The authors have declared that no competing interests exist.
Second-hand smoking has been a battle in almost every field. Typically, a nonsmoker who is an alcohol consumer, complains of secondhand smoke, without even considering second-hand risk health tragedies and human rights violations due to ethanol consumption.
We expose here the concept, mainly unexplored, of tragic adverse health effects and human rights violations to third parties due to alcohol consumption by others; as well as disability due to chemical transient prefrontal lobotomy with alcohol consumption.
Alcohol has been an integrated part of the human diet for centuries, in part, due to the fact that alcoholic beverages have constituted a safe means of hydration whenever pure clear water was scarce
Old patients could be part of the ethanol consumers and/or secondhand victims. However, before deciding to approach the geriatrical problems, we propose the allegorical pedagogical model, based on Scott, Ellison, and Sinclair, as published in Nature Aging, in July 2021. We divide the theoretical approach with four elemental alternatives
Life extension (the Struldbrugg case). In Jonathan Swift’s 1726 novel Gulliver’s Travels, the struldbrugg are humans who are born seemingly normal. The Struldbruggs, are immortal but age normally, live in continuously worsening health. It takes us to the philosophical alternative of: “to live or to last”
To Diminish morbidity (the Dorian Gray case). Accordingly The Picture of Dorian Gray is aphilosophical novel by Oscar Wilde. Dorian Gray possesses a portrait of himself and while the picture ages, Dorian Gray does not, keeping his health and appearance until death
To Slow aging (the Peter Pan case), In the extreme case, where aging is not just slowed but eliminated, mortality and health become independent of age and the individual is ‘forever young’. This refers to the ‘Peter Pan’ case, after the play and novel about a boy who never grows old. This corresponds to the Hypocaloric diet claim that slows aging
Reversing aging biological damage is repaired rather than slowed. This is analogous to the Theseus Boat and the regeneration of salamanders and lizards and transplants from donors. Obviously, this is the future of organoids and the engineering of pluripotent cell
Ethanol consumption has been estimated to be responsible for more than 80,000 deaths a year in the United States. More than 50% of these deaths are made up of drunk driving accidents and ethanol-related homicides and suicides, and approximately 15,000 deaths per year are the result of cirrhosis
Social determinants are the product of composite behavior of the subset of the population that determines the effect on the passive health victims. Since all there is in the universe are the subatomic particles, namely leptons and quarks, Higgs Boson, and obeying the four only existing forces, gravitational, electromagnetic, nuclear weak, and strong nuclear. There has been no evidence of physical-chemical unique properties inside of the head different from the chemistry outside. Therefore as Peter W. Atkins, Fellow of Lincoln College at the University of Oxford and author of the most prestigious text on physical chemistry: Because our brains are made of elements, even our opinion is, in a sense, properties of the chemical elements
All this is evidenced as accidents, abandonment of minors, breach of family and professional commitments (pacta sunt servanda), failure in the need for a reliable work team; as well as a decrease in the attention span in important aspects, intellectual, professionals in risk situations, etc. Additionally, there is a decrease in the acquisition of new concepts, high failure in complex tasks, underestimation of adverse consequences due to impaired judgment, greater willingness to take risks due to a damaging prefrontal effect; As can be seen, pilots, surgeons, bus drivers, taxi drivers, operation of high-risk machinery in factories and outdoors, and in general, being part of trusted teamwork becomes a cause of harm to third parties. This is hamartia and a tragedy.
The larger the damage to the patient due to ethanol consumption, the less probable is that the patient could produce a secondhand effect on passive subjects.
The older the patient with ethanol organic damage, the less probable it is that the patient could produce a secondhand effect on passive subjects.
Health is a state of complete physical, mental and social well-being and not merely the absence of disease or infirmity
The extension to all peoples of the benefits of medical, psychological, and related knowledge is essential to the fullest attainment of health
Accepting these Principles and for the purpose of co-operation among themselves and with others to promote and protect the health of all peoples, the Contracting Parties agree to the present Constitution and hereby establish the World Health Organization as a specialized agency within the terms of Article 57 of the Charter of the United Nations
The enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being without distinction of race, religion, political belief, economic or social condition. The health of all peoples is fundamental to the attainment of peace and security and is dependent upon the fullest cooperation of individuals and States
The extension to all peoples of the benefits of medical, psychological, and related knowledge is essential to the fullest attainment of health5.
Chapter I
Article 1 The objective of the World Health Organization shall be the attainment by all peoples of the highest possible level of health
Francis Bacon, the father of empirism, and thus one of the founders of science, introduced to a French audience as the "father" of the scientific method in 1733 by Voltaire himself, clearly warned about the idols of the mind and the process of purging information. All this constitutes incurring in the idols. Bacon’s epagogic inference, probabilistic inductive inference insisting in that the experience must be purged (pars destruens), as precursors of John Stuart Mill`s methods, for the right approach to the understanding of every natural phenomenon
He principles and objective of the CONSTITUTION OF THE WORLD HEALTH ORGANIZATION constitute desiderative and aspirational concepts, they are Baconian Idols of the Tribe, according to which we always assume order and purpose in things; as well as the Idols of the Theatre, considering the world as a stage, the Idols of the theatre are prejudices coming from authority or traditional philosophical systems, that resemble plays in so far as they render fictional worlds, which have never been exposed to an experimental check. The idols of the theatre, therefore, have their origin in a dogmatic philosophy or, worse, in wrong laws of demonstration
As stated by Dr. Tedros Adhanom Ghebreyesus, Director-General World Health Organization in the Global status report on alcohol and health 2018 World Health Organization: Alcohol use is part of many cultural, religious, and social practices, and provides perceived pleasure to many users. This new report shows the other side of alcohol: the lives of its harmful use claims, the diseases it triggers, the violence and injuries it causes, and the pain and suffering endured as a result
While less than half of the world’s adults have consumed alcohol in the last 12 months, the global burden of disease caused by its harmful use is enormous. Disturbingly, it exceeds those caused by many other risk factors and diseases high on the global health agenda. Over 200 health conditions are linked to harmful alcohol use, ranging from liver diseases, road injuries and violence, to cancers, cardiovascular diseases, suicides, tuberculosis, and HIV/AIDS. We have no time to waste; it is time to deliver on alcohol control
In 2016, of all deaths attributable to alcohol consumption worldwide, 28.7% were due to injuries, 21.3% due to digestive diseases, 19% due to cardiovascular diseases, 12.9% due to infectious diseases, and 12.6% due to cancers. About 49% of alcohol-attributable DALYs are due to non-communicable and mental health conditions, and about 40% are due to injuries
The Second-Hand Risk health Tragedies and Human Right Violations due to Ethanol Consumption, constitute a violation of human rights.
As established in the Universal Declaration of Human Rights in its Article 25.1:
Everyone has the right to a standard of living adequate for the health and well-being of himself and of his family, including food, clothing, housing, and medical care and necessary social services, and the right to security in the event of unemployment, sickness, disability, widowhood, old age or other lack of livelihood in circumstances beyond his control
The three major overlapping lesions, Fatty Liver Disease, Alcoholic Hepatitis, and Cirrhosis are inversely related to the third-party passive injury. It is the intoxicated man with normal liver, after a binge drinking more than the cirrhotic patient with encephalopathy, who is the principal cause of death and lesions to the third parties
Ethanol is a direct hepatotoxin; however, only 10 to 20 % of alcoholics will develop alcoholic hepatitis
Ethanol is the third principal risk for disease burden. Cirrhosis and its complications are closely correlated with the volume of ethanol consumed; in both senses, per consumption, and cumulatively.
The most important risk factors in the development of alcoholic liver disease are quantity and duration
According to The National Institute on Alcohol Abuse and Alcoholism, in 2016, of all deaths attributable to alcohol consumption worldwide, 28.7 percent were due to injuries, 21.3 percent were due to digestive diseases (primarily cirrhosis of the liver and pancreatitis), 19 percent were due to cardiovascular diseases, 12.9 percent were due to infectious diseases (including tuberculosis, pneumonia, and HIV/AIDS), and 12.6 percent were due to cancers (most prominently those of the upper aerodigestive tract.)
In addition, all the unconsidered effects in the number of incarcerated persons that are in jail for having produced health damage or death to third parties constitutes the basis for the rule that alcohol consumption takes more people to jail than to cirrhosis. Thus, we can say, like an adagio: the drinker should have more fear to end in jail than becoming cirrhotic.
Comparatively, approximately 12 g of alcohol are contained in one beer, four ounces of wine, or in one ounce of 80 proof spirit
There is an evident paradoxical event such that, the more deteriorated is the patient due to ethanol consumption the less probability he has of causing secondhand damage to others. Therefore having a clear parallel picture of the physiopathological effects in the ethanol consumer, together with the neurochemical alterations causing the behavioral effects which constitute the deleterious condition caused by the consumer of ethanol in third parties, is paramount in this presentation.
Once acetyl-CoA is generated, it enters the normal Krebs cycle
The excess of NADH also inhibits fatty acid oxidation. A fundamental metabolic result of fatty acid oxidation is the generation of NADH for ATP production through the electron transport chain, but alcohol consumers' NADH needs are met by ethanol metabolism. The excess NADH signals that conditions are appropriate for fatty acid synthesis. Therefore, triacylglycerols accumulate in the liver, leading to fatty liver, all of which is exacerbated in obese patients
The first pathway for ethanol metabolism is by the enzyme alcohol dehydrogenase which oxidizes ethanol to acetaldehyde reducing NAD+ to NADH. Then acetaldehyde is oxidized by the acetaldehyde dehydrogenase, again reducing NAD+ to NADH.
The second pathway for ethanol metabolism utilizes the cytochrome P450 enzymes, the microsomal ethanol-oxidizing system (MEOS) generates acetaldehyde and subsequently acetate while oxidizing biosynthetic reducing power, NADPH, to NADP+. The fact that oxygen is used in this pathway leads to the production of free radicals that damage tissue. This oxidative stress is exacerbated as NADPH is being consumed, decreasing the capacity to neutralize this oxygen reactive species by preventing the regeneration of glutathione
The effects of the other metabolites of ethanol: Liver mitochondria can convert acetate into acetyl CoA in a reaction requiring ATP through a thiokinase
Additional processing of Acetyl-Co A by the Krebs cycle is blocked
The accumulation of acetyl CoA has several consequences: First, ketone bodies will form and be released into the blood, worsening the acidic condition already resulting from the high lactic acidosis. The metabolism of lactate in the liver becomes inefficient, leading to the accumulation of acetaldehyde, which is a very reactive compound that forms covalent bonds with many essential functional groups in proteins, damaging protein function. When ethanol is persistently consumed at high levels, acetaldehyde can importantly damage the liver and eventually produce cell death
Ketone bodies are synthesized in the mitochondrial matrix. Acetyl-CoA formed in the liver during oxidation of fatty acids or metabolism of alcohol, can either enter the Krebs cycle or undergo conversion to the ketone bodies, D-𝞫-hydroxybutyrate, acetoacetate, and acetone, that are exported to other tissues
In an extremely fine-tuned regulatory process, the pyruvate dehydrogenase complex is specifically Inhibited by ATP, acetyl CoA, NADH, and fatty acids; the Citrate Synthase is inhibited by NADH, citrate, and ATP; the Isocitrate dehydrogenase is Inhibited by ATP; and, the 𝞪-ketoglutarate dehydrogenase complex is inhibited by NADH
Then the surplus of acetyl CoA in the mitochondria enters the process of synthesis of ketone bodies that initiates from two molecules of acetyl-Co A.
The brain which preferentially uses glucose as a fuel can, if needed, adapt to the use of acetoacetate and β-hydroxybutyrate. The brain cannot utilize fatty acids as fuel because they are unable to cross the hematoencephalic barrier
Whenever a cell or organism possesses more than enough metabolic fuel to satisfy its energy requirements, the excess is usually converted to fatty acids and stored as lipids such as triacylglycerols. The reaction catalyzed by the enzyme acetyl CoA carboxylase constitutes the rate-limited step in the biosynthesis of the fatty acids. Whenever the acetyl CoA concentrations of mitochondrial and ATP are increased, citrate is transported outside of the mitochondria; it then becomes the precursor of cytosolic acetyl-Co A and an allosteric signal that activates acetyl CoA carboxylase.
Malonyl CoA is generated from acetyl Co-A and bicarbonate. A carboxyl group, which is derived from bicarbonate (HCO-3 ), is first transferred to biotin in an ATP-dependent reaction. The biotinyl group constitutes a temporary carrier of CO2, transferring it to acetyl CoA to produce malonyl-CoA.
The enzyme is in a collective manner denoted as fatty acid synthase. The reducing agent is NADPH, two per cycle (stoichiometrically) and the activating groups are two different -SH groups in the fatty acid synthase.
Fatty acid synthesis occurs in the cytosol. This location separates synthetic processes from degradative reactions.
Typically NADPH is the electron carrier for anabolic reactions
Carbohydrates, fat, protein, and ethanol ingested in excess are stored in the form of triacylglycerols.
Ammonia is highly toxic to animals
Clearing the cytosol from ammonia requires the reductive amination of α-ketoglutarate to glutamate by the enzyme glutamate dehydrogenase and the conversion of glutamate into glutamine by the enzyme glutamine synthetase. In the brain exclusively the astrocytes express glutamine synthetase. Glutamate and its derivative γ amino butyrate (GABA) are very important neurotransmitters; some of the high sensitivity of the brain to ammonia reflects depletion of glutamate in the glutamine synthetase reaction
The Metabolic destine of the amino groups: Due to only a few microorganisms are able to convert N2 to NH3, amino groups are sophisticatedly husbanded in biological systems.
Four amino acids have fundamental roles in nitrogen metabolism: glutamate, glutamine, aspartate, and alanine. These amino acids are the most easily convertible into citric acid intermediates. Glutamate and glutamine are converted into α-ketoglutarate, alanine into pyruvate, and aspartic acid into oxaloacetate
The cirrhotic liver is metabolically unable to convert ammonia into urea, and blood levels of ammonia rise continuously. Ammonia is highly toxic to the nervous system and can produce coma and death
Retinol (Vitamin A ) is converted into retinoic acid, which is an important signal molecule for growth and development in vertebrates, using the same dehydrogenase that metabolizes ethanol. Consequently, this activation does not take place in the presence of ethanol, because it acts as a competitive inhibitor. Furthermore, the p-450 enzymes induced by ethanol inactivate retinoic acid. These disruptions are probably responsible for fetal alcohol syndrome as well as the development of diverse types of cancers
Constitutes the existence of neurological symptoms caused by biochemical alterations of the central nervous system after exhaustion of B-vitamin reserves, mainly thiamine (vitamin B1). The condition forms part of a larger group of thiamine deficiency disorders, including beriberi in all its forms, and alcoholic Korsakoff syndrome. Whenever occurs simultaneously with alcoholic Korsakoff syndrome it is called Wernicke–Korsakoff syndrome.
Classically, Wernicke encephalopathy is structured by the triad: ophthalmoplegia, ataxia, and confusion
Alcohol ingestion produces an initial inflammatory cascade because of its metabolism, resulting in steatosis produced by lipogenesis, fatty acid synthesis, and depletion of fatty acid oxidation appears as secondary to effects on the sterol regulatory transcription factor and the peroxisome proliferator-activated receptor α (PPAR-α). The intestinal derived endotoxin initiates a pathogenic cascade through toll-like receptor 4 and tumor necrosis factor α (TNF-α) that promotes hepatocyte apoptosis and necrosis. The cell damage and the endotoxin release initiated by ethanol and its metabolites also produce activation of innate and adaptive immunity pathways, thus releasing proinflammatory cytokines (TNF-α) chemokines and proliferation of T and B cells
The hepatic parenchyma has a limited repertoire in response to injury. Fatty liver constitutes the initial and certainly most common response to hepatotoxic stimuli, including excessive ethanol consumption. Remarkably, the accumulation of fat within the perivenular hepatocytes is coincident with the location of the enzyme alcohol dehydrogenase, the major enzyme responsible for alcohol metabolism
The transition between the fatty liver and the development of alcoholic hepatitis is continuous, smooth, and blurred. The significant hallmark of alcoholic hepatitis is represented by hepatocyte injury which is characterized by ballooning degeneration, spotty necrosis, polymorphonuclear infiltrate, and increasing fibrosis in perivenular and perisinusoidal space of Disse
Usually, the clinical manifestations of alcoholic fatty liver are subtle and detected during a medical visit for an apparently unrelated matter. Previously unsuspected hepatomegaly is often the only clinical finding. Occasionally patients with fatty liver could present with right upper quadrant discomfort, nausea, and rarely, jaundice
Alcoholic hepatitis is manifested as a gamut of clinical features
Gastric alcohol dehydrogenase initiates alcohol metabolism. There are three enzyme systems in the liver: Cytoplasmic alcohol dehydrogenase, Microsomal Ethanol oxidizing System (MEOS), and Perixosomal Catalase. Acetaldehyde is a highly reactive molecule that is metabolized, in the mitochondria, to acetate by aldehyde dehydrogenase
The alcohol oxidation by the alcohol dehydrogenase causes the reduction of NAD+ to NADH, with a consequent decrease in NAD+ and an increase in NADH. NAD is required for fatty oxidation in the liver and also for the conversion of lactate into pyruvate. Its deficit is a main cause of the deposition of fat in the liver of alcohol consumers. The increase in NADH/NAD_ ratio in alcohol consumers also produces lactic acidosis. NAD is needed for the conversion of glyceraldehyde 3 phosphate to 1, 3 bisphosphoglycerate, by the enzyme glyceraldehyde 3 phosphate dehydrogenase
ROS generation: The metabolism of ethanol in the liver by CYP2E1 produces ROS, which causes lipid peroxidation of hepatocyte membranes
Ethanol consumption augments the intracellular triglyceride accumulation by increasing fatty acids' cellular intake and by suspending the fatty acid oxidation and lipoprotein secretion.
The protein synthesis, glycosylation, and secretion are altered
Acetaldehyde is a very reactive molecule that reacts with proteins forming protein acetaldehyde molecular additions. These adducts might interfere with some specific enzyme activities, including the microtubular formation and the hepatic trafficking of proteins. With the acetaldehyde-mediated hepatocyte damage, several reactive oxygen species could result in the Kupffer cell activation with the consequent production of excess collagen and of extracellular matrix
Consists of an alternate pathway of the ethanol catabolism that occurs in the smooth endoplasmic reticulum in the process of oxidation of ethanol molecule to acetaldehyde
The MEOS pathway metabolizes the ethanol to acetaldehyde by a
The increment in the rest energy expenditure has been hypothesized as if the MEOS would expend 9 Cal/gram of ethanol to catabolize versus 7 Cal/ per gram of the ingested ethanol
Ethanol (CH3CH2OH) in a direct manner affects different types of neurochemical systems and many signaling cascades and, especially has powerful rewarding and addictive properties. It is without any doubt the oldest recreational drug and probably contributes to more morbidity, mortality, and public health cost than all the rest of illicit drugs combined
The mechanisms of the ethanol effects in the central nervous system constitute the basis for understanding the rewards, disease processes, and treatment for ethanol-related conditions
Aspirin use inhibits gastric alcohol dehydrogenase and increases the bioavailability of ethanol
The main enzymes involved in ethanol metabolism are Alcohol dehydrogenase and aldehyde dehydrogenase, followed by catalase and CYP2E1, CYPs 1A2, and 3A4 in some metabolic instances
Each step of metabolism requires two molecules of NAD+ stoichiometrically to oxidize it, reducing them to NADH. Oxidation of one mole of ethanol (46 gr), the equivalent to three glasses of wine, requires 1.3 Kg of NAD+. This highly exceeds the availability of NAD+ in the liver. Thus, the bioavailability of the NAD+ limits the metabolism of ethanol to approximately 8 grams per hour, maintaining it in zero-order kinetics
The results of the oxidation of ethanol are increase NADH; increase lactate by lactate dehydrogenase; reducing pyruvate into lactate and converting NADH into NAD+.
The conversion of glyceraldehyde 3-phosphate into 1,3 Bisphophoglycerate by the glyceraldehyde 3 phosphate dehydrogenase requires NAD+ to convert into NADH
Increase Acetyl CoA from ethanol derived acetic acid decrease Krebs cycle activity and increase of fatty acid synthesis is a cytosolic process
In the synthesis of fatty acids, each step of two carbon additions comes from the molecule of malonyl-CoA, which is produced by the enzyme Acetyl-CoA carboxylase
NADH, acetyl-CoA, and ATP are expected to be increased
As explained, cytoplasmic ADH and mitochondrial ALDH, stoichiometrically convert 2 NAD+ to 2 NADH for each molecule of ethanol. Ethanol is eventually converted to acetic acid
Two thiokinases are associated with the conversion of acetic acid to acetyl-CoA1). acyl-CoA synthetase short-chain family member 2 ACSS2 (EC 6.2.1.1) and acetyl-CoA synthase 2 (confusingly also called ACSS1) which is localized in mitochondria
The Complete Reaction with all the Substrates and Products Included is
ATP + Acetate + CoA <=> AMP + Pyrophosphate + Acetyl-CoA
Ethanol has many diverse and widespread effects on the whole body and impacts directly or indirectly almost on every neurochemical system in the CNS
Even at relatively low doses, alcohol can exacerbate most clinical problems and perturbates the medications metabolized in the liver, and at higher doses can, per se, transitively mimic many medical (diabetes) and also psychiatric (depression) diagnoses
Alcohol use disorders, as a such, decrease the lifespan by approximately ten years
Congeners could include other alcohols like methanol and butanol, acetaldehyde, histamine, tannins, and the metals iron, and lead
Alcohol also interferes with the absorption of diverse vitamins in the small intestine and decreases their amount stored in the liver, with some effects on vitamin A, folate, thiamine, pyridoxine, and nicotinic acid
Fasting heavy drinking in a healthy individual may produce transient hypoglycemia within six to thirty-six hours, secondary to the acute actions of ethanol which decreases gluconeogenesis. All this could result in temporary abnormal glucose tolerance tests (diabetes mellitus
A glucose load can not be totally catabolized into pyruvate, through glycolysis, because there are no enough NAD+ available, which is required in order to convert glyceraldehyde 3 phosphoglycerate into 1,3 bisphosphoglycerate by the enzyme glyceraldehyde 3 phosphate dehydrogenase, which incorporates inorganic phosphate and is considered the substrate-level phosphorylation for antonomasia, stopping glycolysis, because NAD+ is being used in the metabolism of alcohol, depleting the cell of NAD+ and giving a high level of glucose evidenced in the glucose tolerance test
The alcohol ketoacidosis, probably as a result of diminished fatty acid oxidation coupled with inadequate diet and/or persistent vomiting can be wrongly diagnosed as diabetic ketosis
The incidence of acute pancreatitis is roughly 25 per 1,000/year and is almost three times higher in patients with alcohol use disorders than in the non-ethanol consuming population
Ethanol consumption causes an increase in red cells´ mean corpuscular volume, which might reflect its effects on the stem cells. If heavy drinking is coincident with folic acid deficiency, there can additionally be hypersegmented neutrophils, reticulopenia, and hyperplastic bone marrow; if additionally malnutrition is present, sideroblastic changes could appear
In the acute case, ethanol diminishes myocardial contractility and produces peripheral vasodilation, thus resulting in a mild decrease in blood pressure and a compensatory increase in cardiac output. Exercise-induced increases in the consumption of cardiac oxygen are higher after alcohol consumption
The consumption of three or more drinks per day produces in a dose-dependent fashion an increase in blood pressure, which tends to return to normal after weeks of abstinence. Therefore, heavy drinking is a main factor in mild to moderate hypertension
As effects in other systems, between 50%-75% of individuals with ethanol use disorders, develop progressive skeletal muscle weakness produced by acute alcoholic myopathy, which is a condition that improves but might not fully remit with abstinence
The fundamental concepts of the cognitive control and the executive function could be defined in terms of their relationships with the goal-directed behavior rather than habits and controlled rather automatic processing, and also related to the functions of the prefrontal cortex (PFC) as well as other related regions and networks
The ventromedial and the dorsolateral prefrontal cortex are two fundamental prefrontal regions that typically interact in different cognitive functions
Ethanol abuse is pervasive in many societies worldwide and is also associated with extensive morbidity and mortality
The experience of the reward stimuli would be encoded into regions of the brain involved in memory and planning, permitting that our ancestors continued to actively feed and procreate, despite many lurking dangers of the time
Alcohol and other drugs work exploiting the mesocorticolimbic reward pathway, the same pathway that has served and permitted humans to learn, survive and reproduce successfully for many generations
All addictive drugs either directly or indirectly modulate the dopamine signaling in the mesocorticolimbic reward pathway. Importantly, not everyone who uses or abuses these drugs will become an addict
On the other hand, for some individuals, a first-time experience can dramatically turn into a lifelong addiction
Often, when an individual consumes a drug for the first time, he experiences an unknown sense of euphoria that could be, in some circumstances, beyond that of any natural reward such as food or sex. Often, as predicted by behavior analysis, the reinforcement which has the feeling of intoxication as an epiphenomenon drives a user to take more of the same drug
This behavior is considered representative of the first stage of addiction: binge and intoxication
During the first stage of addiction, the alcohol or the drug targets a region of the midbrain, known as the ventral tegmental area (VTA), producing the release of dopamine into the nucleus accumbens
Endorphins, which are our body’s primary natural opioids, are also released. It is believed that the combined activation of both dopamine and endorphins is what underlies the reinforcement and the sensation of pleasure following drug use
The reinforcer is constituted by the drug and sometimes could be more powerful than any other natural reinforce
The globus pallidus is also activated and it is associated with the formation of the habit; The prefrontal cortex, corresponding to the Freudian superego, normally regulates the activity from the nucleus accumbens, but not during the drug's effects
The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia
During this first stage, alcohol and the drugs of abuse, make the globus pallidus encode drug-related behaviors as habits. The globus pallidus is associated with the formation of habits and automatic behaviors
The prefrontal cortex is a region responsible for the executive functions as are planning and decision making
A completely different subset of neuronal structures is involved in the withdrawal, and negative affect, which is considered the second stage in the addiction cycle
Because drug use increases dopamine levels beyond what is normal, the chronic consumption of ethanol and other drugs leads to a number of compensatory responses
The neural systems that underlie this negative affective state include a group of midbrain structures conceptualized as the extended amygdala
Learning which environmental conditioned stimuli predict danger is essential for survival through Pavlovian fear conditioning. In both, humans and rodents, fear conditioning is amygdala-dependent and rests on analogous neurocircuitry
The behavior has become compulsive rather than the original pleasurable desire. Thus, the behavioral changes from impulsive to compulsive. The bed nucleus of the stria terminalis constitutes the anatomical substrate of this condition
The activations of these systems tend to increase the production of stress hormones
Skinnerian escape and avoidance responses characterize this stage. Therefore alcohol and drug consumption has become a highly compulsive need rather than the pleasurable impulsive desire of the beginning.
Therefore the last stage of the ethanol and drug addiction cycle is the anticipation and craving stage, which frequently means the level whereby an individual`s chronic ethanol or drug consumption may lead to the development of a substance abuse disorder
During the anticipation and craving stage, the large amount of dopamine received by the prefrontal cortex during drug and ethanol consumption promotes the reciprocal release of glutamate in the midbrain, thus committing the alcohol or the drug, and the experience to memory
As the plasticity of the brain is continuously shaped and reshaped by the consumption of ethanol and drugs, new paths become consolidated as alcohol-related contextual information is stored by the hippocampus, through the establishment of operant behavior and activation of the basolateral amygdala leads to conditioned responses to a highly specific, ethanol-related cues (reinforced conditioned stimulus)
Extended ethanol consumption then leads to the exploitation and the restructure of the neural circuitry consolidating memories, habits, and goals that place much greater importance on alcohol and drug consumption behavior rather than on the natural rewards
In the brain, ethanol affects almost all neurotransmitters systems, with acute effects that are frequently the opposite of those following desistance after a period of heavy consumption. The most profound acute actions relate to boosting 𝞬-aminobutyric acid (GABA) activity, especially at the GABAA receptors
As happens with all pleasurable activities, ethanol consumption acutely increases the dopamine levels in the ventral tegmentum and in the related brain regions, also this effect plays a major role in continued ethanol consumption, craving, and relapse
Several additional neurochemical alterations include an increase in the synaptic levels of the neurotransmitter serotonin during acute ethanol consumption and subsequent upregulation of serotonin receptors
Beverage ethanol is perhaps responsible for more overdose than other drugs
The cellular biochemical perturbations caused by chronic ethanol consumption may not resolve for a month several or longer following cessations of ethanol consumption. Rapidly decrease in blood ethanol levels before the time can produce a withdrawal syndrome, which is most intense during the first week, but with some symptoms as disturbed sleep and anxiety lasting probably up to 4-6 months as a component of a protracted withdrawal syndrome
It is considered that any potential healthful effect attributed to ethanol consumption, is overridden by continuous consumption of three or more daily drinks
The subject with acute ethanol intoxication may experience a blackout which is an episode of anterograde amnesia, even though the person was awake but has forgotten all of what occurred during the acute drinking period
Another very common problem that is seen after as few as one or two drinks before bedtime is a state of disturbed sleep
Another common very significant adverse consequence of ethanol consumption even at relatively low concentration is impaired mathematical and logical judgment, as well as coordination, which increases the risk of injuries and other personal adverse consequences
Heavy ethanol consumption could also be associated with headache, thirst, nausea, vomiting, and fatigue the next day, also, the hangover syndrome that is responsible for much-missed time in work and l time, and much more important, with temporary cognitive deficits
The chronic high ethanol doses produce peripheral neuropathy in around 10% of patients with alcohol use disorders which is similar to diabetes, experiencing bilateral limb numbness, tingling, and paresthesias, all being more pronounced distally
Humans inadvertently have produced an artificial selection of organisms that are producers of substances that release dopamine in the nucleus accumbens.
Humans have artificially selected organisms that produce substances that activate the mesocortical-limbic dopamine reward pathway. The ability to produce these substances has been selected. It is the evolutionary historical origin of all-natural drugs.
Furthermore, synthetic or artificial drugs are specifically designed to activate the mesocortical-limbic Dopamine reward pathway.
The human digestive system produces approximately 3 g of ethanol daily through fermentation. Catabolism of ethanol is thus essential, not only of humans but of all organisms. Several amino acid sequences in the enzymes used to oxidize ethanol are evolutionary, going back to the last common ancestor more than 3.5 billion years ago. This function is necessary since all organisms produce small amounts of alcohol by several pathways, mainly through fatty acid synthesis, the metabolism of glycerolipids , the biosynthesis of bile acid pathways. Without this mechanism for catabolizing the alcohols, the body would build up alcohol and become toxic. This is evidence of evolutionary advantage for alcohol catabolism and by sulfotransferase too
Survival by augmenting the capacity for fructose present in dwindling fruit to be stored as triglycerides, as a consequence of increased uric acid production during the fructose metabolism that emulated lipogenesis and also blocked the fatty acid oxidation
We must ask ourselves in the frame of evolution by natural selection: Cui bono? Cui prodest?:
Saccharomyces cerevisiae and other types of yeast in winemaking.
These microorganisms have evolutionary hijacked mesocortical-limbic dopamine reward pathway in the human brain, as has happened with D. dendriticum in ant Formica fusca and, toxoplasma gondii in rats or even more dramatically, dogs which have evolved and hijack in a manner analogous to drugs, the same mechanisms in our brains that create the strongest social bonds, including those between mother and child
We must be dialectical. If the experimental results are against our expectations, against our desires, against our ideology; furthermore, if our ideas about democracy
Man, at last, knows that he is alone in the unfeeling immensity of the universe, out of which he emerged only by chance. Neither his destiny nor his duty have been written down. The kingdom above or the darkness below: it is for him to choose