This paper asks an excellent question that I have asked myself many times: why is phenylephrine still being sold as an oral decongestant drug? Well, OK, I know how we ended up in this situation, but why are we still there?
Here's some chemistry and some history. First, we will examine a decongestant that actually works: pseudoephedrine. It's a natural product from plants of the Ephedra genus, especially E. sinica, where it occurs along with ephedrine and other alkaloids. The (S,S) and (R,R) enantiomers are known as pseudoephedrine, while the (S,R) and (R,S) pair are ephedrine. They're all phenethylamine stimulants, and there are plenty more where those came from - in fact, if you reduce off that OH group and just make that a methylene spacer, you have methamphetamine, which is technically also a name applied to that racemic pair, with the single chiral center remaining at the methyl group. Pseudoephedrine is an adrenergic receptor ligand, but it has far less stimulating properties than methamphetamine and a better pharmacological profile than ephedrine. It is famous for drying nasal passages during colds and allergies, at which it excels. Some people still notice amphetamine-like effects of sleeplessness and jitters at those doses, and at higher doses (not recommended!) pretty much everyone will. Across the board, these compounds can cause other CNS symptoms, increased blood pressure, loss of appetite, cardiac effects, difficulty urinating and more, but the window for these does seem to be widest with pseudoephedrine.
Now we turn to phenylephrine. As you can see, that's a somewhat different structure - there's a phenol on the aryl ring, and there's no longer a chiral methyl group bretween the hydroxy and the N-methyl. It also has adrenergic effects, but different (and often weaker) ones than either ephedrine or pseudoephedrine. Its main effect seems to be raising blood pressure, and it has medical uses in that area as an addition to anaesthesia agents. But what it does not do well is act as a decongestant. There have been several controlled studies that show that it is indistinguishable from placebo in conditions like allergic rhinitis. Pseudoephedrine, however, is very clearly distinguished from placebo and in most people has very noticeable decongestant effects that last for several hours.
Why is oral phenylephrine so useless? It is extensively metabolized, starting in the gut wall. You can find a bioavailability figure of 38% in the literature, but that appears to be the most optimistic number possible, and you can also find studies that show 1% or less. Overall, the Cmax is highly variable patient-to-patient, and the lack of cardiovascular effects at low doses argues for very low systemic effects (and expected low efficacy as a decongestant). The bioavailability increases at higher doses as you apparently saturate out some of the metabolic pathways, but at the 10mg dose typically used for decongestants, you can forget it.
But here in the US, if you go to the drugstore and purchase an over-the-counter nasal decongestant (as a single agent or a combination of drugs that includes a decongestant), you will in every single case be buying phenylephrine. Which does not work. It is found (according to the paper linked above) in 261 different OTC products, and it is a useless bait-and-switch on the consumer in every one of them. I have always told friends and family members to avoid these products if at all possible, and to go back to the pharmacy counter to get something that actually works. This situation obtains, of course, because as mentioned above you can make methamphetamine from pseudoephedrine. There are a number of synthetic procedures for doing this, some of them quite alarming, and several of which can indeed be performed in the barn, garage, basement, or trailer park of your choice - if you can get enough pseudoephedrine. Thus the move to put medications containing this behind the pharmacy counter, with limits on their sale. No more walking in with a duffel bag and buying every single Sudafed package in the store.
But it's quite possible that that era is gone anyway. The Mexican drug cartels have apparently been putting some real effort into process improvements and economies of scale, and I am told that the drug is (sadly) cheaper than it's ever been and available in higher purity than all but the most dedicated basement lab would be able to provide. As that article details, this includes an interesting and concerning increase in the compound's enantiomeric purity over the years. Whatever the current synthesis is - and you can be sure that the DEA knows the details, even if they are understandably not going into them in public - it is strongly skewed towards the more pharmacologically desirable D-methamphetamine. All this means that even if pseudoephedrine were more freely available, it might not be as much of an illegal article of commerce as it was twenty years ago.
But be that as it may: the fact remains that its alleged replacement, phenylephrine, is of no real use and does not deserve its FDA listing. There's no reason to think that it's a safer compound than pseudoephedrine or one with fewer side effects - if you can get enough of it into your blood, you'll probaby have a rather similar profile. The only reason it's sold is to have some alternative to offer consumers, even if it's a worthless one. There have been several attempts over the years to do something about this (here's an earlier one from the authors of the current paper), but absolutely nothing has happened. Perhaps the agency does not wish to be put in the position of having nothing available than can be put out on the open shelves, and perhaps the pharmacies themselves prefer things as they are as well. It's for sure that the companies producing phenylephrine-containing products like the current situation a lot better than the alternative. But for people who actually want to be able to breath for a while as we enter allergy season, wouldn't it be better just to stop pretending and to stop wasting everyone's time and money?