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My question is actually referred to hallucinogenic substances, in particular to mushrooms.

I can understand why alcohol or other substances that relate to body mass (fat in some cases) affect people to a greater or a lesser extent depending on their weight (for a given amount of a certain drug).

What I do not understand (perhaps this is not even true) is why the more mass a person has, more grams of mushrooms that person has to take in order to get the same psychoactive effect.

If the active substance finally goes to the brain, where is the weight's role in this process?

People with experience in this recommends intakes of a certain amount of grams depending on one's weight. Does this have a logical reason?

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I think the centre of confusion for you is this question:

If the active substance finally goes to the brain, where is the weight's role in this process?

The thing is, when a substance has a systemic effect (as opposed to local) it somehow has to get from the point where it is applied to the site of action. So, if one ingests something that affects the brain, it has to travel from the stomach to the head somehow - and substances do this via blood. So the substance is liberated from the form in which one took it, then dissolved and absorbed into the bloodstream. Since blood reaches all parts of the body, so does the substance. We usually see most of its effects on one body part/organ, but it gets distributed (more or less) everywhere.

  • What does this have to do with body mass?

To answer this, we must look into the process in which a substance passes from the blood stream to a tissue. This can be done by several mechanisms such as: diffusion, active transport, pinocitosis etc. For many xenobiotics (substances foreign to our body) the route of transport is diffusion through cellular membranes. The rate and the extent of diffusion are proportional to concentration gradient.
This means two things:

  • The higher the difference in the concentrations between the blood and the other tissue, the higher the rate and extent of diffusion will be.
  • This process doesn't depend solely on the total amount of the substance taken; it depends on concentration.

And since: c = amount/V

we can see that, if we dissolve the same amount of a substance if different volumes (of blood e.g.) we will get different concentrations. Which brings us to the fact that blood volume is important. Among other factors, blood volume depends on body mass. The mass of the blood amounts for roughly 7% of our body mass, and the volume is proportional to that.*

  1. Bigger body mass => higher blood volume => lesser substance concentration => lesser the rate and the extent of diffusion into the target organ (such as the brain)

When the substance gets into a tissue, depending on its chemical structure it can: find a target protein and have an effect (note that this doesn't have to be the "desired" effect); it can dissolve in fat tissue; it can bind to proteins or other structures such as bones. Again the strength of these bonds depends on the chemical structure of the substance (among other factors) - it can bind reversibly and soon be on its way again or it can get deposed in a tissue it has chemical affinity for. We say that the substance is distributed to various compartments**. If the size of these compartments is bigger, than there is more "room" for the substance to be distributed, and potentially "stored", so to speak.

  1. Bigger body mass => (usually proportionally) bigger mas of many tissues => bigger volume to distribute the substance and potentially bigger deposing capacity. enter image description here

Source: ref. 4

  • The catch

Things get complicated because many substances in our blood bind to plasma proteins (usually albumin) and the bound fraction is in equilibrium with the unbound (free fraction). It is only the free fraction of the substance that can diffuse through cell membranes (protein-substance complex is too large). Various substances have different binding potential, and they compete with each other for the same binding sites, and affect each other's kinetics. What's more, Liberation, Absorption and Distribution are followed by Metabolism and Excretion (the so called LADMER system). All these processes happen simultaneously after a (usually short) lag time.

This means that the concentration of a substance in blood depends on many factors. We calculate most of these factors in, based on information we get from testing on animals and from clinical trials, and use mathematical models and computer simulations to determine the dose and dosage which would achieve and maintain the concentration of a substance in blood in a certain range, and assume that this will have a predicted effect. All these calculations are approximations. Although body mass is an important factor in them, calculating a dose of a substance based only on total body mass is a very rough approximation.

Another catch for controlled substances: there is significantly less data on the kinetics of these substances than on medicines (which are intended to cure or manage a disease). So the "calculations" are limited. On the other hand when these substances reach other parts of the body, and are metabolised, aside from their psychoactive effects they can affect other organs as well, causing liver or kidney failure, for instance.


*Gender, body structure (especially lean body mass), age and other factors determine the exact mass and volume of the blood; still total body mass is strongly correlated with the amount of blood in the body.

** The division into compartments is theoretical, designed to make the calculations easier. It is based on the fact that the concentrations of a substance change differently in different compartments. In reality, all "compartments" are connected, and interact with each other at all times.

*** This explanation is simplified for general public. The equation above is for concentration in general. Blood concentration of a substance is never equal to simple quotient of the quantity and volume (remember to take point 2 and the catch into account). The theoretical term volume of distribution or apparent volume of distribution is not equal to blood volume - it is calculated by considering various factors.


References:

  1. Biopharmaceutics and Clinical Pharmacokinetics: An Introduction, Fourth Edition, Notari, CRC Press, 1986; chapter 2, pages 48-49
  2. Pharmacokinetics and Pharmacodynamics of Abused Drugs edited by Steven B. Karch, MD, FFFLM, CRC Press, 2007 - chapter 1 (especially: 1.2.1, 1.2.2 and 1.6)
  3. DRUG ABSORPTION, DISTRIBUTION AND ELIMINATION; PHARMACOKINETICS - pages 25-26
  4. Pharmacology 3rd Edition, By George M. Brenner, PhD, Professor Emeritus of Pharmacology, Oklahoma State University College of Osteopathic Medicine, Tulsa, OK; and Craig Stevens, PhD, Professor of Pharmacology, Oklahoma State University, Tulsa, OK
  5. Estimated blood volume
-1

The volume of blood that the psychoactive substance dissolves in will be roughly proportional to the lean body mass, making its concentration in the brain inversely proportional to lean body mass. If the substance were highly lipophilic then it might additionally partition into fat, further reducing its blood concentration. An exception to this

This study of the best way to calculate a dose of propofol adjusts the dose to depend on body weight, after excluding the weight of the fat. Propofol is a slightly polar phenol like the psilocin in Psilocybe mushrooms.

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