I.

If you look at any list of side effects for the FDA-approved version of s-ketamine (Spravato), you see things like urinary tract problems, bladder problems, pain on urination, feeling of urgency to urinate. You can find a bunch of papers like Ketamine: An Important Drug With A Serious Adverse Effect, where they say that ketamine is potentially great for depression, but that the risk of bladder injury needs to be taken really seriously.

When I first considered prescribing ketamine, the bladder injury stories scared me so much that I asked a bunch of veteran ketamine prescribers how I should monitor it. They all gave me weird non-commital answers like “I’ve prescribed ketamine to thousands of patients and never had a problem with this, so I guess don’t worry”. But why not? There are all these papers saying we should worry, and all these reports in the literature of ketamine-induced bladder injury!

A standard psychiatric dose of ketamine might be 0.5 mg/kg IV, 2x/week, for four weeks. So a 70 kg patient would get about 280 mg over the course of a month. This Chinese study and this UK study analyze recreational ketamine users, and both find they take about 3g daily, every day. That’s 90,000 mg over the course of a month. Again, that’s 280 mg for the psych patients and 90,000 mg for the recreational users (and you wouldn’t believe how many hoops the psych patients have to jump through to get their 280, or how terrified their doctors are that something could go wrong). Drug users use a lot of drugs! So why don’t psychiatric patients get bladder injuries? It’s because you get bladder injuries when you’re taking more like 90,000 mg of ketamine a month, and not when you’re taking 280 mg.

There is one (1) case report in the literature of somebody getting a bladder injury after taking prescription ketamine in a clinical setting (though also rumors of three other cases that were mentioned on a mailing list I can’t access). That person was prescribed a dose 10x higher than ordinary psychiatric patients. I hesitate to say the risk of bladder injury from a normal psychiatric dose of ketamine is literally zero. But I’ve never heard of it happening.

Same with the cognitive risks of ketamine. See eg Controversies of the effect of ketamine on cognition, which is speaking for the psychiatric consensus when it says that “Although ketamine might seem like a promising antidepressant that could relieve treatment refractory depressive symptoms, the induction of memory impairments in the longer term is of concern”. Against this, I present Morgan, Muetzelfeldt, and Curran, who study ketamine abusers for one year. They find that severe abusers, who are taking an average of 60,000 mg/month, experience cognitive problems. But mild abusers, who take more like 3,500 mg/month, don’t. Again, psychiatric patients are taking about 280 mg/month. I think this is pretty strong evidence that the psych patients shouldn’t worry that much.

II.

Every so often somebody realizes that there’s not much chemical difference between methamphetamine and Adderall. Then they freak out that we give ADHD kids Adderall all the time. Isn’t that like giving them crystal meth?

See eg Shoblock et al:

Despite the repeated claims of METH being more addictive or preferred than AMPH, proven differences between METH and AMPH in addiction liability and in reward efficacy have evaded researchers. Animals self-administer METH and AMPH at comparable rates (Balster and Schuster 1973) and humans prefer similar doses (Martin et al. 1971). Also, neither humans nor animals discriminate between equal doses of METH and AMPH (Huang and Ho 1974; Kuhn et al. 1974; Lamb and Henningfield 1994). Furthermore, while METH is commonly believed to be a more potent central psychostimulant than AMPH, no direct comparison on the potency of the two drugs to stimulate central processes have been verified. In addition, no previous study has directly compared the acute effects of the two drugs on locomotor activity, an important central process that contributes tothe definition of psychostimulant. Moreover, there are no known neurobiological differences in action between METH and AMPH that would account for the putatively greater addictive, rewarding, or psychomotor properties of METH.

So should we be less concerned about methamphetamine? More concerned about Adderall? Or what?

The average crystal meth addict uses about 500 mg a day. And they snort it, which probably produces about double the peak plasma level as taking it orally. So they’re getting the equivalent of 1000 mg oral amphetamine daily. The average Adderall patient takes 20 mg. The most important reason meth makes your teeth fall out and ruins your life but Adderall just makes you study a little harder is that the meth users are taking 50x higher doses (yeah, okay, there are also some pharmacokinetic differences, but those are less important). Drug users really do use a lot of drugs!

I recently had a patient stop their Adderall after reading this paper on how amphetamines appear to accelerate cardiovascular aging. The study was done on polysubstance abusers who were probably taking 50x higher doses than they were. This Reuters article on the study actually gets this exactly right, and has an interview with an expert saying the doses are so high that it can’t be extended to clinical practice. I don’t want to claim total victory here, because nobody’s done a study on clinical users proving they don’t get accelerated aging. But given the high doses necessary to produce the small effects found in the original paper, I’m not losing sleep.

III.

In general, recreational drug users take their drugs at doses so much higher than psychiatric patients that they’re basically two different chemicals. A lot of our impressions of drugs, what side effects they have, and how dangerous they are, get shaped by the recreational users, not the patients. This is sometimes even true for the doctors who are supposed to prescribe to the patients and give them good advice. While studies of recreational user populations can sometimes be helpful in flagging an issue for consideration, we should be judging the clinical risks based on studies of clinical populations.

This isn’t medical advice. Don’t go out and take a mix of ketamine and amphetamine, then tell the cops that it was “just a clinical dose” and “this blog on the Internet told me it was okay”.