Who the hell gets miserable on MDMA? Or calm on speed, or aggressive on pot? Every group of friends has the rogue drug user with a strange reaction to a particular substance.

What’s unclear is why one person’s reaction to a drug can be so altogether different from another person’s. Is it genetic makeup, an interaction with other drugs, the wiring of the brain, or something else entirely?

We asked Stephen Bright, a psychologist and ethno-pharmacologist who teaches psychopharmacology at Edith Cowan University in Australia, to shed light on some of the more paradoxical drug reactions.

Why does MDMA make me feel tired and cold?

Just as everyone else feels up on MDMA, Sophie is overcome by exhaustion every time. In fact, she gets so sleepy and cold that she has to exit the dance floor and sit down, and eventually just go home. “My theory is that my heart can’t handle the stimulation so tries to shut me down,” she said, “but I can’t find any evidence of that because the internet is just full of chat about exhaustion the day after.”

Bright said this could be a result of the high potency of the MDMA she’s taking. “MDMA gives you the push, but too much of it makes you trip out and start seeing hieroglyphics on the wall, which is why it used to get called a ‘trippy pill’ in the old days,” he said. “With too much MDMA, people might call that a ‘smacky [opiate-like] pill’ because you just melt into your seat.”

A sense of fatigue can also come from the yawning response that some people have upon sudden serotonin release, Bright added. Taking MDMA messes with your body temperature, and researchers have hypothesized that yawning could be a way of cooling the brain when it overheats.

As for Sophie feeling cold, in 2002, US researchers measured the skin and core temperatures of eight subjects before and after dosing MDMA, and found that skin temperatures decreased as the body’s heat became concentrated at its center. Some MDMA users experience uncontrollable shaking, known as “tremors,” which are caused by overstimulation of nerve receptors (this occasionally happens with the use of SSRI antidepressants such as Prozac and Lexapro). “Her body temperature was probably going up, but she might have been feeling tremors and perceiving that as cold,” Bright surmised.

Why do stimulants like modafinil and meth make me feel so chill?

“I prefer to call my ADHD ‘Border Collie syndrome’," said Brad. "I need to have five or six frisbees thrown at me at the same time. If I don’t, I’ll tear the couch apart. I think it’s about needing rewards and stimulation all the time."

“I used to use meth a lot. It gave me positive thoughts and a sense of relief. I would feel an initial high, but then I'd feel focused and I could actually work on one thing instead of trying to do every job at once.” These days Brad uses modafinil, a prescription stimulant drug used to treat narcolepsy. So do stimulants mellow him out?

Firstly, as Bright explained it, the baseline level of dopamine is lower in people with ADHD, but their reward system is more sensitive than other people’s, which means they’re more likely to be drawn to anything shiny in the periphery, be it the coffee machine, their phone, a different conversation, or anything else distracting. Unmedicated, their attention will likely jump around. “By increasing their baseline level of dopamine with medication, they’re less distracted and more able to focus,” Bright explained.

The idea that people with ADHD are "calmer" when taking, say, Ritalin, is just because they’re able to focus better, not because it actually sedates them. As Yale neuroscientist Amy Arnsten put it in her paper Stimulants: Therapeutic actions in ADHD: “For years, it was assumed that stimulants had paradoxical calming effects in ADHD patients … It is now known that low doses of stimulants focus attention and improve executive function in both normal and ADHD subjects.”

Bright adds that people with ADHD can certainly still feel the upper effects of their medication if they try hard enough—Brad certainly felt the euphoria of the stimulants he took. “The route of administration makes a difference,” Bright said. “And someone taking prescribed speed for ADHD can up the dose and they’ll get a high like anyone else.”

Why does weed make me feel wide awake?

Jo has a chronic pain condition that’s moved her to seek out all kinds of self-medication. “I've tried smoking weed as a sleep aid but it leaves me awake for hours at night, especially if I smoke it or have too many edibles that are high in THC before bed,” she said. “I'm wide awake with a whirring brain, producing a bunch of increasingly expansive ideas and scenarios… it's really disruptive.”

Jo said using cannabis did not make her hyper until she had a “super-traumatic acid trip.” Now, she said, “smoking feels like sitting at the top of a roller coaster, with that anticipation and dread that comes with waiting for that big drop.”

Bright isn’t surprised that a bad experience on acid had that effect on Jo’s experience with cannabis. “If you’ve ever taken acid and smoked weed on top of it, it has a multiplication effect. Then if you smoke weed a couple days later, it feels like you're on acid again,” he said. Jo hadn’t done both together, but weed could still act like a trigger. “With drugs that are more ‘sideways moving’, like cannabis and psychedelics, the mindset and expectation are much more significant than with, say, a stimulant,” Bright said. “The interesting thing about cannabis is it’s not a stimulant, a depressant or a psychedelic. It causes tachycardia in most people—increased heart rate—and issues with motor coordination, and a perceptual shift. So set and setting are important. The person might get paranoid, depending on their environment.” As for the insomnia, he said: “If you’re not a frequent smoker, and particularly if you’re smoking something high in THC, there’s a lot of thinking going on in your head and you might not be able to turn the thinking process off.” Researchers from the National Center for PTSD-Dissemination & Training Division reviewed the literature on sleep and cannabis up to 2014 and found that while CBD may have therapeutic potential for the treatment of insomnia, THC may impair sleep quality long-term.

Why does my body reject alcohol?

There’s some truth in the idea that some people are born lightweights when it comes to booze, Bright said. It’s connected to the mechanism by which our bodies process alcohol. “Alcohol is broken down into acetaldehyde, which in turn is broken down by an enzyme, called alcohol dehydrogenase, into acetic acid, sugar and water,” he said. “If you haven’t produced enough of the enzyme by the morning, one of the reasons you’re going to feel sick is because you’ve still got this awful toxin, acetaldehyde, in your system.” Our ability to produce the enzyme that breaks down alcohol toxins is where we all differ.

Researchers in 2009 found that more than one in three people with East Asian heritage experience facial flushing when drinking alcohol. “There’s a gene variation more common among some East Asians that means they don’t produce enough alcohol dehydrogenase, so they get a flushing reaction and can become violently ill after just a few drinks,” said Bright. “It’s similar to the reaction of Antabuse, the drug used to treat alcohol dependence. That works by blocking the production of alcohol dehydrogenase so that you end up getting the effects of the acetaldehyde, making you feel so unwell that you don’t want to drink.”

It’s clear that even if we were aware of exactly what is in the drugs we are taking, their effects are not straightforward, because our individual biology is so complex.