This guy posted this on a smaller training forum at something awful. It was a really good read, and very fitting considering all of the pot alcohol threads lately.
Originally Posted by Cavefish
Ever wondered exactly just how alcohol effects your body? Read on (warning: its long) The first post deals more with the chemistry side of things, then part 2 relates to how it actually effects training.
Ethanol, aka "alcohol", is perhaps the most widely consumed drug on Earth. With the exception of its effects on heart disease, few people would claim it is good for you. But, because of its legality, omnipresence, and just the fact that it is so much fun, most think very little of having a few beers or even a few six packs. This includes many bodybuilders.
However, it is far from being a harmless vice, even in non-alcoholics. It affects numerous neurotransmitters, metabolic processes, and hormones -- and many of these effects go beyond the time period of intoxication. These have ramifications, not only for general health, but as you will see, body composition as well.
This is the first of a two parts series -- We will first look at the basic science of ethanol, then we will turn to its effects on body composition in the second installment. We will not be looking at the effects of chronic ethanol consumption, addiction, and withdrawal, as they are not relevant to what I consider as my target audience. Suffice it to say, such a lifestyle is utterly incompatible with getting the most out of one's bodybuilding efforts.
Ethanol, in addition to being a drug, is also a nutrient (1). However, unlike the other nutrients such as carbs, fat and protein, the body lacks the ability to store ethanol (1) -- It is also the only toxic macronutrient (1). These two characteristics lead to some important consequences -- namely, it must be metabolized, and this metabolism take precedence over all other nutrients (2).
It is metabolized by one of two pathways, depending on blood levels. The primary is to aldehyde, via alcohol dehydrogenase (ADH) (3). However, at high levels, what is known as the microsomal ethanol oxidizing system (MEOS) becomes a significant pathway (4). Both result in conversion to acetate, then acetyl-CoA -- where it can either a) enter the tricarboxylic acid cycle and be oxidized into CO2 and water, or b) be stored a fat (1).
Ethanol is readily bioavailable with oral administration, however, oral clearance rate and % absorption decrease in the post-prandial state (i.e. with food) (5), due to the presence of ADH activity in the stomach (6). The more food in the stomach, the longer the ethanol stays there to be metabolized before it reaches the bloodstream. The type of food will effect this, with protein and fat have the greater effect. Fat, due to slowing transport into the small intestine, protein, probably through direct binding with the ethanol molecule (7).
The type of drink can also effect blood alcohol levels obtained - particularly in the fed state. For instance, after a meal, a less concentrated drink (such as a beer) will be absorbed more quickly than a more concentrated one (such as a shot) -- and, in rats, this led to an 80% higher peak blood alcohol level and 95% higher overall absorption (8). However, on an empty stomach, the opposite was found, though the magnitude of the difference was not as strong.
It is also interesting to note that when large amounts are taken in, absorption can exceed systemic distribution, thus exceptionally high concentrations can occur in arterial blood, and, therefore, the brain (7). This is why bonging 6 beers right in a row hits you harder than drinking 8 drinks over 2 hours.
Despite popular opinion to the contrary, women do not metabolize ethanol more slowly than men - the opposite is in fact true. Failure to take into account differences in total body water (i.e. LBM) between men and women has accounted for much of this confusion (9). But, when normalized for total body water, women metabolize ethanol 33% faster than men, due to a proportionally larger liver (10).
Due to limitations of ADH, metabolism of ethanol follows zero-order, straight line kinetics - meaning it is broken down at a constant rate (about a drink per hour) rather than having a half-life as most drugs do (11).
DHT has been shown to decrease breakdown of ethanol by increasing the breakdown of ADH, thus a good testosterone cycle will increase susceptibility to intoxication (12).
Aldehyde, as mentioned, is a product of ethanol metabolism. In the literature, its presence has generally been found to produce an aversive response, thus the basis of treatment of alcoholics with disulfiram (13). It is responsible for the flushing seen in some drinkers, usually Asians -- this can be reduced with the use of antihistamines (14). However, a few studies have shown it to be involved in the reinforcement of ethanol intake (15).
Aldehyde is also implicated in ethanol's hepatotoxic effects (16). The amino acid taurine enhances the metabolism of aldehyde by activating the hepatic enzyme aldehyde dehydrogenase, thus lowering levels -- though this was with the equivalent of 45 grams for a 200lb person (17), so who knows if supplementing with reasonable levels would be effective.
Following oral, intravenous, or intraperitoneal administration, ethanol produces central nervous system (CNS) effects of a biphasic nature. Lower concentrations (10-25mM -- 3 to 8 drinks) tend to produce stimulant effects (euphoria) while higher doses result in CNS depression (anti-anxiety, sedation) (18).
It was thought for quite some time that ethanol produce its effects through nonspecific means, by acting as a solvent, or interfering with lipid membranes (19, 20). In fact, as late as a 1997 drug education class I took in college, we were informed that it worked by coating the cells rather than interacting with specific receptors like all other drugs. This view has recently fallen out of favor for several reasons that I won't go into detail on, and it is now considered to exert its effects through binding to proteins on specific receptors (21). It is widely held that no specific ethanol receptor exists, though one prominent researcher suggests that the evidence suggests we should be moving toward the concept of a specific ethanol receptor (22).
The exact mechanism behind its subjective effects are still not completely understood, and involve multiple neurotransmitter systems and ion channels with many studies reporting effects that completely contradict other ones, and all of this is further complicated by the fact that ethanol seems to preferentially affect certain subtypes of the various receptors. An exhaustive presentation is best suited for a 500 page book, thus I have weeded through and analyzed the research in order to give what I consider the best overall generalization about its effects on the various systems.
Levels of the central neurotransmitter dopamine have been consistently shown to be increased by ethanol (23,24), and it is considered as the primary mediator of the reinforcing effects of all drugs of abuse (25). It is also involved in behavioral reinforcement in general. Of particular importance is the mesolimbic dopamine system, which is regulated by neurons in the Ventral Tagamental Area (VTA) and Nucleus Accumbens (NAC) (26).
Alcohol-preferring rats have been shown to have lower basal mesolimbic dopaminergic activation and innervation than non-preffering rats (27) -- as well as altered serotonin, GABA, and opioid activity, all of which are major modulators of the mesolimbic dopamine system and likely contribute to the hypofunctioning of this area (27, 28). Acute administration of ethanol increases extracellular dopamine levels in the NAC as a result of increased firing of dopamine neurons in the VTA, thus bringing mesolimbic activity toward normal (29). Thus, ethanol intake is merely representing self-medication -- bringing about behavioral activation (thought analogous to euphoria in humans) and decreased anxiety in alcohol-preffering rats, while non-preferring rats, whose dopamine system is not faulty, tend to just become sedated (27).
Ethanol has been found to increase brain levels of the endogenous opioid beta-endorphin (31), and it is likely that the opioid system mediates a large part of its effects on dopamine levels, by removing GABA mediated inhibition of dopamine neuron firing (32).
It has been found that alcoholics have lower basal levels of endogenous opioids than non-alcoholics, and when ethanol is consumed these levels increase to a level higher than those reached by non-alcoholics with ethanol consumption (33). Opiod receptor antagonists have been found to inhibit the reinforcing effects of ethanol in animals and the euphoric effect in humans (34). one of these, nalaxone, is considered a very promising drug in the fight against ethanol addiction.
However, if I may opine for a moment, I would like to point out that opioids are the brain's happy hormones, so alcoholics are self medicating to bring themselves happiness that the biochemistry of their brain withholds from them, so a drug that keeps someone from drinking by making it ineffective at making them happy seems a piss poor approach to me. But, of course, they would never allow a long-acting morphine for such purposes, because, heaven forbid, someone might want a little more happiness than The Man deems appropriate and thus might "abuse" it.
The NMDA receptor is one of three types of glutamate receptors -- the body's primary excitatory neurotransmitter. It is named for n-Methyl-d-Aspartate, its synthetic, high-affinity ligand (35). Ethanol has been found to block the action of this receptor (36). The likely mechanism is by preventing glutamate's removal of a magnesium ion which blocks calcium influx into the cell (37). This decreases the excitation of the cell, which, along with increased inhibition via GABA, results in the sedative-depressant effects of ethanol, particularly at higher doses.
This blockade leads to upregulation of glutamate receptors (38), which leads to hyperexcitability of the cell when ethanol is no longer present -- this is one of the mechanisms responsible for ethanol induced neurotoxicity seen with withdrawal (39). It has also been postulated that the end of each drinking episode represents a mini-withdrawal complete with the aforementioned excitotoxicity (40). Because magnesium is the natural antagonist for the receptor (41), it would probably not be a bad idea to take 400-800 mg before bed after a night of drinking. Zinc, and the amino acid taurine may be as well (42,43).
By the way, magnesium and zinc's antagonism of the NMDA receptor may account for ZMA's positive effects on sleep. Unfortunately, it is disruption of the NMDA receptor that leads to the decrease in REM sleep caused by alcohol (43b).
The NMDA receptor complex is also implicated in memory loss and blackouts from ethanol (35) -- This is due to its effects on long-term potentiation (LTP). We will address this in more detail later.
Another very important system is the gamma-aminobutyric acid (GABA) system -- the body's primary inhibitory pathway (44). Ethanol potentiates GABA's activity at its receptor (45). It likely has a biphasic effect on behavior, with lower doses inhibiting inhibitory GABA interneurons on dopamine receptors in the VTA -- thus causing dopamine induced stimulation and euphoria, and higher doses producing widespread inhibition of CNS activity, thus overriding the stimulant effects (46, 47). This is likely one of the major mechanisms through which it produces its sedative-hypnotic and anxiolytic actions.
Ethanol also has significant effects on serotonin (5-HT), though it is not as well characterized as the afore mentioned ones. Ethanol has a biphasic effect on serotonin, first raising levels, then lowering them (48).
5-HT2 agonists, as well as serotonin reuptake inhibitors, have been found to substitute for ethanol in drug discrimination tests (49, 50). 5HT3 activity is probably responsible for the nausea with excessive consumption (51). It is also likely to partially account for increased dopamine release as antagonists have been shown to block ethanol induced dopamine release (52).
Ethanol administration eventually results in depressed 5-HT levels, and thus activity, due to increased peripheral metabolism of its precursor, l-tryptophan (53). Low levels of 5-HT are associated with increased aggression (53), and it is also quite likely that subsequent drinking episodes (and their accompanying initial increase in 5-HT levels) represent self-medication, to be followed by a fall in levels and repeat of the cycle. It seems possible that lowered 5-HT levels could contribute to the malaise of a next-day hangover, so the use of 50mg of 5-HTP upon waking might not be a bad idea.
The cholinergic system is yet another target for the actions of ethanol (54). It has been found to act as a CO-agonist with acetylcholine at the nicotinic acetylcholine receptors, as well as to potentiate the effect of nicotine at this receptor, both of which ultimately results in an increase in mesolimbic dopamine (55). This interaction accounts quite nicely for the fact that 90% of ethanol addicts are also nicotine addicts (56).
There is also likely some interaction by ethanol with the endocannabinoid system. They are somewhat similar in their effects in that both produce euphoria and stimulation at low doses and CNS depression at high doses (57). Cross-tolerance between the effects of THC and ethanol have been shown in rats (58), and down regulation of the CB1 subtype of cannabinoid receptors has been reported in rats chronically exposed to ethanol (59).
N-arichidonyl-ethanolamide (AnNH) is a naturally occurring derivative of the long-chain fatty acid, arachidonic acid, which has been found to bind to the CB1 cannabinoid receptor and to mimic the effects of THC (60). Ethanol increases the formation of AnNH from arachidonic acid.
The administration of a CB1 antagonist has been shown to limit ethanol consumption, suggesting that it might be involved in ethanol's reinforcement (62).
Ethanol consumption increases central and peripheral levels of epinephrine (E) and norepinephrine (NE), which contributes to the stimulatory affects of ethanol, particularly in the ascending arm of the blood alcohol curve (63, 64). Brain levels of norepinephrine have been shown to increase up to three-fold (64). These elevations occur primarily due to increased release and decreased clearance, rather than increases in synthesis (65). A consequence of this is eventual depletion of E and NE stores -- to as low as 8% and 20% in the adrenals after 4 days of ethanol intoxication (66). This fall likely contributes to the CNS depression that occurs with prolonged drinking.
There exists a real and significant relationship between ethanol and aggression (67), which might be of particular importance to bodybuilders who are supplementing with exogenous androgens or an EC stack, reading T-Mag on a regular basis, or any other things which could already be facilitating aggressive behavior.
The possible mechanisms by which it does this are several. As an anxiolytic, it can reduce fear of retaliation and consequences of behaviors, as a psychomotor stimulant, it can increase sensation-seeking behavior, and as an analgesic, it can reduce the perception of consequences of painful stimuli (68).
Another interesting possibility, is that ethanol disrupts executive cognitive functioning (ECF) (68). ECF encompasses higher order mental abilities such as abstract reasoning, attention, planning, self-monitoring, and the ability to adapt future behavior based on feedback from the outside world - basically ECF is the ability to use the above to consciously self-regulate goal directed behavior (69).
ECF is governed by the prefrontal cortex (70), and patients with lesions in this area have been noted to have decreased regulation of social behavior, including a "disinhibition syndrome" characterized by impulsivity, socially inappropriate behavior, and aggression (71, 72) - sound at all familiar? Lower scores on tests of ECF processes, such as the ability to inhibit aggression to obtain a monetary reward, have been reported for both prefrontal cortex lesioned patients and those intoxicated with ethanol (73). It should also be noted that it is on the ascending limb of the blood ethanol curve - i.e. when blood ethanol levels are increasing - when effects on ECF are particularly apparent (68).
The neurotransmitter, serotonin, has been implicated in this ethanol induced aggression as well. Decreases in serotonin levels, as well as 5-HT receptors, have been correlated with aggressive behavior (53). Acute ethanol consumption decreases the availability of the 5-HT precursor l-tryptophan to the brain (53). So, it might not be a bad idea to take 25-50mg of 5-HTP if you are prone to aggressive behavior when drinking.
Alcohol is neuorotoxic, and this toxicity is likely mediated by several factors. Fatty acid ethyl esters are a toxic byproduct of fatty acids and ethanol (74) which increase mitochondrial uncoupling and disrupt lipids of cell membranes (75) -- both l-carnitine and acetyl-l-carnitine in doses of 50mg/kg have been shown to decrease formation of FAEE by 3 to 6 fold, with ALC being particularly effective (75).
There is also strong evidence that ethanol induces oxidative damage -- in the form of increases free-radicals and indirect markers of oxidative damage such as lipid peroxides and protein carbonyl (76), thus the use of antioxidants is recommended -- Grape seed extract, resveratrol, SAMe, ALC, vitamin E, and selenium have all been shown effective (77, 78, 79, 80). As mentioned previously, NMDA modulated excitotoxicity is another mechanism.
Hepatotoxicity will not be reviewed as it is not a real concern for non-alcoholics, and alcoholics are not the intended audience of this article. Though, I will note that the notion that a single episode of concomitant Tylenol and ethanol use causing permanent liver damage has no basis in fact (81).
The NMDA receptor complex is implicated in memory loss and blackouts from ethanol. This is due to its suppression of long-term potentiation (LTP) in the hippocampus (35). LTP is a sustained increase in synaptic efficacy following brief intense stimulation of presynaptic inputs (82) - basically, it is a physiological change by which memories are formed.
NMDA activation is required for the induction, but not sustaining of LTP (83), and as mentioned, ethanol results in the blockade of NMDA receptor transmission. Indeed, ethanol has been directly shown to inhibit LTP in concentrations as low as 5mM (equivalent to 1-2 drinks) (84).
This effect is very much dose dependent (as well as exhibiting interindividual differences and tending to be related to rapidly rising blood ethanol levels) and exists as a continuum, with lower concentrations producing minor loss and concentrations between 50-100mM (20+ drinks) producing so-called "blackouts" (85).
Contrary to popular notion, the occurrence of more frequent blackouts is not a predictor of subsequent alcoholism (86). Blackouts and short-term memory deficits have been found to be related (87), so if you want to test whether your drunken friend will experience a blackout the next day, ask him about a conversation 5 minutes earlier, and if he does not remember it at all, you will know that he will.
GABA (88), dopamine (89), and serotonin (90)are also likely to be involved in ethanol induced memory disruption, though the data for both is scarce at present. With serotonin, this is likely due to decreased availability of tryptophan and has been shown to be reversible with an SSRI. Thus, 25-50mg of 5-HTP is again recommended.