No single chemical flips a switch in the brain to produce hallucinations. Serotonin is the molecule most strongly linked to the vivid perceptual distortions caused by classic psychedelics, but dopamine, glutamate, and acetylcholine each trigger hallucinations through their own distinct pathways. The honest picture is that hallucinations arise when the brain’s normal system for sorting real signals from internally generated ones breaks down, and that breakdown can be caused by too much of one chemical, too little of another, or a disrupted conversation between several at once.
Serotonin and the 5-HT2A Receptor
When people think of hallucination-causing chemicals, serotonin is usually the first answer, and for good reason. Classic psychedelics like LSD, psilocybin (the active compound in “magic mushrooms”), and mescaline all work primarily by activating a specific type of serotonin receptor called 5-HT2A. These receptors are found throughout the cerebral cortex but are densely concentrated on a particular class of brain cells: pyramidal neurons in layers deep within the cortex. The densest clustering sits along the parts of those cells closest to the cell body, forming what researchers have described as a “hot spot” for the receptor’s effects on both normal and altered mental states.1PubMed. 5-Hydroxytryptamine2A serotonin receptors in the primate cerebral cortex: possible site of action of hallucinogenic and antipsychotic drugs in pyramidal cell apical dendrites
What makes this receptor so important is not just that psychedelics bind to it but what happens downstream. When a hallucinogen activates 5-HT2A receptors on cortical pyramidal cells, it amplifies glutamate signaling in the cortex, boosting certain components of communication between neurons that are not normally that strong. Researchers have proposed that this surge in glutamate-driven excitation is what produces the higher-level distortions in thinking, perception, and emotion that define a psychedelic experience.2PubMed. Serotonin and hallucinogens In other words, serotonin is the trigger, but glutamate is doing a lot of the heavy lifting in terms of what the person actually experiences.
The involvement of 5-HT2A receptors extends beyond recreational drug use. People with Parkinson’s disease who experience visual hallucinations show increased 5-HT2A receptor binding across multiple brain regions, including the visual cortex, prefrontal cortex, and areas involved in face and object recognition. This increase occurs independently of their medication dose, suggesting the receptor plays a role in hallucinations driven by neurodegeneration as well.3JAMA Neurology. Serotonin 2A Receptors and Visual Hallucinations in Parkinson Disease
Dopamine and Hallucination-Like Perception
If serotonin is the chemical behind psychedelic hallucinations, dopamine is the chemical most associated with the hallucinations of psychosis. The “dopamine hypothesis” of schizophrenia has been around for decades, and it is grounded in a straightforward observation: drugs that block dopamine receptors tend to stop psychotic hallucinations, while drugs that flood the brain with dopamine (like high doses of amphetamines) can cause them.
Recent work has moved beyond correlation to show a more direct causal link. A 2021 study in mice found that hallucination-like perceptual errors were preceded by spikes in dopamine levels in the striatum, a brain region involved in reward and action selection. Artificially stimulating the dopamine neurons projecting into that area produced the same hallucination-like behavior, and the antipsychotic drug haloperidol reversed it.4PubMed. Striatal dopamine mediates hallucination-like perception in mice That is about as clean a causal chain as neuroscience gets in animal models: more dopamine led to false percepts, less dopamine stopped them.
In humans, the story is consistent. Imaging studies of people with schizophrenia have found that greater dopamine release capacity in the striatum correlates with a reduced ability to adjust perceptions based on uncertainty. In practical terms, people with higher dopamine tone tend to overweight their brain’s predictions about what they expect to see or hear, making them more prone to perceiving things that are not there.5Current Biology. Striatal Dopamine Determines Susceptibility to Apparent Hallucinations in Schizophrenia This dovetails with a broader theory about hallucinations that we will come back to: the brain generates predictions about the world, and when those predictions become too strong or too rigid, you start perceiving things that exist only in your head.
Glutamate and the Ketamine Route
Glutamate is the brain’s main excitatory chemical messenger. It is involved in nearly every brain process, so it might sound too general to point to as a hallucination cause. But a specific disruption of glutamate signaling produces a very specific kind of hallucinatory experience, best illustrated by ketamine.
Ketamine blocks NMDA receptors, which are a major type of glutamate receptor. The hallucinations it produces tend to feel different from those caused by serotonergic psychedelics: users often describe dissociative experiences, distortions of body perception, and a dreamlike detachment from reality rather than the vivid geometric patterns typical of LSD or psilocybin. Researchers have proposed that ketamine disrupts the brain’s ability to balance its internal predictions against incoming sensory information, effectively amplifying neural “noise” from the bottom up while the brain’s top-down prediction systems scramble to make sense of it.6PubMed Central. Ketamine-Induced Hallucinations
This glutamate disruption also connects back to serotonin. As noted earlier, when classic hallucinogens activate 5-HT2A receptors, one of the downstream effects is a boost in glutamate signaling in the cortex. So even though serotonin and glutamate are different chemicals acting through different receptors, they converge on a shared downstream mechanism: too much excitatory activity in the cortex, with the brain’s internal models overriding or distorting what the senses are actually reporting.
Acetylcholine and Deliriant Hallucinations
Acetylcholine is a chemical messenger involved in attention, memory, and the regulation of sleep-wake cycles. Unlike the previous examples where adding a substance triggers hallucinations, the acetylcholine pathway illustrates the opposite principle: taking acetylcholine away can cause them.
Drugs that block muscarinic acetylcholine receptors, known as anticholinergics, are among the oldest known hallucinogens. Atropine and scopolamine, found naturally in plants like belladonna and jimsonweed, produce a distinctive kind of hallucination: vivid, often realistic and terrifying visual images, accompanied by confusion, disorientation, and memory loss. Unlike psychedelic hallucinations, which users typically recognize as not real, anticholinergic hallucinations tend to be indistinguishable from reality to the person experiencing them.7ACS Chemical Neuroscience. DARK Classics in Chemical Neuroscience: Atropine, Scopolamine, and Other Anticholinergic Deliriant Hallucinogens
This is not just a historical curiosity. Anticholinergic side effects are a common cause of hallucinations in hospital settings, particularly among older adults taking multiple medications. A case report documented a patient who developed sudden disorientation, behavioral changes, and visual hallucinations that resolved dramatically once an anticholinergic medication was stopped.8PubMed Central. Delirium secondary to anticholinergics The lesson here is that hallucinations are not only about chemicals being present in excess; they also arise when a chemical the brain depends on for stable, grounded perception gets suppressed.
The Thalamus as a Gatekeeper
Chemicals do not act in isolation. They alter the behavior of brain circuits, and one circuit that keeps appearing across different types of hallucination is the connection between the thalamus and the cortex. The thalamus functions as a relay station, filtering and routing sensory information to the appropriate cortical regions. When that filtering breaks down, the cortex gets flooded with signals it cannot properly sort.
Brain imaging studies have found a remarkably similar pattern across both psychotic states and psychedelic experiences: the thalamus becomes hyperconnected to sensory and motor areas of the cortex while becoming hypoconnected to prefrontal regions responsible for executive control and reality testing. In psychosis, this pattern tracks with the severity of symptoms like hallucinations and cognitive disturbance. In psychedelic states, the same thalamus-to-sensory-cortex hyperconnectivity correlates with altered visual and auditory perceptions.9PubMed Central. Bridging the Gap? Altered Thalamocortical Connectivity in Psychotic and Psychedelic States
This disrupted thalamic filtering creates what amounts to an input overload: too much raw sensory-like information reaches the cortex while the prefrontal regions that would normally flag it as internally generated go quiet. The result is that the brain’s default mode network, which is involved in self-referential thinking and internal narrative, decouples from the networks that handle external tasks, producing dreamlike or dissociative states.10PubMed Central. The central role of the Thalamus in psychosis, lessons from neurodegenerative diseases and psychedelics Whether the chemical trigger is serotonin, dopamine, or glutamate, disrupted thalamic gating appears to be part of the final common pathway.
When the Brain’s Prediction Engine Misfires
Across all these different chemicals and circuits, a unifying theory has emerged: hallucinations happen when the brain’s internal predictions override actual sensory input. Your brain does not passively receive information from the world. It constantly generates models of what it expects to see, hear, and feel, and then checks those models against what the senses actually report. When incoming data matches the prediction, perception feels normal. When there is a mismatch, the brain updates its model.
Hallucinations, under this framework, are what happen when the brain’s predictions become too strong, too rigid, or too disconnected from the error-correction signals that would normally keep them in check. Researchers have described hallucinations as “top-down effects on perception, mediated by inappropriate perceptual priors,” meaning the brain’s expectations essentially become so powerful that they manufacture sensory experience without any real-world input to justify it.11PubMed Central. Hallucinations as top-down effects on perception
This framework explains why so many different chemicals can cause hallucinations. Dopamine makes predictions stickier and harder to override. Serotonin-driven glutamate surges amplify cortical activity, making internally generated signals look and feel like real ones. Anticholinergics impair the brain’s ability to stay oriented and distinguish memory from perception. Ketamine blocks the error-correction signals that would normally dampen false predictions. Different chemicals, same outcome: the brain’s prediction engine runs unchecked.
The Excitation-Inhibition Balance
Another way to frame the chemistry of hallucinations is as a problem of balance. The brain maintains a careful equilibrium between excitatory signals (which activate neurons) and inhibitory signals (which quiet them down). GABA, the brain’s primary inhibitory messenger, plays a critical role in this balance. When GABA transmission is impaired or when the receptors that rely on it malfunction, the excitatory side wins, and cortical areas that process sensory information can become hyperactive.
Research has linked hallucinations to multiple signs of inhibitory failure: impaired GABA transmission, altered NMDA receptor function, reduced high-frequency brain oscillations that depend on inhibitory circuits, excessive activity in sensory cortex regions, and deficits in cognitive inhibition (the ability to suppress irrelevant information).12PubMed Central. Are Hallucinations Due to an Imbalance Between Excitatory and Inhibitory Influences on the Brain? In this view, it is not just about having too much of one chemical. It is about the ratio between excitation and inhibition tipping in the wrong direction.
Less Obvious Chemical Players
Beyond the big four of serotonin, dopamine, glutamate, and acetylcholine, several other chemical systems contribute to hallucinations in less well-known ways.
The kappa-opioid system provides one of the more surprising examples. Salvinorin A, the active compound in the plant Salvia divinorum, is a potent hallucinogen that works entirely through kappa-opioid receptors, with no significant activity at serotonin receptors. Its effects are short-lived but intense: users report vivid, immersive hallucinations that differ qualitatively from anything produced by classic psychedelics. The fact that activating the kappa-opioid system and its natural counterpart, the dynorphin system, can produce hallucinations implicates these pathways in higher cognitive and perceptual functions that researchers are still working to understand.13PubMed Central. Salvinorin A, a kappa-opioid receptor agonist hallucinogen: pharmacology and potential template for novel pharmacotherapeutic agents in neuropsychiatric disorders
The endocannabinoid system, which includes the brain’s own cannabis-like molecules, has also been implicated. In people with schizophrenia, studies have found increased density of CB1 cannabinoid receptors in subregions of the prefrontal cortex and elevated levels of anandamide (an endogenous cannabinoid) in cerebrospinal fluid.14PubMed Central. New perspectives in the studies on endocannabinoid and cannabis: cannabinoid receptors and schizophrenia Whether these changes are a cause of psychotic symptoms or a compensatory response to them remains an open question, but the connection is strong enough that it has attracted sustained research interest.
Trace amines represent an even newer frontier. A receptor called TAAR1 (trace amine-associated receptor 1) has attracted attention because it appears to inhibit both dopamine and serotonin signaling. Drugs that activate TAAR1 may offer a way to dampen the overactive dopamine and serotonin systems that drive hallucinations, without the heavy side effects of traditional antipsychotics.15Trends in Neurosciences. Trace amine-associated receptor 1: a new horizon in the pharmacotherapy of schizophrenia
Does the Brain Make Its Own Hallucinogens?
One of the more fascinating findings in recent years is that the mammalian brain naturally produces DMT (N,N-dimethyltryptamine), a compound that is also the active ingredient in the psychedelic brew ayahuasca. Researchers found that the enzymes needed to synthesize DMT are present in multiple brain regions, including the visual cortex, hippocampus, and pineal gland. Under normal conditions, rat brains contained detectable DMT at concentrations in the same general range as other monoamine neurotransmitters like serotonin and dopamine.16Scientific Reports. Biosynthesis and Extracellular Concentrations of N,N-dimethyltryptamine (DMT) in Mammalian Brain
What role endogenous DMT plays under normal circumstances remains unknown. The concentrations are low, and no one has shown that natural DMT levels rise high enough during any ordinary brain state to cause hallucinations. But the presence of the machinery to produce a potent hallucinogen right inside the brain has fueled speculation about whether near-death experiences, extremely vivid dreams, or certain meditative states might involve a spike in endogenous DMT production. The evidence for that is still speculative rather than established.
Hallucinations Without Any External Chemical
Not all hallucinations require a drug or a neurotransmitter disorder. Some arise simply because sensory input is reduced. Charles Bonnet syndrome occurs in people who have lost significant vision: their visual cortex, deprived of normal input, begins generating its own images. EEG studies of people with the condition have found that hallucinations emerge during periods when alpha-wave activity in the occipital (visual) cortex drops, suggesting that intermittent dips in baseline brain rhythms create the neural conditions for hallucinations to appear.17PubMed Central. EEG changes associated with hallucinations caused by Charles Bonnet Syndrome
In Parkinson’s disease, visual hallucinations are common and involve disrupted activity in the default mode network. Brain imaging has shown higher-than-normal co-activation within this network, particularly in the posterior cingulate and prefrontal cortex, in Parkinson’s patients who hallucinate compared to those who do not.18PubMed Central. The default mode network is disrupted in parkinson’s disease with visual hallucinations Combined with the serotonin receptor changes described earlier, these network-level shifts paint a picture of hallucinations emerging from a convergence of chemical and circuit-level dysfunction rather than any single broken part.
Sleep-related hallucinations offer yet another angle. The vivid imagery that occurs as you fall asleep (hypnagogic) or wake up (hypnopompic) shares some characteristics with waking hallucinations and with dreams. Some researchers have explored whether hallucinations in psychiatric conditions represent an intrusion of dream-like REM processes into waking consciousness, though the evidence for that model remains insufficient to make it a firm conclusion.19PubMed Central. What Is the Link Between Hallucinations, Dreams, and Hypnagogic–Hypnopompic Experiences?
Why Some People Hallucinate More Easily Than Others
Genetic variation helps explain why some individuals are more susceptible to hallucinations than others. A key finding involves two genes that affect the serotonin and dopamine systems. A specific variant of the serotonin 5-HT2A receptor gene (the T/T genotype of the T102C polymorphism), which implies stronger receptor binding, is associated with higher scores on a personality trait called absorption, which measures openness to unusual perceptual experiences. On its own, a variant of the COMT gene (which regulates dopamine breakdown) had no main effect, but the interaction between the two gene variants was significant, underscoring the functional interplay between serotonin and dopamine systems in shaping who is prone to hallucination-like experiences.20PubMed. Evidence for a common biological basis of the Absorption trait, hallucinogen effects, and positive symptoms: epistasis between 5-HT2a and COMT polymorphisms
This gene-gene interaction is a useful reminder that hallucinations rarely come down to a single chemical acting alone. The serotonin and dopamine systems are in constant dialogue, and individual differences in how those systems are tuned, whether by genetics, illness, medication, or aging, determine where someone falls on the spectrum between solid, grounded perception and experiences that drift into the hallucinatory.
Inflammation and Delirium
One cause of hallucinations that often surprises people is plain old inflammation. Hospital delirium, a state marked by confusion, agitation, and frequently vivid hallucinations, is strongly associated with elevated inflammatory markers in the blood. The evidence implicates inflammatory cytokines, the signaling molecules released during immune activation, as playing a role in the cognitive dysfunction seen in both delirium and dementia.21PubMed Central. The role of inflammation in the pathogenesis of delirium and dementia in older adults: a review
The mechanism is thought to involve cytokines crossing into the brain (or signaling through it indirectly) and disrupting neurotransmitter balance, particularly acetylcholine and dopamine. An older adult recovering from surgery or fighting a urinary tract infection may start seeing people who are not there, not because of a psychiatric disorder but because their immune response has temporarily destabilized the brain’s chemical equilibrium. This is one of the most common and most under-recognized causes of hallucinations in clinical practice, and it reinforces the point that the chemistry of hallucination is not just about recreational drugs or mental illness. Any process that pushes the brain’s chemical balance far enough off center can cause the perceptual machinery to generate false experiences.