Adaptogens

Adaptogens are natural compounds or plant extracts that increase an organism’s non-specific resistance to stress by increasing its adaptability (ability to adapt) and survival (1).

The principal active constituents of adaptogenic plants (as investigated thus far, table 1) can be divided into two main chemical groups (1):

o    Terpenoids, with a tetracyclic skeleton such as cortisol and testosterone: ginsenosides, sitoindosides, cucurbitacines, and withanolides. 

o    Aromatic compounds, that are structurally like catecholamines or tyrosine, including:

·      lignans: e.g. eleutheroside E (Eleutherococcus senticosus), schizandrin B (Schizandra chinensis)

·      phenylpropane derivatives: e.g. syringin (Eleutherococcus senticosus), rosavin (Rhodiola rosea)

·      phenylethane derivatives: e.g. salidroside, tyrosol (Rhodiola rosea).

Many studies indicate direct interactions between tetracyclic terpenoids and corticosteroid and estrogenic receptors (1).

Table 1. Plants Mentioned in Literature as Adaptogens (1)*

 

Ajuga turkestanica (Regel) Briq.

Emblica officinalis Gaetrn.

Piper longum L.

Alstonia scholaris (L.) R. Br.

Eucommia ulmoides Oliv.

Potentilla alba L.

Anacyclus pyrethrum (L.) Lag.

Evolvulus alsinoides (L.) L.

Ptychopetalum olacoides Benth.

Andrographis paniculata (Burm.f.) Nees (92)

Firmiana simplex (L.) W.Wight

Rhaponticum carthamoides (Willd.) Iljin

Aralia mandshurica Rupr. & Maxim

Gentiana pedicellata (D.Don) Wall

Rhodiola heterodonta (Hook. f. & Thomson) Boriss.

Argyreia nervosa (Burm. f.) Bojer

Glycyrrhiza glabra L.

Rhodiola rosea L.

Argyreia speciosa (L. f.) Sweet

Heteropterys aphrodisiaca Machado

Rostellularia diffusa (Willd.) Nees .

Asparagus racemosus Wild

Hippophae rhamnoides L.

Salvia miltiorrhiza Bunge

Bacopa monnieri (L.) Wettst

Holoptelea integrifolia Planch

Schisandra chinensis (Turcz.) Baill.

Bergenia crassifolia (L.) Fritsch

Hoppea dichotoma Willd.

Scutellaria baicalensis Georgi

Bryonia alba L.              

Hypericum perforatum L.  

Serratula inermis                     

Caesalpinia bonduc (L.) Roxb

Lepidium peruvianum/ Lepidium meyenii Walp.

Sida cordifolia L.

Centella asiatica (L.) Urb.

Ligusticum striatum DC.

Silene italica (L.) Pers.

Chlorophytum borivilianum Santapau & R.R.Fern.

Melilotus officinalis (L.) Pall.

Sinomenium acutum (Thunb.) Rehder & E.H.Wilson

Chrysactinia mexicana A. Gray

Morus alba L.

Solanum torvum SW.

Cicer arietinum L.

Mucuna pruriens (L.) DC.

Sutherlandia frutescens (L.) R.Br.

Codonopsis pilosula (Franch.) Nannf.

Nelumbo nucifera Gaertn.

Terminalia chebula Retz.

Convolvulus prostratus Forssk.

Ocimum sanctum L.

Tinospora cordifolia (Willd.) Miers

Curculigo orchioides Gaertn.

Oplopanax elatus (Nakai) Nakai

Trichilia catigua A.Juss.

Curcumin from Turmeric (Curcuma longa)

Panax ginseng C.A.Meyer.

Trichopus zeylanicus Gaertn.

Dioscorea deltoidea Wall. ex Griseb.

Panax pseudoginseng Wall.

Turnera diffusa Willd. ex Schult. 

Drypetes roxburghii (Wall.) Hurus. 

Pandanus odoratissimus L.f.

Vitis vinifera L.

Echinopanax elatus Nakai

Paullinia cupana Kunth

Withania somnifera (L.) Dunal

Eleutherococcus senticosus (Rupr. & Maxim.) Maxim.

Pfaffia paniculata (Mart.) Kuntze

 

*This table is an update from the reviews Wagner et al. 1994 and Panossian and Wagner 2011.  It includes plants which do and do not meet the formal definition of adaptogen.

In various countries, adaptogens are used as dietary supplements or/and conventional and traditional medicinal products (2-5).

Definition and Background

The term adaptogens is used in alternative and complimentary medicine, pharmacognosy, phytomedicine, phytopharmacology, and phytotherapy research (6-14).  Initially, the term adaptogen was coined to describe substances that can increase the “state of non – specific resistance to stress” (15,16). Originally, the adaptogenic concept (3,7-12) was based on Hans Selye’s theory (17,18) of adaptive stress response of neuroendocrine immune complex (19,20) and long-term traditional use of some medicinal plants that are believed to promote physical and mental health, improve defense mechanisms of the body, and enhance longevity (7-14, 21-33).  It was suggested that certain compounds and herbal extracts, termed adaptogens, could diminish the magnitude of the alarm phase of adaptive stress response and prolong the duration the phase of non-specific resistance to stress (7,15). Based on evidences mainly from animal studies, adaptogens were defined as nontoxic “metabolic regulators, which increase the ability of an organism to adapt to environmental factors and to avoid damage from such factors” (6, 9).  It should be emphasized that the term “adaptogen” is associated with a physiological process – adaptation to environmental challenges, which is a multistep process that involves diverse mechanisms of intra- and extracellular interactions.  The updated definition of adaptogens (1) is supported by results of recent studies of molecular mechanisms of action of adaptogens on a variety of regulatory systems from the cellular level to whole organism (1, 34-48).

Pharmacology and the Mechanism of Action

Stimulating and stress-protective effects are characteristic and common pharmacological effects of adaptogens (9,11,31). These have been observed in many animals and humans by testing their cognitive function and physical endurance under stressful conditions (8,9,11,39, 42,43). Skillnaden mellan adaptogener och konventionella stimulantia, som koffein, nikotin, amfetamin med flera, är att de senare efter en längre tids användning kan göra att användaren utvecklar både tolerans och beroende. The main difference between adaptogens and conventional stimulants, such as caffeine, amphetamine, etc., is that after prolonged use, the later can cause the user to develop both tolerance and addiction, Table 2 (12, 43). Som ett exempel kan nämnas att adaptogener inte ger upphov till de sömnproblem som centralstimulerande ämnen gör. Adaptogens exhibit polyvalent beneficial effects against chronic inflammation, atherosclerosis, neurodegenerative cognitive impairment, metabolic disorders, cancer, and other aging-related diseases (22, 27, 49, 50). All of them are associated with the metabolic regulation of homeostasis and threatened adaptability of stress system.

Table 2. The Differences in Properties Between Adaptogens and Other Stimulants ().


Stimulants

Adaptogens

Stress protective (neuro-, hepato-, cardio-protective)

No

High

Recovery process after exhaustive physical load

Low

High

Energy depletion

Yes

No

Performance in stress

-

Increased

Survival in stress

-

Increased

Quality of arousal

Poor

Good

Addiction potential

Yes

No

Side effects

Yes

Rare

DNA/proteins synthesis

   

Decreased

Increased

NPY mediated activation of Hsp70

-

Increased

The metabolic regulation of homeostasis by adaptogens at the cellular and systemic level is associated with multiple targets (1, 34-47). Consequently, the pharmacology of adaptogens is a typical example of network pharmacology that can be approached using the systems biology concept (1). The classic reductionist model that presumes a specific receptor/drug interaction (51) is unsuitable for this scenario and insufficient when attempting to understand the mechanism of action of adaptogens. Molecular targets, signaling pathways, and networks common to adaptogens have been identified (1, 34-47). They are associated with stress hormones () and key mediators of the regulation of homeostasis (molecular chaperons Hsp70, neuropeptide Y, G protein-coupled receptors, dopamine-cAMP-PKA-CERT, IP3,  PLC, DAG, PI3K, NFkB,  mediated signaling pathways, stress activated kinase JNK, FOXO3, cortisol, estrogens, nitric oxide, etc.) (1, 34-47).  The mechanisms of action of adaptogens are “specifically” related to stress-protective activity and increased adaptability of the organism (1). 

A characteristic feature of adaptogens is that they act as eustressors (i.e. “good stressors”), and as mild stress mimetics or ‘stress- vaccines’ that induce a stress-protective response (44, 47).  Adaptogens exhibit multitarget action and the shared use of several different receptors, including receptors for corticosteroid, mineralocorticoid, progestin, estrogen, serotonin, NMDA, and nicotinic acetylcholine, receptor tyrosine kinases, and many G-protein coupled receptors (1, 34-47, 50,52-72). Therefore, the possibility that numerous molecular network interactions (with feedback regulation of the neuroendocrine and immune systems) contribute to the overall pharmacological response and result in agonist-dependent antagonism is most suitable for understanding the mechanisms of action of adaptogens (1).

Molecular targets, signaling pathways, and networks common to adaptogens are associated with chronic inflammation, atherosclerosis, neurodegenerative cognitive impairment, metabolic disorders, and cancer, all of which are more common with age (14, 34,35,36).

Current and Potential Use

Current and potential uses of adaptogens are mainly related to stress-induced fatigue and cognitive function, mental illness, and behavioral disorders (9, 13, 32, 42, 43, 76-85). Their prophylactic use by healthy subjects to ameliorate stress and prevent age-related diseases appears to be justified (14, 21, 23-26, 42,43).

I ett antal kliniska studier har man påvisat signifikanta effekter av adaptogener vid stresstillstånd.In a number of clinical studies, beneficial effects of adaptogens have been demonstrated on healthy subjects in stress conditions (42,43, 73-81 ). Det gäller särskilt den mentala och fysiska prestationsförmågan vid utmattning och psykisk påfrestning [ 19 ] [ 20 ] [ 21 ] [ 22 ] [ 23 ] [ 24 ] [ 25 ] . This is especially true of the mental and physical performance of fatigue and mental strain (42,43, 73-81). Furthermore, efficacy of adaptogens in mild and moderate depression has been demonstrated (32, 82-85).

Adaptogens have been used for the last decades in the official medicine of Russia and neighbor countries (Estonia, Ukraine, Armenia, Kazakhstan, etc.) as a stimulant against fatigue by patients who suffered asthenic states and by healthy people who showed asthenia during periods of high mental exertion or after intensive physical work (2, 27, 86, 87). Adaptogens are also applied in psychiatric practice.  (13, 32, 84, 85).

In Sweden, Norway and Denmark, rhodiola traditional herbal medicinal product is indicated as an adaptogen in situations of decreased performance such as fatigue and sensation of weakness.

Dietary supplements containing rhodiola, withania, ginseng, eleutherococcus, schisandra and other adaptogenic plant extracts are widely used all over the world (6).   

 

 

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