary upstream molecular targets of adaptogens in neuroglia cells .

Repeated administration of adaptogens vs single dose administration

The repeated administration of adaptogens gives an effect analogous to that produced by repeated physical exercise by a transition from homeostasis to heterostasis. The effect is mainly related to the HPA- (Hypophys-Pituitar-Adrenal)-axis. Repeat dose administration of adaptogens has been shown to be of values in sports medicine and can lead to increased endurance for long distance runners, cross-country skiers etc, or to a more rapid recovery from a stressors events . It should be pointed out that the stress protective effect by repeated intake is not the result of inhibition of the stress response, but of adaptive changes in the organism to the repeated stress-mimetic effect of the drug. Adaptogens are stress agonists and not stress-antagonists .

Administration of adaptogens in a single dose is relevant when a rapid response to stress and strain is required. This effect is associated with the sympatho-adrenal (SAS) system. Suitable crude drugs for this purpose are eleutherococcs, rhodiola and schisandra, which also can be used for repeated administration .

Ginseng, on the other hand give and adaptive effect only after repeated administration for periods of 1-4 weeks .

Adaptogens as stimulants

There are important differences between the stimulating effect of adaptogens and other stimulants of the CNS as summarized :

Effect	Stimulant	Adaptogens
Recovery process after exhaustive physical load	Low	High
Energy depletion	Yes	No
Performance in stress	Decrease	Increase
Survival in stress	Decrease	Increase
Quality of arousal	Bad	Good
Insomnia	Yes	No
Side effects	Yes	No
DNA/RNA and protein synthesis	Decrease	Increase
Example	Example	Example

In contrast to conventional CNS stimulants, as caffeine, nicotine, amphetamine etc, which can impair mental function and lead to addiction, tolerance, with long term use, adaptogens by definition and from numerous studies do not exhibit such negative effects .

One plant adaptogen that derived from Rhodiola rosea has been shown significantly to regulate high-altitude sleep disorders and improve sleep quality. Plant adaptogens stimulate the nervous system by mechanisms that are totally different from those of traditional stimulants as associated with metabolic regulation of various elements of the stress system and modulation of stimulants-response comply.