The gabapentinoids are a class of drugs vaguely resembling the neurotransmitter GABA. Although they were developed to imitate GABA’s action, later research discovered they acted on a different target, the A2D subunit of calcium channels. Two gabapentinoids are approved by the FDA: gabapentin (Neurontin®) and pregabalin (Lyrica®).

Gabapentin has been generic since 2004. It’s commonly used for seizures, nerve pain, alcoholism, drug addiction, itching, restless legs, sleep disorders, and anxiety. It has an unusually wide dose range: guidelines suggest using anywhere between 100 mg and 3600 mg daily. Most doctors (including me) use it at the low end, where it’s pretty subtle (read: doesn’t usually work). At the high end, it can cause sedation, confusion, dependence, and addiction. I haven’t had much luck finding patients a dose that works well but doesn’t have these side effects, which is why I don’t use gabapentin much.

Pregabalin officially went generic last month, but isn’t available yet in generic form, so you’ll have to pay Pfizer $500 a month. On the face of things, pregabalin seems like another Big Pharma ploy to extend patents. The gabapentin patent was running out, so Pfizer synthesized a related molecule that did the same thing, hyped it up as the hot new thing, and charged 50x what gabapentin cost. This kind of thing is endemic in health care and should always be the default hypothesis. And a lot of scientists have analyzed pregabalin and said it’s definitely just doing the same thing gabapentin is.

But some of my anxiety patients swear by pregabalin. They call it a miracle drug. They can’t stop talking about how great it is. I can’t use it too often, because of the price, but I’m really excited about the upcoming generic version coming out so I can use it more often.

Still, I have to wonder – why am I sitting around waiting when I could just give people gabapentin? Confirmed pharmacodynamically-identical, generic, and cheap? The answer is, gabapentin doesn’t seem to work that well. I’ve never had patients with more than minimal anxiety happy on gabapentin alone. Am I imagining a difference betwee these two supposedly-similar medications? I don’t know. Although studies confirm pregabalin is great for anxiety, nobody has done the studies on gabapentin that would let me compare it. For now, the apparent difference between pregabalin and gabapentin is one of the great mysteries of life, one of the things that makes me doubt my own sanity.

One possibility is that we’re getting the doses wrong. UpToDate recommends treating anxiety disorders with gabapentin using a starting dose of 300 mg twice a day = 600 mg daily. But it recommends 100 mg three times a day = 300 mg of pregabalin. This dosing table suggests 1 mg pregabalin = 5 mg gabapentin, so 300 mg of pregabalin = 1500 mg gabapentin! So we’re starting gabapentin patients on less than half as much medicine as we start pregabalin patients on. If this forms a reference point in the doctor’s mind, then maybe what we think of as a “high dose” of gabapentin is the same as what we think of a “low dose” of pregabalin. Maybe all our gabapentin doses are just too low.

I usually avoid higher gabapentin doses because I feel like they have more side effects than low pregabalin doses. Is this just an illusion? Is it my bias? If a patient reports feeling dizzy on high-dose gabapentin, do I say “Yeah, you’re on a really high dose, I’m not surprised you feel that way, let’s back off?” And then if they feel the same thing on low-dose pregabalin, might I say “It’s a low dose, you’re just getting used to the medication, give it a few more weeks”? Might my biases even be affecting how patients report their own experiences?

Or might there be some obscure pharmacologic mechanism? This paper tries to compare the pharmacology of the two drugs. They say the body can easily absorb pregabalin, but has a limited ability to absorb gabapentin – the more gabapentin there is, the lower a percent gets absorbed:

With regard to the fraction of the dose absorbed, the lowest gabapentin dose studied (100 mg every 8 hours) is associated with absolute bioavailability of approximately 80%. This value was shown to decrease with increasing dose to an averageof 27% absolute bioavailability for a 1600 mg dose every 8 hours. In contrast, oral bioavailability of pregabalin averaged 90% across the full dose range of 75 to 900 mg/day studied

This doesn’t match the dosing table linked above, which suggests a 1:5 constant ratio between gabapentin and pregabalin dose. It also doesn’t really match the paper’s Figure 3, which shows a linear effect of gabapentin up to 1800 mg for nerve pain. It does match the paper’s figure 4, which shows little to no effect of gabapentin past 600 mg for seizures. I don’t really know what’s going on here. It would make some sense if the bottleneck were plasma -> CSF absorption, but that’s not what the paper’s saying. In any case, if the gabapentin/pregabalin relationship followed the same pattern for anxiety as for seizures, it would be impossible to ever get a dose of gabapentin as high as the starting dose for pregabalin, which would explain perceptions of pregabalin’s superiority. Try to increase gabapentin dose, and you just have extra gabapentin sitting around in the GI tract causing trouble. I don’t know if this is at all the right way to be thinking about this.

One more difference: gabapentin is not a controlled substance, but pregabalin is Schedule V, the designation the government uses for things that are technically addictive but that it’s not going to worry about too much. Why the difference? The government’s documentation of their decision doesn’t say. It could be total chance: both substances are right on the border, and a different bureaucrat got assigned to each case. But the decision doesn’t seem totally off-base to me. Although it’s theoretically possible to get addicted to gabapentin if you use a really high dose and try really hard, you’d have to be pretty desperate even by drug addict standards. I’ve seen a little more pregabalin addiction, though I agree with the FDA that it’s still pretty unusual (some people in the comments disagree). One likely culprit is the absorption rate: pregabalin gets absorbed in an hour or so, gabapentin takes three or four. Faster-acting substances are always more addictive; they peak higher and sooner, and it’s easier for the brain to associate stimulus (taking the drug) with response (feeling good). Could this also explain some of the efficacy difference? I don’t know.

Phenibut is not FDA-approved; it’s a common medication in Russia which gets sold as a supplement/nootropic/recreational drug in the US. The FDA occasionally asks people to stop selling it, but they’ve never gotten serious, and it’s still easily available on the open Internet.

Phenibut has the kind of approval ratings usually associated with North Korean dictators who kill anyone who disapproves of them – including the highest median rating on my nootropics survey. It’s phenomenal for social anxiety – not in the SSRI way of making you a little calmer, but more in the “getting just the right amount of drunk” way that turns you into a different, bolder, and more fun-loving person. Aside from this, it can give a hard-to-describe sense of tranquility and well-being.

(it also makes you feel like you’re wearing a hat even when you aren’t. I swear this is a real side effect.)

Needless to say, it’s potentially addictive and can seriously ruin your life. Conventional wisdom in the phenibut user community is that you can use 500 mg once every week (or maybe every two weeks) safely. Anything beyond that and you develop rapid tolerance. Increase the dose to fight the tolerance, and you start feeling worse on the days you don’t take it, using it more and more to compensate for the rebound, and eventually getting a withdrawal syndrome closely related to the delirium tremens that sometimes kills recovering alcoholics.

(does this mean that responsible phenibut use is a free way to have one great day per two weeks? depends how good your willpower is, I guess. see also this graph from this source)

The discovery of ketamine’s efficacy for depression was a mixed blessing. Ketamine such is a difficult medication to use – dangerous side effects, intolerable hallucinations, IV delivery – that it could never be a panacea, whatever its potential. But the discovery sparked a hunt for other ketamine-like chemicals that shared its efficacy but not its downsides. It also started a race to figure out how ketamine worked, with the hope that this would provide the key to what depression really was, deep down. Phenibut should inspire the same kind of interest. It’s too dangerous to use regularly, but it’s great enough that we should be looking into what the heck is going on.

Early research into phenibut focused on GABA, the main inhibitory neurotransmitter. The brain has two kinds of GABA receptors, GABA-A and GABA-B. Alcohol, Xanax, Valium, Ambien, barbituates, and the other classic sedatives all hit GABA-A. There aren’t that many chemicals that hit GABA-B, and the few that are out there tend to be kind of weird – one of them fell to Earth on a meteorite. But phenibut is a GABA-B agonist. This sounds like a neat solution to the mystery: a drug with unique anti-anxiety properties affects a unique inhibitory receptor. But another GABA-B agonist, baclofen, has minimal anti-anxiety effects. It is mostly just a boring muscle relaxant (there was some excitement over a possibility that it might cure alcoholism, but the latest studies say no). So probably GABA-B on its own doesn’t explain phenibut.

This led researchers to propose that phenibut might work as a gabapentinoid. It has the defining GABA backbone, and it has activity at the A2D calcium channel subunit. But its gabapentinoid activity is much weaker than gabapentin itself, so why should its effects be stronger?

Baclofen outdoes phenibut as a GABA-B agonist, and gabapentin outdoes phenibut as a gabapentinoid, but phenibut works better than either. This is the other big gabapentinoid mystery that keeps me awake at night.

Might it be a synergistic effect between the two different actions? If this were true, we would expect taking gabapentin and baclofen together to have phenibut-like effects. But these drugs are sometimes used for the same kinds of neuromuscular conditions and nobody has ever noticed anything out of the ordinary. I would love to see this studied but I don’t expect much.

Phenibut has two enantiomers, r-phenibut and s-phenibut. Both are decent gabapentinoids, but only r-phenibut has GABA-B activity. If both worked equally well, that would suggest phenibut worked on A2D; if r-phenibut worked better, that would implicate GABA. The best source I can find is this study, which says that only r-phenibut has effects on rats. Do the hokey tests they run rats through exactly correspond to treating anxiety in humans? Unclear, but this pushes me more in the direction of thinking GABA-B is an important part of phenibut’s effects. So does a passing resemblance between phenibut and GHB, an unusual drug that works on GABA-B among other things.

Overall I think phenibut is probably more GABA-B agonist than gabapentinoid, but I can’t explain why it’s so different from baclofen.

One fringe possibility: it isn’t. I’ve said that these two drugs are used for different indications, by different populations, and get different results. But the map isn’t the territory, and the way humans use and think about drugs doesn’t always reflect chemical reality. Everyone knew the second generation antipsychotics were totally different from the first generation ones, until we learned that they weren’t really, and the different effects we saw were a combination of using them differently plus having different expectations. And placebo alcohol can still get people pretty drunk. The only study I’ve found directly comparing phenibut to baclofen finds they work for similar indications, at least in rats (see bottom of page 476). And I can find a few comments on Reddit backing this up from experience.

My odds are against this theory – I think there’s probably some real difference between these drugs that we don’t understand. But constant vigilance never hurts.

[EDIT: commenter dtsund points out that baclofen has some issues with blood-brain barrier permeability; see here for more. Although some of it gets through, it could build up in the plasma much faster than in the brain, giving it disproportionately peripheral effects]