Your Brain on LSD: Why Acid Trips Last So Long and Make Everything Seem So Meaningful.

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While LSD has been around since 1938, when it was synthesized by the Swiss scientist Albert Hoffman, how exactly it works has continued to be a mystery. As LSD research has picked up, two new studies provide insight on what happens to the brain on LSD, the common name for Lysergic acid diethylamide. One group of scientists figured out the structural changes LSD makes in the brain while the other looks at how LSD makes people create meaning.

Research published in Cell zeroed in at what LSD looks like when attached to a brain receptor.

The team led by Bryan L. Roth, MD, PhD from the UNC School of Medicine used x-ray crystallography to “freeze” and capture images of LSD attached to a serotonin receptor (a protein that senses serotonin, a chemical messenger). The researchers found that the LSD molecule is essentially locked on to that part of the brain as the receptor folds over it like a lid. This explains why the effects of an LSD trip last so long, lingering for 12 hours or more even if LSD molecules are known to clear from the blood in a few hours.

“We think this lid is likely why the effects of LSD can last so long,” said Roth, “LSD takes a long time to get onto the receptor, and then once it’s on, it doesn’t come off. And the reason is this lid.”

The answers his team was able to get clears up the question Roth held from his youth.

“When I was younger, and The Grateful Dead was still around, I would occasionally go to Grateful Dead concerts. A lot of people took LSD and similar drugs during concerts, and it would be interesting to be in the parking lot hearing people wondering when their LSD experience was going to end,” said Roth. “A lot of people who take the drug are not aware of just how long it lasts.”

LSD molecule

A molecule of LSD bound to a larger serotonin receptor. The ‘lid’ that keeps LSD bound so long is the orange bar running through the center. Credit: Lab of Bryan Roth, UNC School of Medicine

The trip ends when LSD molecules get off their receptors, while brain cells eventually pull the receptors into the cell, where they (along with the LSD) get degraded or recycled.

The scientists think their research will help in the development of new treatments, especially considering the recent popularity of LSD microdosing to combat depression or increase creativity.

Another study, this one published in Current Biology, looked at how LSD affects perception. They found specific neurochemicals and receptors in the brain responsible for “loosening” the boundaries of the self and creating a sense of meaning while on an LSD trip. What they were after is to understand why people on LSD paid so much attention to details or objects which normally would not elicit such a focus.

“Our results increase our understanding of how personal relevance attribution is enabled in the brain,” said Katrin Preller of the Zürich University Hospital for Psychiatry. “[We now know] which receptors, neurotransmitters, and brain regions are involved when we perceive our environment as meaningful and relevant.”

In particular, the researchers studied a group of people on LSD versus a group on placebos, having them rank the meaning of specific songs or musical compositions. It turned out that songs which previously didn’t mean much became very significant to the subjects on LSD. Doing this, while scanning the brains of the participants, allowed the scientists to identify the specific receptors involved in creating that meaningfulness.

“By combining functional brain imaging and detailed behavioral assessments using a specific experimental paradigm to investigate personal relevance or meaning of music pieces, we were able to elucidate the neurobiological correlates of personal relevance processing in the brain,” explained Preller. “We found that personal meaning attribution and its modulation by LSD is mediated by the 5-HT2A receptors and cortical midline structures that are also crucially involved in enabling the experience of a sense of self.”

Further studies of the identified 5-HT2A receptors may lead to understanding how “excessive stimulation” of these receptors can be responsible for the peculiar feelings and sensations of people on a psychedelic trip. The goal is to develop new treatments for psychiatric illnesses.

Chemically-induced synesthesia

In April 1943, scientist Albert Hoffman ingested 250 micrograms of a substance he had synthesized five years prior. Less than an hour later, he “perceived an uninterrupted stream of fantastic pictures, extraordinary shapes with intense, kaleidoscopic play of colors.”1

Hoffman had discovered lysergic acid diethylamide, a psychedelic drug commonly known as LSD. He had experienced the world’s first acid trip.

Psychedelic drugs like LSD are often associated with experiences that can only be described as synesthesia—the rare neurological phenomenon in which a stimulus produces a second concurrent, involuntary experience—although scientists are still unsure if chemically-induced synesthesia is a genuine synesthetic experience.

The majority of studies on the topic have focused on congenital synesthesia. To date, there have only been four direct studies on chemically-induced synesthesia which were conducted between 1934 and 1966. Indirect studies picked up again in the early 1990s with the work of neurologist Richard Cytowic.

Direct studies suggest it’s possible to chemically-induce synesthesia

In 1934, research conducted by E.L. Kelly and published in the Journal of Experimental Psychology tested auditory-visual synesthesia using five non-synesthetes who first spent seven-weeks being presented with eight different tone-color pairs 1000 to 2000 times. The subjects demonstrated no evidence of developing synesthesia after this initial testing phase. When they consumed 15g of peyote cactus (estimated to contain between 0.15 and 1.2g of the psychoactive stimulant mescaline), four of the participants perceived colorful visual imagery and experienced haptic-visual, kinesthetic-visual, and algesic-color synesthesia. However, the researchers suggested that consumption of mescaline did not enhance trained associations and they observed no evidence of spontaneous auditory-visual synesthesia.2

A second study conducted in 1955 by Simpson and McKeller in the Journal of Mental Science involved two congenital synesthetes (auditory-visual and multiple types). The researchers themselves acted as non-synesthete controls. On separate occasions, subjects were given four mescaline doses (between 0.3 and 0.5g) and were then presented with various stimuli (i.e. visual, auditory, tactile, etc.). Subjects reported experiencing several distinct types of synesthesia, including auditory-visual, kinesthetic-visual, tactile-visual, olfactory-visual, and algesic-visual. Synesthetes and non-synesthetes were equally prone to developing new inducer-concurrent associations. In addition, one of the congenital synesthetes reported enhancements of his regular associations. Once again, the researchers concluded that mescaline seemed to be able to trigger synesthesia among non-synesthetes, but they also suggested that it could enhance the phenomenon in congenital synesthetes.3

A third blind study conducted in 1963 by Hartman and Hollister in Psychopharmacologia compared the effects of mescaline, LSD, and psilocybin (the psychedelic compound found in certain mushrooms). Eighteen participants were given each substance a week apart and were subjected to 16 sonic tones before and after drug administration. Under the influence of LSD and mescaline, but not psilocybin, participants reported significantly more auditory-visual associations compared to baseline levels. Less than 50% of participants experienced auditorily-induced synesthesia under the influence of the drugs.4

The last direct study, conducted in 1966 by Masters and Houston in The Varieties of Psychedelic Experience, was extremely informal. In it, participants were interviewed after consuming psychedelic drugs.  The study covered 206 drug sessions and involved a total of 214 subjects.2The researchers reported successfully inducing auditory-visual and auditory-gustatory synesthesia with LSD, but no other details were provided in their report.5

Possible mechanisms for chemically-induced synesthesia

Because the genetic mechanisms underlying congenital synesthesia are still not well understood and chemically-induced studies are so scarce, scientists are unsure if mechanisms influencing chemically-induced synesthetic episodes are—or are similar to—genuine synesthetic experiences.

In congenital synesthesia, very little systematic quantitative research has investigated the neurochemical factors involved. In mechanisms that propose the phenomenon is promoted by disinhibition, y-aminobutyric acid (GABA) plays a role in the disruption of inhibitory activity.2,6In 2008, scientists Brang and Ramachandran suggested serotonin (5-hydroxytryptophan) may also play a role.2,7

According to scientist Christopher Sinke from the University of Hannover, hallucinogens appear to inhibit serotonergic neuron transduction.8 The majority of hallucinogens affect activity in two areas: the locus coeruleus and pyramidal cells in the cortex. Because serotonin is primarily an inhibitory neurotransmitter, when its activity is decreased due to drug intake, the activity of the next neuron in the chain increases when it is no longer inhibited. This mechanism would be similar to the disinhibited feedback models of genuine synesthesia.

Crucial differences between congenital and chemically-induced synesthesia

While any two or more combinations of inducer-concurrent experiences are possible, in congenital synesthesia the grapheme-colour association is the most common type. Meanwhile, auditory-visual synesthesia is the most common form noted in chemically-induced cases (approximately 23%).  Additionally, visual concurrents are more complex in these cases than in congenital cases. Genuine synesthesia is characterized by consistency and automaticity. Currently, there is still no clear evidence that chemically-induced synesthesia is consistent or automatic.

The limitations of scarce research

It is critical to keep in mind when analyzing the existing chemically-induced research that study participants may have been biased to expect synesthesia under the influence of psychedelics and that the drugs increased participant suggestibility. Additionally, as in Albert Hoffman’s initial experience with LSD in 1943, most studies relied on subjects to self-report their experiences rather than using more consistent, objective methods to screen or measure participants.

While the studies discussed here suggest that it is possible to induce synesthesia using psychedelics, a systematic review conducted in 2013 by the University of Greenwich and Oxford recommends more rigorous examination of the subject including placebo-controlled and double blind investigations.2 Promisingly, we have taken steps in this direction with new research attempting to elucidate the mechanisms that may activate chemically-induced synesthesia through more controlled studies.9

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