Zeroing in on a group of cells in a high layer of the cortex, a team of researchers from Mount Sinai School of Medicine, Columbia University and the New York State Psychiatric Institute may finally have found the cause of the swirling textures, blurry visions and signal-crossing synesthesia brought on by hallucinogenic drugs like LSD, peyote and "'shrooms." The group, which published its findings in this week's issue of Neuron, may have settled a long-simmering debate over how psychedelic drugs distort human perception.

"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."

6 Comments

1. 1. Valvicus 10:20 AM 10/16/08

   "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."
   This sentence from the concluding paragraph of the article "How Hallucinogens Play Their Mind-Bending Games" reeks of pro forma accession to prevailing judgmental conservative pseudo-mores. In order to evince proper scientific detachment, Nikhil Swaminathan should have referred to, say, "... the effects of (psychotropic or psychedelic) (substances or drugs)."
   In covering such a research-oriented topic, SciAm needs to be vigilant in keeping such bias out of its articles.

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2. 2. Valvicus 10:21 AM 10/16/08

   Enter Your Comment Here."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."
   This sentence from the concluding paragraph of the article "How Hallucinogens Play Their Mind-Bending Games" reeks of pro forma accession to prevailing judgmental conservative pseudo-mores. In order to evince proper scientific detachment, Nikhil Swaminathan should have referred to, say, "... the effects of (psychotropic or psychedelic) (substances or drugs)."
   In covering such a research-oriented topic, SciAm needs to be vigilant in keeping such bias out of its articles.

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3. 3. magic mushroomer32 09:58 AM 12/18/08

   I LOVE SHROOMS MAN THEY ARE PRETTY SWEET AHAHAHAHAHA

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4. 4. artistkvip 04:57 AM 6/29/09

   how do theorize this information fits in with the fact that nmda inhibitors also can cause visual and auditory hallucinations. would this be part of the cascade of neurotransmitters, or is it also found in the lsd and peyote, or as a base causal agent. with the case study featured maybe being the minor cascade or do you theorize multiple ways to experience hallucinations? when dealing with the glutamate breakdown in the brain you are also dealing with nitrous oxide levels and other clearly functional interpretation modifiers when it comes to the senses. it may be possible most halucinations are more correctly explained as altered version of the way reality truly is, or the input from the senses is interpreted in the brain differently just as it is in all cases where the conscious level has been altered. Some simple examples are alcohol, and even sleepiness or severe illness causes a change in the conscious level.. The fact that auditory and sight and memory of the interpretation which we call hallcinations which I think would involve the limbic system, may be a clue on how a brain picture or memory is actually produced in the brain. The brain would have the ability to distort or imagine in normal function. why not the possibility that the brain is simply imagining with out realizing it is imagining or who is to say what reality actually looks like. I have experienced flashbacks from ptsd and they would seem to be some where between a hallucination and a memory. This brings up another reason to suspect the limbic system and nmda inhibitors causing hallucinations and the actual clinical studies which state that large doses of yohimbine can cause flash backs in a person with ptsd. It is a n-methy-D-aspartate (nmda) potentiator . My last twig to put on the pile is the fact that in certain instances ethanol can be a nmda inhibitor and it may explaining alcoholic hallucinations or the neurochemical process that causes them... thanks . artistkvip

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5. 5. artistkvip1 12:30 AM 10/20/10

   some other things which have occurred to me since posting this .. the fact that the way eye takes in information is it focuses on a narrow field or chunk then adds it to other ones in effect stitching them together to make a larger more complete picture and uses the difference in the angle of the two eyes to comprehend depth of field. The persistance of the memory is dependent upon the level of cortico steroids and other fight lite or freeze neurochemicals which alter the perception of time which is a for m of hallucination. which in effect sear in or burn in things where emotion either good or bad is present. That is why we remember the good times and the bad times with so much more clarity. Also i theorize these memories are in-coded in several different parts of the brain as i was unable for years to access some of my memory. Hallucinations could be the exaggerated process or the incorrect process of extrapolating the bigger picture from the series of small ones. who know what rue reality is there is the possibility that somethings we attribute to be hallucinations could be theoretically closer to the real veiw of the object or scene. I had vastly lessened short term memory because of an infection close to my brain and the ability to quickly reproduce a correct drawing or recreation of what i saw before me as an artist was one of the consequences during the period of lessened memory due also partially to the fact that you are on a lower for m of conciseness when you are very sick almost like you don't totally wake up. It is possible people we attribute to having higher iq's and smarter or just more awake than other people or in better physical health. It is possible aseptic meningitis may be the most under diagnosed serious illness in the world. . I SAY AGAIN ASCEPTIC MENINGITIS MAY BE THE MOST UNDER DIAGNOSED REAL UILLNESS IN THE WORLD BECAUSE IT CAN COME FROM SO MANY CONDITIONS WITH ARE CONSIDERED TO BE CHRONIC BUT NOT LIFE THREATENING, THE QUALITY OF LIFE POSSIBLE BY THE INDIVIDUAL IS THE THING THAT IS EFFECTED. I was like a comPuter with very little ram but it was the intake by my eyes or the number of different small pictures to put together that was limited. I theorize all p[people have different levels of awareness. In my photography now i seem to be able to see and take photographs of things in nature that are there for a spit second that others don't see because of not looking or being possibly unable to see what i see.

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6. 6. hot fries 05:20 AM 11/6/10

   I ate acid about four years ago and ever since then i havent been the same.It lead to serious drug problems because after eating acid im pretty sure i ended up with social phobia.Thats where the drug problems came into play.Now ive read up on social phobia and the medication for it which from what i read paxel should help but what im wondering is obviously it affected somethin in the limbic system but could that be a perminite promblem?ive read that social phobia is something that might be caused by how your childhood was and things like that but i didnt have this problem until i took the acid so could this be a problem that im gonna have to deal with for the rest of my life?Geeze i hope not that would suck!

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