How Do Hallucinogen Drugs Induce Hallucinations?

A new study comes to solve the mystery surrounding the brain mechanism that induces hallucinations due to the intake of hallucinogen drugs, like LSD, mescaline and psilocybin.

This research also explains the pathway followed by drugs employed for treating neuropsychiatric disorders, largely used but without an understanding of their basic mechanism.

It was long known that hallucinogens turn on specific brain receptors, called 5-HT2A receptors (2ARs), that are in normal physiological conditions activated by the neurotransmitter serotonin, the "happiness" hormone.

Neurotransmitters are chemical compounds that one neuron expels to the receptors of another, at the place of the synapse, to start a nerve impulse in the receiving cell.

The research solved a fundamental puzzle: why other chemicals that activate the same receptors are not hallucinogenic (here enter many other drugs that only give the "high" sensation).

The team investigated the differences between the effects of LSD and a non-hallucinogenic compound that also turns on 2AR receptors on the mouse neurons.

As the animals could not communicate the kinds of perception-altering effects like humans on hallucinogens, the scientists assessed hallucinogenic effects by measuring a characteristic head twitch in mice, displayed only under hallucinogens but non existent in case of non-hallucinogen drug intake.

The team focused its research on the brain cortex, proven by previous studies to be the center target for the action of the hallucinogens.

The investigation showed that LSD induced genetic, electrophysiological and internal cellular signaling responses that were very different from those provoked by a non-hallucinogenic drug.

The researchers also looked if 2ARs were central to the hallucinogenic effect of LSD by engineering mice devoid of the receptors, but in which receptors could be selectively reactivated in the cortex.

Animals lacking active receptors displayed no hallucinogenic behavior to LSD, but reactivating the receptors turned LSD hallucinogenic in animals.

"These studies identify the long-elusive neural and signaling mechanisms responsible for the unique effects of hallucinogens," wrote the researchers.

"The strategy we developed to elucidate [hallucinogen] action should be applicable to [central nervous system]-active compounds, with therapeutic potential in other disorders. Thus, our findings may advance the understanding of neuropsychiatric disorders that have specific pharmacological treatments whose mechanisms of action are not fully understood."