Readers of a certain age will know the reference: This is your brain. This is your brain on drugs.

The simple PSA, put out by the Partnership for a Drug-Free America in 1987, accompanied these words with an image of an egg — first intact, then sizzling on a frying pan. Gripping stuff — but what do drugs do to your brain, really?

The answer to that question depends on the drug, of course, but researchers have found that one common thread is that drugs of abuse alter the brain's so-called mesolimbic pathway, known in plain English as the reward pathway. Substances act on this pathway in different ways, said Stella Vlachou, an assistant professor of psychology at Dublin City University in Ireland, but "one way or another, different drugs of abuse would definitely affect the brain's rewards system." [10 Things You Didn't Know About the Brain]

Reward circuits

This oh-so-crucial system consists of several brain structures that communicate closely with one another via nerve impulses. At one end, deep in the midbrain, is the ventral tegmental area. At the other are the nucleus accumbens and the olfactory tubercle, both found in a region called the ventral striatum in the forebrain. The main neurotransmitter responsible for firing off signals in this pathway is dopamine, which plays an excitatory role, stimulating neurons to fire. Dopamine is a major culprit in addiction, Vlachou told Live Science, though it plays a role in normal, healthy behaviors, too.

"It is released at higher levels when we are motivated to work on something that we like, when we have a strong desire about something, when we experience something we would call reward or pleasure," she said.

Whether directly or indirectly, habit-forming substances act upon this reward system. Psychostimulants such as cocaine and amphetamines affect levels of dopamine directly, Vlachou said. In contrast, other drugs — such as opioids, nicotine and even THC (tetrahydrocannabinol), the psychoactive ingredient in marijuana — act on neurotransmitters or their receptors that indirectly affect the amount of dopamine the brain releases or detects. Some drugs, Vlachou said, have even more complex actions, perhaps interacting with the molecules that shuffle neurotransmitters across the synapses, or gaps between neurons.  

Drug by drug

There are a lot of drugs out there, especially since the advent of synthetic compounds that can mimic naturally derived substances or combine the effects of the old standards. The National Institute on Drug Abuse (NIDA) curates a long list of drugs and their effects, but here are some highlights:

Marijuana: The psychoactive ingredient in cannabis is called delta-9-tetrahydrocannabinol, better known as THC. As the name suggests, THC is a cannabinoid, and it just so happens that the body has its own cannabinoid system, known as the endocannabinoid system. Endocannabinoid receptors are found in both the brain and the immune system. In the brain, they're linked to a huge range of functions, including memory, appetite, pain sensation and sleep. They're even partially responsible for the "runner's high" that comes from intense exercise — at least in mice. As one 2013 paper in the journal Cerebrum put it, "Given the enormous complexity of the brain, the endocannabinoid system could affect behavior in an almost limitless number of ways: Simple generalizations of what will happen when CB1 receptors are globally turned on or off are not feasible." (CB1 receptors are the most prominent cannabinoid receptors in the brain.)

Thanks to the widespread nature of the endocannabinoid system, it's no surprise that THC's effects on the brain are also widespread. By interacting with cannabinoid receptors in the hippocampus and the orbitofrontal cortex — two areas of the brain associated with attention and memory — THC can create short-term memory loss and impair thinking. There are also cannabinoid receptors in the cerebellum — the structure in the back of the brain that regulates movement — which explains why someone who's high on pot may not move quickly. And yes, the cascade of THC's effects also stimulates dopamine release, making the whole experience (usually) quite pleasant. [7 Ways Marijuana May Affect the Brain]

Nicotine: Present in tobacco products and e-cigarettes, nicotine is the stuff that makes smoking so addictive. By coincidence, nicotine is very similar in structure to a neurotransmitter called acetylcholine, Vlachou said. Once in the brain, nicotine binds to acetylcholine receptors. This abundance of compounds binding to the receptors prompts the brain to release less acetylcholine, meaning the person needs nicotine to feel normal, according to the NIDA.

But nicotine affects other neurotransmitters, too. Some of the acetylcholine receptors it binds to are on cells that are responsible for releasing dopamine, so nicotine indirectly increases dopamine, tickling those mesolimbic reward pathways. It may also affect dopamine through its interactions with acetylcholine receptors that control an inhibitory neurotransmitter called gamma-aminobutyric acid and an excitatory neurotransmitter called glutamate, which, in turn, can also influence how much dopamine is released.

Opioids: Opioids include naturally derived substances, like heroin, as well as synthetic ones, like fentanyl. They're powerful short-term painkillers because they act on opioid receptors in the brain and spinal cord, which — sensing a theme? — themselves evolved to respond to compounds produced naturally inside the body, including endorphins.

When stimulated by an opioid, whether homemade or not, these receptors inhibit the nerves from sending pain signals. But opioid receptors are also found across the brain, including in the rewards pathway, where they may be involved in pleasurable sensations associated with food and sex, according to a 2009 review. Repeatedly dosing oneself with substances like heroin or prescription opioids, though, prompts the brain to stop producing as many of its own opioids. This can lead to tolerance (the need to take more opioids to get high) and dependence (horrible withdrawal symptoms that drive people to take the drug simply to feel well), according to a 2002 review in the journal Addiction Science and Clinical Practice.

What makes opioids truly deadly, though, are their actions in the brain stem, which controls breathing and other basic, automatic functions. When a person takes a high level of opioids, the molecules inhibit the neurons in the brain stem that control breathing. The result is overdose, often fatal.

Cocaine: Cocaine affects dopamine levels in the brain directly, creating an extremely pleasurable rush as the neurotransmitter floods the mesolimbic reward system. Cocaine molecules bind to a protein in the brain called a dopamine transporter, which acts like a synaptic garbageman, clearing dopamine from the gaps between neurons so that it doesn't continually stimulate the nerve cells to fire. With cocaine as a hitchhiker, the dopamine transporter can't do its job. So dopamine builds up in the synapse, and nerve cells keep firing. It's euphoric in the short term but may rob the brain of gray matter in the long term, according to 2012 research.

Psilocybin: The active ingredient in "magic mushrooms" can create quite a trippy experience, with effects ranging from the sense that time is slowing down to the feeling of being one with the universe. Research suggests that psilocybin works mostly by mimicking the neurotransmitter serotonin. Serotonin plays an important role in how the brain processes emotions, and the frontal cortex — the seat of personality and complex thought — is abundant with serotonin receptors. [Trippy Tales: The History of 8 Hallucinogens]

That means psilocybin has strong effects on complex processes — it might even alter personality permanently. The hallucinatory effect that causes people to see auras or colorful trails behind moving objects seems to be linked to the way psilocybin alters the functional connections, or communication pathways, between brain regions, according to 2014 research. The drug seems to promote the appearance of strong, long-range connections that could explain why people using it feel more connected and creative.

Originally published on Live Science.

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