In short: classic psychedelics mainly activate one type of serotonin receptor. Ketamine blocks a glutamate receptor. MDMA releases serotonin and other brain chemicals. All three appear to make the brain temporarily more flexible, but much of that evidence comes from animal studies, and the full picture is far from settled.
Three different families
“Psychedelic” is used loosely. The substances in this library fall into three broad groups, and they work in different ways.
| Group | Examples | Main target |
|---|---|---|
| Classic psychedelics | Psilocybin, LSD, DMT, 5-MeO-DMT, mescaline, 2C-B | Serotonin 2A receptors |
| Dissociatives | Ketamine, esketamine | NMDA receptors (glutamate system) |
| Entactogens | MDMA | Release of serotonin, plus noradrenaline, dopamine and oxytocin |
Ibogaine and salvia (salvinorin A) don’t fit neatly into any group. Ibogaine acts on many systems at once. Salvinorin A acts on kappa-opioid receptors.
Classic psychedelics: the serotonin 2A receptor
Serotonin is one of the brain’s messenger chemicals, and it acts through more than a dozen receptor types. Classic psychedelics activate one of them, the 5-HT2A receptor, which is especially common in the brain’s outer layer (the cortex).
The best evidence that this receptor matters comes from blocking it. When volunteers took ketanserin, a drug that blocks 5-HT2A receptors, before psilocybin, the psychedelic effects largely disappeared.1 Psilocybin itself is a “prodrug”: the body converts it into psilocin, which does the work.
Ketamine: a glutamate surge
Glutamate is the brain’s main “go” signal. Ketamine blocks NMDA receptors, one of glutamate’s main receptors. The leading theory is a little counterintuitive. Blocking NMDA receptors on certain inhibitory cells briefly increases glutamate activity elsewhere. That burst switches on growth signals, including a protein called BDNF, which helps brain cells form new connections.
In mice, a single dose of ketamine rapidly increased the number of synapses (connections) in the prefrontal cortex, a region involved in mood and decision-making.2
MDMA: a different mechanism
MDMA mostly works by making neurons release stored serotonin, along with noradrenaline, dopamine and the bonding hormone oxytocin. People often describe feeling less fear and more connection, which is why it has been studied alongside psychotherapy for PTSD. It’s usually not called a classic psychedelic because it doesn’t cause strong visual changes at typical doses.
A shared idea: a window of plasticity
Neuroplasticity is the brain’s ability to change its wiring. Several lines of research suggest these substances increase it, at least for a while.
- In lab dishes and animals, psychedelics made neurons grow more branches and connections.3
- In mice, a single dose of psilocybin increased connections in the frontal cortex, and many were still there a month later.4
- A 2023 mouse study suggested several psychedelics can reopen a “critical period”, a stretch of time when the brain is more open to learning from social experience.5
Many researchers think this window helps explain why the therapy around the experience matters: the brain may be more open to change, so what happens during and after the session could shape the result.
Brain networks and the “default mode network”
Brain imaging shows psychedelics change how brain regions talk to each other. One network in particular, the default mode network, is active when we daydream, think about ourselves or ruminate. Early imaging studies found psilocybin reduced activity and coordination in this network.6 A popular theory proposes that psychedelics loosen the brain’s firmly held beliefs and habits of thought, which might allow stuck patterns, like the repetitive negative thinking common in depression, to shift.7
These are theories supported by early evidence, not established facts.
What we still don’t know
- Whether the experience is necessary. Some companies are developing psychedelic-like drugs that don’t cause a “trip”. Whether they help as much is an open question.
- How much animal findings apply to people. We can’t yet directly count new connections in a living human brain.
- Why effects last. A single psilocybin session can be followed by weeks of improvement, long after the drug has left the body. The reason isn’t known.
- Ketamine’s full mechanism. A small study suggested the brain’s opioid system plays a role in ketamine’s antidepressant effect; other research disagrees.
Sources
- Vollenweider FX, et al. Psilocybin induces schizophrenia-like psychosis in humans via a serotonin-2 agonist action. NeuroReport, 1998. PubMed
- Li N, et al. mTOR-dependent synapse formation underlies the rapid antidepressant effects of NMDA antagonists. Science, 2010. PubMed
- Ly C, et al. Psychedelics promote structural and functional neural plasticity. Cell Reports, 2018. PubMed
- Shao LX, et al. Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron, 2021. PubMed
- Nardou R, et al. Psychedelics reopen the social reward learning critical period. Nature, 2023. PubMed
- Carhart-Harris RL, et al. Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin. PNAS, 2012. PubMed
- Carhart-Harris RL, Friston KJ. REBUS and the anarchic brain: toward a unified model of the brain action of psychedelics. Pharmacological Reviews, 2019. PubMed