The Body and Extreme Doses of Psychoactive Substances

The Body and Extreme Doses of Psychoactive Substances. The article shows that the current level of physiology does not disclose the biological mechanisms of the organism transition from one range to adapt to a higher with an increase in the regular forces of the stimulus above sub-extreme. A new trend in the physiology of adaptation progredient adaptation, explains the mechanism of increasing the tolerance of the organism, with dependence on Psychoactive Substances (PAS). It is scientifically proved, that dependences of the organism on PAS are the states of progredient adaptation.

and results in no euphorizing effect. To achieve neurophysiological shift sufficient for euphoria, a larger dose is required. But increase in the dose of PAS after the activation reaction is stressful for the organism. Stress in its development has three stages. The first stage is the "anxiety reaction", the second one is the stage of tolerance, when hypertrophy of the adrenal cortex with a steady increase in the formation and secretion of corticosteroids develops. They increase the amount of circulating blood and blood pressure, have an antihistamine effect, enhance gluconeogenesis, normalize physiological reactions, etc. The tolerance of the organism to the stimulus increases. Prolonged exposure to the stimulus results in the stage of exhaustion, and death may occur. Doses of PAS above the stress level are lethal [1].
L Kh Garkavi and co-authors showed that: "the reactivity of the organism is represented by a number of floors (ranges), which does not exceed ten. In each floor: a weak stimulus causes the training reaction, an average sub-extreme stimulus -the activation reaction, a strong stimulus -the stress. The ranges are separated by the zone of non-reactivity, when increasing the stimulus level above the stress one or decreasing below the training one causes no reaction. Transition to the next range shows again the same order of reactivity: the reactions of training, activation, and stress.
As it was mentioned above, an increase in the effect of an external stimulus up to a high level and the rise to the second stage of the stress reaction, the resistance stage, lead to the development of hypertrophy of the adrenal cortex with an increase in the secretion of corticosteroids increasing, in turn, resistance to the stimulus. But L.Kh.Garkavi and co-authors could not explain the mechanisms providing the human organism's transition (bypassing exhaustion and death stages) from one floor (range) of adaptation to a higher one, under the conditions of further increase in the force of impact above stress level.
Indeed, according to pathophysiology, without such adaptation mechanisms increasing the tolerance, the body must die from "exhaustion", from failure of adaptation mechanisms, when the organism transits from the first adaptation range to the second. But in a PAS dependent people, this is not observed. This indicates failure of the current level of physiology to explain the mechanisms providing the body transition from one adaptation range (reactivity) to a higher one. In the history of narcology, attempts were made to explain the increase in tolerance organism by different causes. They are accelerated disintegration of PAS in the addict's, development of chronic stress, activation of other states inactive in normal conditions, or activation of systems that fulfil other functions, but with an increase in a PAS dose are forcedly involved in detoxification, etc. But all those assumptions have not been scientifically confirmed. No matter how full modern scientific research explain qualitative changes at the cellular and molecular level that lead to an increase in tolerance in PAS dependent patients, it is clear that these changes can only be of adaptive, not pathological and damaging nature, otherwise they would lead not to an increase in tolerance, but rather to a decrease in it, and the body would already die when transiting from the first floor of adaptation to the second.  The observations of L.Kh. Garkavi and co-authors indirectly proves possible accumulation of reserves in the neuroendocrine system during the activation reaction; "Although the metabolism is highly active during the activation reaction, it is characterized by an equilibrium", since to ensure "equilibrium" of constantly growing metabolic processes, a "powerful" neuroendocrine system is necessary. But in PAS dependence, after the completion of the activation reaction and in further enhancement of the stimulus above the sub-extreme level and transition to the subsequent adaptation floor, the "equilibrium" of the metabolic processes takes place, too. But this is possible only when the functional adequacy of the neuroendocrine systems grows in direct proportion to the strength of the external factor, which is possible only with hypertrophic neuroendocrine system and, as a consequence, its hyper productivity. The neuroendocrine system consists of the Vegetative Nervous System (VNS) and the endocrine part -the endocrine glands. In the functioning of the vegetative nervous system, a special mechanism is evolutionary provided that contributes to the accumulation of reserves -"advanced excitation" described in the no doubt that the mechanism of "advanced excitation" also inherent in the endocrine part of the neuroendocrine system, when the endocrine glands, releasing excessive hormones, also "take a pause" for their own trophic recovery processes, but unlike the VNS, these processes lead them to hypertrophy and hyper productivity. After all, hypertrophy resides in structures. Histological evidence of the endocrine system hypertrophy with regular exposure to a mediumstrength stimulus is Selye's stress research: "adrenal glands bloom".

Object and Methods of Investigation
Speaking of adrenal hypertrophy, one should mean the adrenal cortex. As early as in 1930s, it was found that chronic morphinization causes hypertrophy of the cortical layer of the adrenal glands in rats, which produces the "adaptation hormones" -glucocorticoids (hydrocortisone, cortisone and corticosterone), increasing the tolerance of the organism to intensive stimuli [3]. There is no doubt that hypertrophy of the adrenal cortex begins already during the activation reaction, since the process of adrenal hypertrophy is not an abrupt process. There is no doubt that due to the mechanism of "advanced excitation" other endocrine glands also "take a pause" for trophic recovery processes, which leads to their hypertrophy and hyper functionality. Evidences of adaptive hypertrophy of the

Results of the Study and their Discussion
Thus, under the regular exposure to PAS as a sub-extreme stimulus, while hypermetabolic processes occur in the "metabolic boiler," accumulation of reserves takes place in the endocrine system, as a result of "advanced excitation". This accumulation of reserves leads to adaptive hypertrophy and hyperfunction of the endocrine system, which results in an increase in the tolerance of the body. That is why, a subsequent, increasing, potentially extreme dose of PAS has a sub-extreme non-pathogenic effect on the body. The condition persists for the further adaptation ( Figure   1). Thus, in PAS dependence, in each range and in the transition to a higher adaptation range, one should speak not of the reaction dyad: activation and persistent activation, but of the reaction tetrad: activation, persistent activation, then stress with "anxiety reaction", and the stage of resistance. And the hypertrophy of the endocrine system that has developed to this moment, does not allow development of the final stage of stress -exhaustion. At this moment, the zone of non-reactivity separating the ranges, is observed, when the intensification of the stimulus above the stress level or the weakening below the training one does not cause any reaction. With an increase in the dose of PAS and transition to another range, everything comes around. It is more correct to call such a process not a state of chronic stress, but a state of regular, unfinished stresses.
Stress without the exhaustion stage, no matter how regular it is, cannot be considered as a disease. That allows the body to transit to a higher range of adaptation without death. It becomes clear that increased resistance in persistent activation reaction responding to regular sub-extreme exposure to PAS and the resistance stage in stress reaction responding to the further regular exposure to an increasing dose of PAS are functional manifestations of adaptive hypertrophic changes in the endocrine system. This process is called progredient (progressive) adaptation. Beliefs about the unity of form and function, the stereotyped thinking that "if changes in the body are acquired and irreversible, therefore, they are pathological," have led to the erroneous judgment that the body's dependencies on PAS should be considered as diseases. There is the expression "any disease is an adaptation." But the opposite statement that "any adaptation is a disease" in relation to PAS dependencies is inadmissible. After all, hypertrophy of the endocrine system, its high adaptation adequacy, leading to an increase in general and specific resistance, do not result in failure or lack of adaptive capabilities.  nature. And thereby, one should talk about the adaptive attraction, adaptively changed behaviour, adaptively changed reactivity to PAS or, conversely, about the readaptation -deprivation syndrome, and so on. In the final stage of the dependence, depletion of the adaptive capabilities of the organism, due to the hypotrophy of the endocrine system, the receptors of the body's protective systems indicate possible PAS overdose. This leads to a parallel decrease in the dose of PAS that a person is able to adapt, the effect of PAS turns out to be sub-extreme again, and pathology is not observed either (Figure 1).

Pathology in PAS Dependence is an Accompanying Phenomenon
The The activity of the sympathetic part of VNS against the background of the gradual exhaustion of the parasympathetic department (the adrenergic system is more stable in ontogenesis, too) also explains the qualitative change (according to narcotism age) of the sedative PAS (hypnotics, alcohol, opiates) effect on the body, transformation of their initial sedative action into a stimulating one. The hypertrophy of the endocrine system due to prior narcotization (and hence an increase in overall resistance) explains the rapid development of alcohol dependence in former opium addicts in alcoholization: rapid increase in alcohol tolerance, the rapid formation of alcohol abstinence syndrome, the development of binge drinking (to develop alcoholism in former drug addicts, it is sufficient to develop only a specific tissue adaptation to alcohol).
Stimulation of the hypertrophic endocrine system and increase in the overall resistance of the organism explain the fact that many stimulants (caffeine), eliminating some effects of ethanol, however, do not change its pharmacokinetics, but prolong its intoxicating effect. Initially the psychomotor agitation in PAS-dependent people getting narcosis can be based on the excitement of the active, sympathetic department of VNS. As the PAS dependence develops, due to the mechanism of "advanced excitation", contributing to adaptive activity-hyper functionality of the sympathetic VNS, the hypertrophy and hyper productivity of the endocrine system lead to the fact that the role of the entire neuroendocrine system as a functional mechanism of protection and adaptation increases and becomes the leading one.