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Most day to day drugs such as caffeine and paracetamol require a dosage in milligrams to have the desired effect.

Why then, does it take many tens of grams of alcohol to have a tangible/noticeable physiological impact on the body? What is it about the composition of alcohol that makes it so weak, gram for gram, compared to other recreational and medicinal drugs? Are there any other psychoactive drugs that require similar dosages to alcohol to have an effect?

For clarification, as per the comments

For example, as a 90kg adult I can consume 30g of alcohol (3 UK units) before it has any noticeable impact, whereas a coffee containing just 100mg of caffeine (300 times less than alcohol) produces a noticeable reaction.

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    $\begingroup$ It is an interplay between pharmacokinetics and pharmacodynamics. The question is superbly broad; you talk about overdose first and next to "being hammered". You won't get 'hammered' by paracetamol. You can get battered by it, as an overdose mostly ends through internal bleeding. In contrast, heroine OD is characterized by respiratory failure. What exactly is your question and could you focus it? I think I know where you are heading, but I'd rather not make drastic edits on such a vague question, given the risk of missing the point. $\endgroup$ – AliceD Mar 16 '16 at 15:02
  • $\begingroup$ Alcohol is easily metabolized to acetyl-CoA. $\endgroup$ – WYSIWYG Mar 16 '16 at 15:03
  • $\begingroup$ Plus: a regular paracetamol dose for an adult is a gram. Which is 1000 mg, but I would call it also the gram range. Likely it's just the worst kind of example drug in the light of this question. $\endgroup$ – AliceD Mar 16 '16 at 15:17
  • $\begingroup$ Fats or sugar are even "weaker" drugs. In any case, don't forget that The dose makes the poison. As a consequence, water is a very "weak" drug. $\endgroup$ – Remi.b Mar 16 '16 at 15:22
  • $\begingroup$ Perhaps because alcohol is fairly common in nature (e.g. in overripe fruit), so fruit-eating creatures with a low tolerance to its effects would have been selected against. $\endgroup$ – jamesqf Mar 16 '16 at 22:10
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As Christiaan already pointed out, this depends on the pharmacokinetic and pharmacodynamic parameters. The effective drug concentration depends on the drug-receptor association constant and the drug degradation constant (for a highly simplified model). The degradation/removal depends on the abundance of the enzyme catalyzing this reaction.

Ethanol is primarily thought to cause intoxication by activation of GABAA receptors. However, only a very specific subclass of these receptors are activated at the levels of alcohol that one consumes during "social/moderate" drinking. Others require very high alcohol concentrations (Hanchar et al., 2006). Basically alcohol is not a very specific agonist/antagonist of any neurotransmitter or neuromodulator receptors. In other words, it does not have high affinity to any of these receptors. There is no answer to "why". I would guess that since ethanol is a very common molecule (and is also used as energy substrate by some organisms, to a certain extent), high sensitivity to ethanol would have been evolutionarily selected against.

Although many proteins show changes in their function at very high alcohol concentrations (>50 mM), the molecular basis for behavioral alcohol effects at low to moderately intoxicating doses experienced during social alcohol consumption remains elusive (1). GABAA receptors (GABAARs) and the inhibitory GABAergic system have long been suspected to be targets for acute alcohol effects (2–4). For example, the GABAAR agonist muscimol potentiates the sedative actions of alcohol, whereas the opposite effect, a reduction of ethanol (EtOH)-produced sedation, is detected with the GABAAR blockers picrotoxin and bicuculline (5). Although most GABAAR subunit combinations can be activated by high (anesthetic) alcohol concentrations (6), only very specific GABAAR subunit combinations (containing the δ as well as the β3 subunit) exhibit dose dependencies that mirror blood alcohol levels that are associated with mild to moderate intoxication in humans (7, 8) (≈3–30 mM, because the legal drinking limit is 17 mM or 0.08%).


From Hanchar et al., 2006

Other psychoactive drugs are highly specific and have high affinity to their corresponding receptors. For example, caffeine acts on the adenosine receptors at µM concentrations (Daly et al., 1983). This is because of caffeine's high affinity to these receptors.

Moreover, ethanol is readily metabolized to acetyl-CoA by alcohol dehydrogenase and aldehyde dehydrogenase enzymes which are quite abundant in the body. Some people who have mutations in these enzymes leading to their reduced activity, "get drunk" and experience hangovers even with a low level of alcohol consumption.

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  • $\begingroup$ Good, nicely formulated and concise answer +1 $\endgroup$ – AliceD Mar 16 '16 at 20:38
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It has to do with the general genetic makeup of most humans (I believe it differs from a a population to another [Genetic polymorphism]), but in general:

There are much more receptors (both in quality and quantity) effected by the active ingredients in alcohol, than there are for other molecules like Heroin or Cocaine, so it takes more dosage to "lay the weight" over it's receptors in compare to those of these material.

To better understand this whole concept you could further read on articles about Physiological addiction, Psychological addiction, and the difference between these two types of addiction:

Alcohol addiction, like Heroin addiction is much more physiological than psychological, but it requires much more material, as I have explained very generally above.

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Some of the information contained in this post requires additional references. Please edit to add citations to reliable sources that support the assertions made here. Unsourced material may be disputed or deleted.

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    $\begingroup$ Is it (your answer) only "maybe/I think" one or does it contain facts? If yes (contains facts), please put some reference to those facts. $\endgroup$ – another 'Homo sapien' Mar 16 '16 at 15:02
  • $\begingroup$ @another'Homosapien' OP certainly homes in on the question, but in the q's current state, I wouldn't put a lot of research effort in an answer either. $\endgroup$ – AliceD Mar 16 '16 at 15:05
  • $\begingroup$ I agree @Christiaan and that is why I aksed OP whether question contains research effort or not. Excuse me if my comment was too rude. $\endgroup$ – another 'Homo sapien' Mar 16 '16 at 15:07

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