How do we know a substance works?
I often assert that most of "alternative" medicine is a scam. It doesn't work, and it is simply a way to part gullible people from their money. How do I know? I know that it is a scam because the various substances and techniques of "alternative" medicine have never been subjected to investigation for either efficacy or safety. Lay people generally do not realize that there are entire branches of science devoted to determining whether substances and techniques work and whether they are safe. Let's look at therapeutic substances (medications, chemicals, herbs) to see what I mean.How do we decide if a substance works? Lay people are often confused on this point. They assume that if a person ingests a substance, and then feels better, that means the substance "worked". Those with a little more sophistication understand that anecdotes are not enough because the placebo effect will always lead to some proportion of people feeling better even if the substance didn't work at all.
Anyone with minimal understanding of basic science and statistics knows that the randomized control trial, and statistically significant results are required to determine efficacy. However, most laypeople do not realize that the RCT and statistically significant results are the tip of the iceberg. There is much more to determining substance efficacy, dosage and safety than successfully demonstrating a difference in an RCT.
The study of drug efficacy and safety is pharmacology. Pharmacology can be roughly divided into two areas: pharmacodynamics, how the substance acts on the body and pharmacokinetics, how the body acts on the substance. These lecture notes provided a more detailed description. In brief:
In order for a drug to work, it must enter the body and somehow be distributed in such a way that it gets to its site of action. In most cases the site of action is a macromolecular "receptor" located in the target tissue. Most drug effects are temporary, because the body has systems for drug detoxification and elimination.Here are some basic questions that must be answered to find out how the drug works on the body:
[Mechanism of Action.] Agonist is a drug which binds to its "receptor" and produces its characteristic effect... An antagonist binds to the receptor without causing an effect, thereby preventing an active substance from gaining access...These are some basic questions that must be answered to show how the body interacts with the substance:
Dose-Response. The sine qua non of drug effect. Simply put, as the dose of drug increases, the response should increase...
ED50. The median effective dose, or the dose which produces a response in 50% of subjects...
Efficacy. Also called Maximal Efficacy or Intrinsic Activity. This is the maximum effect of which the drug is capable...
Therapeutic Window. For every drug, there exists some concentration which is just barely effective (the Effective Concentration) and some dose which is just barely toxic (the Toxic Concentration). Between them is the therapeutic window where most safe and effective treatment will occur...
[How does the substance enter the body?] The drug may enter the body in a variety of ways: as an oral liquid, pill, or capsule; as an inhaled vapor or aerosol; absorbed through intact skin or a mucous membrane; injected into muscle, subcutaneous tissue, spinal fluid, or directly into the bloodstream...This brief overview demonstrates that determining drug efficacy and safety is complex. An RCT with statistically significant results can demonstrate that a substance has an effect, but that is just the starting point. It is absolutely imperative to determine the pharmacodynamics and pharmacokinetics of a substance before you can claim that it is effective and safe. When it comes to herbs and other substances used in "alternative" health, these questions have usually not even been asked, let alone answered.
[How does the substance get absorbed into the circulation?] ...If it is absorbed from the skin, mouth, lungs or muscle it will go directly into the systemic circulation. If drug is injected directly into the bloodstream (e.g., intravenous injection), 100% of it is available for distribution to tissues. This is not usually the case for other modes of administration. For example, drug which is absorbed via the portal circulation must first pass through the liver which is the primary site of drug metabolism (biotransformation). Some of the drug may therefore be metabolized before it ever reaches the systemic blood...
[What happens to the substance in the circulation?] Once the drug is in the bloodstream a portion of it may exist as free drug, dissolved in plasma water. Some drug will be reversibly taken up by red cells and some will be reversibly bound to plasma proteins... [This] is also important because protein-bound drug can act as a reservoir which releases drug slowly and thus prolongs its action.
[How is the substance distributed around the body?] The unbound drug may then follow its concentration gradient and distribute into peripheral tissues. In some cases, the tissue contains the target site and in others the tissue is not affected by the drug. Sites of non-specific binding act as further reservoirs for the drug...
[How is the substance removed from the body?] ... The liver metabolizes most drugs into inactive or less active compounds which are more readily excreted. These metabolites and some of the parent compound may be excreted in the bile and eventually may pass out of the body ...
Parent drug and metabolites in the bloodstream may then be excreted: most are filtered by the kidney, where a portion undergoes reabsorption, and the remainder is excreted in the urine... Smaller amounts of drug are eliminated in the sweat, tears and breast milk...
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