Abbreviations: Adenosine triphosphate (ATP), Metabolic Correction (MC), Physiological Modulation (PM), Systemic Medicine (SM), Systemic Theory (ST)
To understand the concepts presented herein, certain terminology must be described. Similar to orthomolecular medicine, physiological modulation (PM) is defined in this context as changes in physiology that improve metabolism, utilizing specific molecules and/or active principles. The intent of PM is to provide a wide variety of metabolically beneficial molecules that have the structure and/or chemical properties needed for a specific physiological situation, increasing available energy and decreasing total entropy of an open biological system. Achieving homeostasis or the balance required for the healthy state is defined herein as a physiological status of balance in which the cells are functioning with all their physiologic capabilities.
PM is based on the Systemic Theory of Living Systems previously described by Olalde, which postulates that the healthy state is based on three synergistic factors: 1) functional organic energy reserve, i.e., the fuel that causes action or movement; 2) active biological intelligence as the regulator that controls and integrates the parts of a living system into a functional unit; and 3) integrity of structure or organization of a group of elements into a functional unit. The second law of thermodynamics states there is a natural tendency of an isolated system to degenerate into a more disordered state. The general change of entropy in a living system consists of internal entropy variations and entropy exchange with the environment. Consistent with this law, Systemic Theory (ST) establishes a common denominator to all sickness, attributing the cause of disease to be an increase in entropy or disorder within the biological system (Olalde, 2005a; Olalde, 2005c).
From this theory, a treatment strategy called Systemic Medicine (SM) is derived. SM largely utilizes PM, which involves identifying and prescribing phytomedicines and/or other natural medications that favor the healthy state by supporting physiological mechanisms. Phytomedicines include adaptogens, which the authors believe may be overlooked and should be incorporated in orthomolecular medicine. Adaptogens are substances of plant origin with polyvalent pharmacological activity that increase an organism’s nonspecific resistance to stress and promote homeostasis at the cellular level (Panossian 2017).
The aim of this article is to provide a scientific explanation of how adaptogens can be useful in orthomolecular medicine for physiological modulation, increasing energy, decreasing entropy and therefore disease, and achieving a healthy state.
Human Physiological Function and Plant Chemistry
Within a biological system, functional fluctuations occur in response to constantly changing cellular environmental conditions. In order to maintain the proper balance (homeostasis), a series of energy-requiring, orderly reactions must occur. Failure in cellular energy metabolism is a common denominator in chronic degenerative diseases. This failure impacts Huntington’s disease (Browne & Beal, 2004); Alzheimer’s disease (Gabuzda, et al., 1994; Valla, et al., 2001) and aging in general (Toussaint, et al., 1995). Further, intracellular communication, which is a manifestation of biological intelligence, is necessary to maintain cellular organization. The tendency to reach order depends on available energy and information within the system. Stable organization cannot be attained in a living system with insufficient information or energy. Disease, therefore, may be defined as a state of disorganization, i.e. higher organic entropy, corresponding with a low energy/informational status of the system (Olalde, 2005a).
A true healthy state facilitates and promotes energy production, formation of structures, tissue growth and repair, cell differentiation, detoxification and production of the necessary chemicals (hormones and neurotransmitters, cytokines, growth factors) in a delicate dynamic balance (Gonzalez, et al. 2018). The pathological state (physiological entropy) usually results from multiple causes and therefore, a synergistic approach is required to correct this state. The Metabolic Correction (MC) concept can supply the necessary cofactors in the right form and dose to influence cellular biochemistry (Gonzalez & Miranda-Messari, 2012; Gonzalez, et al. 2015); PM can function as a synergistic partner to MC by providing key exogenous molecules that produce, replicate or enhance a necessary physiological effect to help restore normal physiology favoring the healthy state.
The application of PM involves classifying and applying botanicals according to a specific type: energy stimulators; biological intelligence modulators and organizational (structural and functional) enhancers. Adaptogenic botanicals contain compounds that possess the structure and/or chemical properties needed for these actions. The therapeutic benefits of adaptogens range from anti-viral to anti-inflammatory, and increased adenosine triphosphate (ATP) production (See Table 1). Note that each of the adaptogens listed in Table 1 also have ATP synthesis and re-synthesis as a main effect making them potential therapies for energy-deficiency related diseases, such as Parkinson’s, Huntington’s, Alzheimer’s, multiple sclerosis, and in general, all chronic degenerative diseases. Adaptogens such as Rhodiola rosea and Eleutherococcus senticosus can also have beneficial effects in fundamental biological processes such as oxidative phosphorylation and nitric oxide production. The Golden Rule of Therapeutics described by Olalde (2005b) recommends at least one of the energy adaptogens listed in Table 1 be used in chronic degenerative disease protocols.
Adaptogenic plants have been used for centuries in Chinese, African, Tibetan, Ayurvedic, and Cherokee medicine to restore balance and health (Antoshechkin, 2001). The term “adaptogen” was originally coined in 1947 when it was recognized that “adaptogens” are able to increase a non-specific resistance of the organism to stress factors and thereby promote its adaptation to stressful external conditions without causing harm. The concept of adaptogen has been modified over the years. In the 1990s, Wagner, Wikman, and Panossian performed many studies on adaptogens and called them “natural bioregulators.”. In 1998, the FDA defined an adaptogens as a new kind of metabolic regulator that has been proved to help in environmental adaptation and to prevent external harms (Lian-ying, et al. 2018). Studies have shown that adaptogens enhance energy mechanisms such as the biosynthesis of ATP (Panossian, et al. 1999 a, b, c).
Adaptogens as a Physiological Modulation Mechanism
Adaptogens normalize endocrine function through numerous broad and non-specific actions, and increase overall resistance to stressors; they exert unique actions on the adrenal system that tend to promote resistance to the negative effects of stress on the body; they support the activation and synchronization of both the neuroendocrine system and cellular energy metabolism, that are reduced by illness, physical/mental fatigue and aging (Gonzalez, et al., 2018). Adaptogens exhibit polyvalent beneficial effects against chronic inflammation, atherosclerosis, neurodegenerative cognitive impairment, metabolic disorders, cancer, and other aging-related diseases (Panossian, 2017).
Several theories have been proposed to explain the effects of adaptogens. One theory proposed by Davydov and Krikorian (2000), stated that adaptogens function primarily due to their antioxidant and free radical scavenging capacity. This theory is only partially accurate since this theory falls short of explaining the full effects of these medicinals. Adaptogens enhance normal physiological functions rather than pushing the body toward a specific outcome. Thus, the administration of adaptogens can result in the stabilization of physiological processes and promotion of homeostasis, leading to the healthy state.
Bidirectional Action of Adaptogens
To normalize body function, adaptogens are capable of producing a bidirectional effect on physiological function. Adaptogens can either downregulate the activity of hyperfunctioning systems or strengthen activity of low-functioning systems. Panax ginseng’s ginsenosides Rg1 and Rb1 are good examples of this bidirectionality. Rg1 can stimulate angiogenesis, mitosis, and the nervous system while Rb1 has the opposite effect. Ginseng also has hypertensive and hyptotensive properties. The directional decision is left to biological intelligence based on the system’s needs (Han, et al., 2005; Ogawa-Ochia & Kawasaki, 2019; Olalde, 2005c; Scott, et al., 2001).
Adaptogenic herbs stimulate and balance several systems, most notably the neuroendocrine and immune systems. Adaptogens can have numerous pharmacological effects and indications that can help the body reach the state of homeostasis. Chemically, the adaptogens are typically either complex phenolics or tetracyclic triterpenoids (Panossian & Wikman G, 2010). The phenolics are presumed to act via the hypothalamic-pituitary-adrenal (HPA) axis, while the terpenoids are presumed to interact with the sympathoadrenal system (SAS). The HPA axis and SAS are anatomically and functionally interconnected. Some plants such as Eleutherococcus, have the potential to modulate both the HPA axis and SAS due to multiple bioactive compounds (Panossian, 2017).
Expanded Explanation of Adaptogens: A Mechanistic View
Adaptogens work in a multi‐targeted, multi‐channel, network‐like manner, sharing a number of different receptors, and acting mainly by affecting the hypothalamic–pituitary–adrenal axis. They can also affect the immune, nervous, and endocrine systems, and therefore, the entire body. Adaptogens also affect gene expression, acting to deregulate genes that code for proteins that play important roles in behavioral, cognitive, and age-associated disorders (Lian-ying, et al. 2018; Panossian, 2017).
A number of studies have suggested several mechanisms of actions related the beneficial stress-protective effect of adaptogens and regulation of aging and disease pathology of age-related disease. Key players in mediating the effects include corticol, neuropeptide Y (NPY), heat shock factor-1(HSF1), heat shock proteins (HSP25, HSP27, HSP70, and HSP 72), stress-activated c-Jun Nterminal protein kinase (JNK1), Forkhead Box O (FOXO) transcription factor DAF-16, cortisol and nitric oxide (NO), with no single contribution that can be estimated with any degree of certainty. The molecular targets HSF1/HSP70 and FOXO are related to complimentary longevity pathways. Whereas chemicals used to induce HSP70 are typically cytotoxic and unsuitable for patients more susceptible to stress, such as the elderly, PM of these pathways using adaptogens to delay the onset of neurodegenerative and age-related diseases is a viable therapeutic solution. (Panossian & Wikman, 2009; Panossian, 2017).
The pharmacology of adaptogens is that of network pharmacology. Multiple molecular networks are involved that coordinate both intracellular and extracellular signaling. The metabolic regulation of homeostasis by adaptogens at the cellular and systems levels is associated with multiple targets. Network pharmacology is a distinctive new approach that involves application of network analysis to determine the set of molecules capable of targeting specific characteristics of a disease. By addressing the true complexity of disease and by seeking to harness the ability of compounds to influence many different pathways, network pharmacology differs from conventional drug discovery approaches which have generally been based on highly specific targeting of a single pathway or protein. Network pharmacology has the potential to provide treatments for complex diseases, chronic conditions, and syndromes where conventional approaches have often been disappointing (Panossian, 2017).
The plethora of terpenoid and phenolic compounds in adaptogens most likely explains their multi-target effects and polyvalent pharmacological actions. This unique set of synergistic, complementary compounds are capable of oxidation–reduction actions depending on the system’s needs, guided by its energy status. Other compounds in adaptogens such as alkaloids and flavonoids have anti-viral, anti-inflammatory, and antioxidant properties. Any adaptogenic plant has dozens of active principles and adaptogens display their greatest efficacy in the form of extracts containing a combination of several active substances from a single plant species. Additionally, combinations of different adaptogens can also act synergistically without adverse effects, provided that they are administered by trained professionals who maintain appropriate patient supervision (Abdimov, et al. 2003; Bucci, 2000; Olalde, 2005c; Panossian, 2003).
The principles of systems biology and pharmacological networks appear to be more suitable for conceptualizing adaptogen function. Understanding the mechanisms of action of adaptogens requires a holistic approach. A one-drug, one-indication paradigm is not suitable for adaptogens. Nor can the mechanistic aspects of the physiological notion of “adaptability” and the adaptogenic activity of adaptogens be adequately described using the reductionist model or single receptor-based pharmacology (Panossian, 2017).
If a reduction in illness is to be achieved, energy must be increased, and entropy reduced. A comprehensive way of accomplishing this is administering negative entropy, or order, through PM using adaptogens that stimulate the production of energy and provide survival information to the immune, neuroendocrine and cellular systems. A more complete result or system optimization can be achieved by complementing the actions of PM with MC via the provision of necessary cofactors and coenzymes that guide cellular metabolism. These two therapeutic physiologic balancing actions may activate biological intelligence and create the necessary environment to favor the healthy state. Protocols combining MC (diet and scientific supplementation or orthomolecular therapy) and PM (botanicals/adaptogens and systemic therapy) may reduce medication requirements and adverse side effects, and improve treatment outcomes for chronic, degenerative and age-related diseases.
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