"There's this huge body of literature about these compounds, and I think this paper begins to nail down how the heck they're working in the brain," says Bryan Roth, a pharmacologist at the University of North Carolina at Chapel Hill. "It's not the end of the story, but I'd say it's the end of the beginning of the story."
Since the 1980s researchers in this field have agreed that LSD, which was first synthesized by Swiss scientists in 1938, likely affects serotonin 2A receptors in the brain (serotonin is a neurotransmitter suspected to play a role in the communication of mood and consciousness). These receptors show up in many places in the brain, including several areas in the cortex (known for sensory perception), and the thalamus (an interior region known for relaying messages to the cortex as well as regulating arousal and awareness).
The current research was performed by creating a mouse model that enabled scientists to observe behavioral and cell-signaling responses to hallucinogenic drugs by comparing them with those triggered by lisuride, an anti-Parkinson's disease drug chemically similar to LSD that does not have hallucinogenic effects. After determining that mice given psychedelic drugs consistently experience head twitching, the team bred mice with the serotonin 2A receptor knocked out to determine whether the hallucinogens still caused head twitching.
After testing many candidate regions, the researchers localized the effects of hallucinogens to the pyramidal neurons in layer V of the somatosensory cortex, a relatively high-level region known to modulate the activity of other sections in the cortex and subcortical areas. Using what he calls an "imperfect but usual analogy," Stuart Sealfon, a neurologist at Mount Sinai Hospital in New York City likens the receptors to a lock into which both hallucinogenic and nonhallucinogenic keys fit. While LSD may turn this lock to the right, kicking off one set of responses, lisuride turns the tumbler to the left, an action that only causes a subset of those responses. "Both the hallucinogens and the nonhallucinogens activate what we would call the classical signaling cascade downstream of this receptor in these cells," Sealfon says. "But, the hallucinogens, we show, are activating an additional signaling cascade and we believe the sum of both of them together is probably what causes the effect we see."
U.N.C., Chapel Hill's Roth says that the new study's localization of LSD's effect on the pyramidal neurons in level V makes sense. "We know that LSD profoundly affects human consciousness and awareness & so this tells us that the receptor on those neurons is an important locus for modulating consciousness," he explains. "If you muck up the actions of those neurons, it wouldn't be so surprising that you would affect consciousness."
Still, the finding does not appear to have silenced the debate.
While Roth concedes that cortical serotonin 2A receptors are likely part of the mechanism of hallucinogenic drugs, Dave Nichols, a molecular pharmacologist at Purdue University, believes the thalamus must be involved in some manner. "The thalamus is the major relay station for sensory information that is sent to the cortex, and there are serotonin 2A receptors localized in the thalamus and the reticular nucleus of the thalamus, which controls the flow of information through the thalamus," he argues. "For the authors to say that a unique mechanism has been identified that does not involve the thalamus, I therefore think cannot be correct."
While consensus on the exact way hallucinogens work may be a ways off, Sealfon says the research goes far in demystifying the effects of drug abuse. Also, he notes, drugs similar to LSD are routinely prescribed to patients suffering from mental illnesses, often without doctors' full understanding their effects. "If you could understand what makes a drug like LSD or mescaline have such a dramatic effect, then the principles behind that and the approaches developed for [gaining that understanding] can be applied to drugs that are used to treat neurological and psychiatric conditions," he says, adding that doctors can then "identify what drugs will have less side-effects and more specific effects"