What would you see if you could look inside a hallucinating brain? Despite decades of scientific investigation, we still lack a clear understanding of how hallucinogenic drugs such as LSD (lysergic acid diethylamide), mescaline, and psilocybin (the main active ingredient in magic mushrooms) work in the brain. Modern science has demonstrated that hallucinogens activate receptors for serotonin, one of the brain’s key chemical messengers. Specifically, of the 15 different serotonin receptors, the 2A subtype (5-HT2A), seems to be the one that produces profound alterations of thought and perception. It is uncertain, however, why activation of the 5-HT2A receptor by hallucinogens produces psychedelic effects, but many scientists believe that the effects are linked to increases in brain activity. Although it is not known why this activation would lead to profound alterations of consciousness, one speculation is that an increase in the spontaneous firing of certain types of brain cells leads to altered sensory and perceptual processing, uncontrolled memory retrieval, and the projection of mental “noise” into the mind’s eye.

The English author Aldous Huxley believed that the brain acts as a “reducing valve” that constrains conscious awareness, with mescaline and other hallucinogens inducing psychedelic effects by inhibiting this filtering mechanism. Huxley based this explanation entirely on his personal experiences with mescaline, which was given to him by Humphrey Osmond, the psychiatrist who coined the term psychedelic. Even though Huxley proposed this idea in 1954, decades before the advent of modern brain science, it turns out that he may have been correct. Although the prevailing view has been that hallucinogens work by activating the brain, rather than by inhibiting it as Huxley proposed, the results of a recent imaging study are challenging these conventional explanations.

The study in question was conducted by Dr. Robin Carhart-Harris in conjunction with Professor David Nutt, a psychiatrist who was formerly a scientific advisor to the UK government on drugs policy. Drs. Carhart-Harris, Nutt, and colleagues used functional magnetic resonance imaging (fMRI) to study the effects of psilocybin on brain activity in 30 experienced hallucinogen users. In this study, intravenous administration of 2 mg of psilocybin induced a moderately intense psychedelic state that was associated with reductions of neuronal activity in brain regions such as the medial prefrontal cortex (mPFC) and the anterior cingulate cortex (ACC).

The mPFC and ACC are highly interconnected with other brain regions and are believed to be involved in functions such as emotional regulation, cognitive processing, and introspection. Based on their findings, the authors of the study concluded that hallucinogens reduce activity in specific “hub” regions of the brain, potentially diminishing their ability to coordinate activity in downstream brain regions. In effect, psilocybin appears to inhibit brain regions that are responsible for constraining consciousness within the narrow boundaries of the normal waking state, an interpretation that is remarkably similar to what Huxley proposed over half a century ago.

The findings reported by Dr. Carhart-Harris are notable because they run counter to the results of previous imaging studies with hallucinogens. Generally, these imaging studies in humans have confirmed what previous studies in animals had suggested: hallucinogens act by increasing the activity of certain types of cells in multiple brain regions, rather than by decreasing activity as indicated by Dr. Nutt’s fMRI study. For example, Positron Emission Tomography (PET) experiments conducted by Dr. Franz Vollenweider in Zürich demonstrated that administration of psilocybin orally to humans increases metabolic activity in mPFC and ACC, effects that were found to be directly correlated with the intensity of the psychedelic response. Preclinical studies, using a variety of different techniques, have shown that hallucinogens increase network activity in the prefrontal cortex and in other cortical regions by activating excitatory and inhibitory neurons, leading to increased release of excitatory and inhibitory neurotransmitters.

Given those earlier findings, the fMRI data reported by Dr. Nutt’s group are somewhat surprising. Methodological issues (such as route of administration, dose, and the spectrum and extent of psilocybin-induced symptoms) may be at least partially responsible for these differences, since the processes being measured are not identical. It is also important to consider that the 5-HT2A receptor is not the only type of serotonin receptor that is activated by psilocybin. Dr. Vollenweider’s experiments have confirmed that the increase in metabolic activity detected by PET is mediated by the 5-HT2A receptor (the serotonin receptor responsible for the psychedelic effects of psilocybin). Because Dr. Nutt’s group did not conduct a similar test to verify that the effects they observed are mediated by the 5-HT2A receptor, this would be a logical next step.

Hopefully, follow-up studies will provide an explanation for these discrepant findings, and will settle the debate over whether hallucinogens act by increasing or reducing brain activity. Clinical trials are currently being conducted to investigate whether hallucinogens can be used to relieve stress and anxiety in terminal cancer patients, to attenuate the symptoms of obsessive-compulsive disorder, and to reduce the frequency of cluster headaches, so it is important to determine the mechanism for the therapeutic effects of hallucinogens. Additionally, there appears to be some overlap between the effects of hallucinogens and the symptoms of psychosis, so understanding how hallucinogens work could potentially provide insight into the causes of schizophrenia and facilitate the development of more effective treatments. In any event, it is important to note that studies have consistently identified the mPFC and ACC as playing key roles in mediating the effects of hallucinogens. In light of what is known about the core functions of these brain regions, it is not unreasonable that they would be involved in mediating the effects of hallucinogenic drugs. Therefore, although it is not yet clear whether hallucinogens act on the mind through the mechanism proposed by Huxley, it appears that we have succeeded in identifying some of the key brain regions targeted by these powerful agents.

Adam Halberstadt is a postdoctoral fellow in the Department of Psychiatry at the University of California San Diego. He studies the serotonin system and its involvement in psychiatric disorders. Mark Geyer is a Distinguished Professor of Psychiatry and Neurosciences at the University of California San Diego. His laboratory uses animal models to study human drug effects and schizophrenia. He is also a co-founder of the Heffter Research Institute, an organization that promotes scientific research with hallucinogens.

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