Do any drugs cause sensitivity rather than tolerance?

A lot of drugs, be they therapeutic or recreational, are known for causing the body to develop a tolerance to them: after taking them for a certain period of time (or sometimes even just once), you need to take a greater quantity to achieve the same effect. Often the tolerance wears off after discontinuing the drug for a time, in which case a new course of treatment can begin at the original dose.

Are there any drugs that work the opposite way, where the longer you take them, the less you need to take to get the same effect? Note that I’m not talking about side-effects here, but rather the actual intended therapeutic or recreational effect. I know from personal experience there are some medications where the incidence of unwanted side-effects increases the longer you take them.

I know that with late stage alcoholism, once your liver gets pickled, you cannot hold booze at all. A beer for a long term alcoholic will get him drunk. I’m not sure if that is what you asked for, though.

Yeah, that sounds like an example of what I’m talking about, I suppose. Anyone know of any other examples?

I don’t know how solid the science is on this, but it’s a common tale that first-time cannabis users often don’t get high. According to this hastily-googled reference:

As I said, though, I don’t know if that’s been conclusively established.

It certainly happened with me. The first and only time I tried it, I felt nothing. On the other hand, the stuff was home-grown in an apartment without artificial lights, so who knows how much active ingredient it had. That was more than 55 years ago, since it was before I gave up smoking.

Not in a you-need-less-to-get-the-therapeutic-effect sense, but a couple of years ago, kaylasmom, after taking lisinopril for some four years, suddenly developed a sensitivity to it.

Angioedema is fucking ALARMING. On the plus side, it tends to get you to the head of the line in the ER waiting room.

Yeah, I think it took until the third time before I got high. It’s quite possible I just didn’t recognize being high the first time or two, but I don’t remember feeling anything out-of-the-ordinary, and it was explained to me at the time that that wasn’t an unusual reaction for a beginner.

I couldn’t find anything about initial effects (and I don’t remember anything like this myself - but then it was a long time ago); but I did see a lot about downregulation of receptors (reduction in receptor numbers) with chronic cannabis use. Here are a couple of examples (neither of which I have read through):

I can’t think immediately of any drug where the primary (ie intended) pharmacological effects increase with use, but I think that an increase in other effects (I mean adverse reactions) with use is fairly common with some classes of biological drugs. I’m thinking particularly of the early non-human derived monoclonal antibodies, where late-onset allergic-type reactions were fairly common. Not at all my area of expertise - my lay-ish way of thinking of it was that the body eventually figures out - hey, wait a minute, these MCAs seem just a bit too mousey for my liking - and reacted accordingly.

(Brief wiki summary on chimeric antibodies, including link to main article).


Postscript: again, it’s not quite what you’re looking for, but many (virtually all?) vaccines contain adjuvants, whose role is to cause an immune system reaction and recruit white blood cells to the injection site to get exposed to the vaccine antigen. Maybe enough repeat exposures to the same adjuvant could cause a larger reaction over time? I’m speculating (and thinking of biologically derived adjuvants, which are (I think) little used in the US). Speculating, merely speculating.

Do side effects count? Because at least one of the common side effects of oxaliplatin (peripheral neuropathy) certainly increases over time.

Before using weed for the first time, I’d read one or more articles saying that feeling anything the first time took some work: inhale deeply and hold and keep smoking. That definitely turned out to be the case, but it finally “worked”.

I am curious about the mechanism for the effect — my assumption (based on nothing substantial) was that the user was activating some dormant neural pathways and over-riding some default perception patterns. However, if weed is usually more effective on the second or third attempt (even when you didn’t feel it on earlier tries), then maybe there is a multiplying of cannabinoid receptors, or they become more sensitive.