[mtex]

Publication Date: April 1, 1999 by Bill Roberts

One rather key issue to usage of anabolic/androgenic steroids (AAS) is how one chooses which to use, or which combination to use, and indeed, why combinations might be superior to comparable amounts of single steroids. The issue of combining AAS for most efficient muscle gain is one that has been entirely neglected in the medical literature, since acquisition of muscle is not considered of therapeutic necessity, and observations by bodybuilders have unfortunately generally not been made in a systematic manner. I cannot yet give definitive and complete answers on this matter, but some things are clear at this point, and general support for the principle of synergy can be found in some scientific studies.


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Pharmacology in the Simplest Case

First, let us consider the case of the simplest kind of drug. This drug would act in only one way, and would do so by binding to a receptor and activating it. The amount of activity performed by that type of receptor would be directly proportional to the number of receptors that bound the drug. Nothing else of any kind would be going on with this drug.

There might also be similar drugs which worked the exact same way, binding to the same receptor. The only ways in which these drugs could differ from the practical point of view are in pharmacokinetics (how fast each drug enters and clears the body) and how potent each drug is. The latter term is one that may easily be misunderstood due to common usage differing from scientific usage. Potency refers to how little of a drug is required to give a defined amount of effect. For example, if one may obtain the desired therapeutic effect in 50% of subjects with 1 mg/day of Drug A or 100 mg/day of Drug B, then Drug A is 100 times more potent.

This does not mean that Drug A is necessarily better! One can get the same effect from Drug B simply by using 100 times as much. It might be the case that Drug B might be preferable despite the higher required dose: for example, if Drug A leaves the body too quickly or too slowly, or has more toxicity for the same therapeutic effect. It means only that in comparing the drugs, to compare them equally, one must compare the effects of 1 unit of Drug A to 100 unit of Drug B.

To understand this a little more, unfortunately we have to use a little math. One could skip over the math if desired and just look at the conclusions which follow fairly easily from the numbers calculated.

Drugs and receptors interact with each other according to a simple equation:

(conc. of drug) (conc. receptor)
Kd = -------------------------------------
(conc. of drug « receptor)

where (conc. of drug « receptor) is the concentration or amount per volume of receptors that have drug bound to them, and (conc. of drug) and (conc. of receptor) refer to the concentrations of free drug and receptor respectively.

This number Kd is a constant (always the same) for any given drug, but will vary between drugs of different potencies. This fact allows us to calculate the percentage of receptors occupied if we know Kd and the amount of drug.

Kd will be expressed in units of concentration, for example, 1 nanogram per liter. More potent drugs have lower Kd values. In our comparison of Drugs A and B where A was 100 times more potent, if Drug A had a Kd value with the receptor of 1 ng/L, then drug B would have a Kd of 100 ng/L: you would need 100 times more of Drug B to get the same effect.

What would happen therapeutically if you "stacked" Drug A and Drug B?

You can play with the math and you will find that using blends of A and B, where one keeps in mind that B is 100 times less potent and therefore uses 100 mg of it for each unit of A it replaces, that one gets the exact same result regardless of the stacking. Let’s say that Drug A comes in 1 mg tablets and Drug B comes in 100 mg tablets. Each tablet therefore gives the same effect. In the case of the simplest type of drug such as these two drugs, the effect is identical whether one uses 10 tabs of A, 10 tabs of B, or 5 tabs of each. The same number of receptors are occupied regardless and the effect is the same.

Therefore, stacking these drugs makes about as much sense as stacking two brands of aspirin or two brands of coffee. It is okay if one happens to have both available, but there is no reason to go out and buy the second brand in the hopes that stacking it will give more of a caffeine buzz, or more pain relief.

The mixing might make sense if there were a pharmacokinetic difference: perhaps one of the brands of aspirin is time-released and you want both an instant hit for immediate pain relief as well as sustained action. (The sustained action though could be obtained with only the regular brand, simply by taking small amounts frequently.)



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Application to AAS

Now the obvious question here is, Is the same type of drug response true with AAS, or are more complex things going on? Let’s say that, used alone, the same effect is obtained from 1 "Deca-unit" of Deca (let’s say that a Deca-unit is 400 mg) or from 1 "Dianabol-unit" of Dianabol (let’s say that this is 280 mg/week in divided doses every day). If these drugs were as simple in action as Drugs A and B, then the math says that the same result will be obtained regardless of whether one uses one "Deca-unit" of Deca per week, one "Dianabol-unit" of Dianabol per week, or half a unit of each respectively in a stack.

This however is not what happens. Using half a Deca-unit and half a Dianabol-unit per week (say 200 mg/week Deca and 20 mg/day Dianabol) gives better gains than using one unit of either alone. This effect is called synergy and results when there is more than one mechanism of action. The above math remains correct for any given receptor but this is saying that there are more things going on in the body than simply binding to one receptor.

Aside from this and other practical but well-confirmed observations, there is scientific evidence that this is indeed the case.


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Scientific Evidence for Multiple Modes of Action



The first thing to consider is whether or not a single mode of action is sufficient to explain all results, as with the simplest case described for Drugs A and B, or whether data is in conflict with such a model.

The equation given earlier allows one, given a measured Kd value, to calculate what percentage of receptors is occupied for a given concentration of drug.

The Kd value for testosterone and the androgen receptor (AR) actually is not known with great precision for humans, but is approximately .44 nmol/L.1 Free testosterone levels in normal men average approximately .07 nmol/L.2,3,4

Contrary to previous statements made by me (although those statements had been made in the scientific literature) this indicates that normal testosterone levels are not sufficient to saturate the AR. The equation given shows that with these values for free testosterone (Tf) and for Kd, one would expect only 14% of ARs to be occupied at any time. Increasing Tf by ten times would improve this to 61% occupancy, which still is not saturated. Increasing twenty times would yield further improvement to 76%. Perhaps this correlates well with the observation that gains improve markedly relative to low dose as one increases amount of testosterone used to 1 gram per week, but going to 2 grams per week offers only a modest further increase.

These results surprise me and are definitely contrary to accepted wisdom. I can only speculate at the moment that those who were trying to determine whether or not receptors are saturated made the mistake of performing the calculation with total testosterone levels instead of Tf. Doing so would lead to that conclusion but is an incorrect method.

I had been going to argue as I had previously that the dose response curve, which extends at least to the 1 gram per week level,5 indicates that there must be more than one mechanism of action, since response increases even past the point of saturation. However these calculations just performed indicate that the dose response curve, through the range that has been studied, is in accord with known values for Kd. This doesn’t prove that there is only one mechanism, but just that one mechanism is not disproven by the dose response curve.

Is there other evidence for multiple mechanisms?

Yes.

First, there are indisputably molecular targets that are not ARs within some cells which bind androgen and give pharmacological response to androgen. These targets may well have (and in some cases are shown to have) quite different binding properties than the AR does. One AAS might be more potent than another at the AR, but less potent at this other target.

Now these targets are not well known or characterized at all, but there is compelling evidence for their existence. First, as discussed above, for any given target (or receptor) drugs acting only at that receptor will behave the same way and differ only in their potencies. Now if all AAS behaved the same way and differed only in their potencies, and had the same ratios of potency regardless of the activity being studied (whether in muscle or skin or nerves, etc.) then this would be consistent with there being only one target or receptor. However, if some AAS are effective in some activities but do nothing in others, while other AAS do have these other activities, then this can’t all be occurring from the same receptor.

Most of the research in this area is rather far removed from bodybuilding, but the principles still apply. Biochemistry is usually much broader than any one specific cell being studied. (For example, most human biochemistry was actually learned originally by study of E. coli and with later research found to be identical in man.) Thus, while we may not care about ductal branching morphogenesis in the developing rat prostate, the fact that a peculiar biochemical mechanism of androgen response occurs here implies that such a mechanism may well exist in things we are interested in, such as bodybuilding. The possibility at least exists.