Embraced then vilified, the drug lysergic acid diethylamide is on a path toward redemption. While LSD remains a legally restricted psychoactive substance, scientists are pursuing its therapeutic potential — continuing a conversation that began in the 1950s.
LSD’s prosocial effects hint at its potential for helping with conditions from anxiety to alcoholism. Happiness, trust, and empathy are all effects of the psychedelic.
Scientists haven't been able to identify the exact neurobiological mechanisms underlying these feel-good experiences, though. And that has stalled efforts to create treatments that use LSD.
A new study might have the answer. The research identifies three features of the brain’s medial prefrontal cortex (the part of the brain that related to social behavior) that are responsible for LSD’s influence: The mTORC1 protein complex and the receptors 5-HT2A and AMPA.
Dr. Gabriella Gobbi is the study’s senior author and the head of the Neurobiological Psychiatry Unit at McGill University. Shell tells Inverse that reading a 1960s research paper inspired her interest in LSD, and the realization “that very little was known about the mechanism of action of psychedelics, and how LSD interacts with our brain."
In the '60s study, theology students administered LSD and experienced, for the first time, mystical and transcendental thinking that “changed their mind forever.” Gobbi is curious as to whether LSD can change behavior, too.
“There are mental diseases affecting social behavior, such as autism spectrum disorders and social phobia, which have no treatments yet,” Gobbi says. LSD, she says, can suggest a “mechanism of action” for treating these conditions.
The findings of Gabbi and her fellow researchers findings were published Monday in the journal Proceedings of the National Academy of Sciences.
The illegal history of LSD — Gobbi tells Inverse that LSD’s classification as a “controlled substance” factored into the delay of this discovery. Modern teams like hers are also benefited by sophisticated tools earlier scientists interested in LSD lacked, including brain imaging techniques and optogenetics, a technique where light is used to control genetically modified neurons.
But interest in the substance is not new. Discovered in 1938 by Swiss chemist Albert Hofmann, it’s “maintained an unstable relationship with psychiatry” since its introduction to the world. LSD was studied as a treatment for anxiety, depression, and addiction from the 1950s to the 1970s, though these studies don’t match contemporary standards.
Recent years have seen a renewed interest in its potential as a therapeutic, and with some success.
A 2016 study on adult participants found that LSD created a shift in brain activity, seemingly possessing “integrated or unified brains” more like the brains of children and potentially explaining why people on LSD experience a shift in consciousness.
Meanwhile, a 2017 study found LSD “alters the energy and power of individual harmonic brain states in a frequency-selective manner.” In 2020, scientists found LSD creates a powerful experience by binding to 5-HT2A receptors — the same implicated in Gobi’s research.
When it comes to therapy, a 2014 study examining 12 subjects found LSD-assisted psychotherapy reduced anxiety levels. There’s currently a clinical trial evaluating how LSD therapy might serve people who suffer from major depression.
What’s new about this study — Compared to previous studies in animals, the team used a relatively low dose of LSD (5 to 20 μg/kg) on mice in an effort to observe behavioral benefits — while avoiding adverse reactions seen in other, higher-dosage rodent research.
Because LSD is a controlled substance, the lab had to ask the government department Health Canada for special permission to use it. The LSD used had a purity of 98 to 99 percent, Gobbi says.
Test mice were injected with LSD or a placebo, then placed in a cage and given 10 minutes to habituate. They were then introduced to a “stranger mouse” and allowed to freely engage in social interactions for another 10 minutes. Positive interactions include actions like nose-to-nose sniffing and social grooming.
Some of these mice were given drugs that blocked the 5-HT2A and AMPA receptors. Subsequent analysis of their brains showed that the social effects of LSD were eliminated because of these drugs.
Meanwhile, other mice were genetically engineered to have neurons lacking the mTORC1 protein complex, a regulator of growth in animals that, when disrupted, is implicated in a wide array of diseases. “The MTORC1 protein is an important molecule for the synthesis of proteins involved in molecular plasticity,” Gobbi says.
These altered mice also did not experience the prosocial effects — their 5-HT2A and AMPA receptors also remained unactivated.
This implies the mTORC1 protein complex is responsible for the effect of LSD on social behavior, because of its relationship to the 5-HT2A and AMPA receptors.
Interestingly, this study did not find LSD worked as an antidepressant for the mice but that may be chalked up to the species examined, and “LSD might require a longer time frame to induce antidepressant-specific molecular changes and neuronal plasticity,” the researchers speculate. Previous studies on ketamine used on rats found activation of mTOR signaling actually induced strong antidepressant effects.
Why it matters — The study — while on mice and not humans — shows the features of the prefrontal cortex that allow LSD to shift the brain and influence behavior.
This is of particular interest to scientists, because disrupted social behavior is prevalent in various mental health conditions, including autism spectrum disorder and social anxiety disorders.
“Few definitive therapies are available,” the team admits.
New knowledge of why LSD can promote prosocial effects may lead to therapies that can help humans — think of your cousins, classmates, brothers, sisters, neighbors — who struggle to socially connect. It could help people, whose lives are largely closed-off from the world around them, form deeper relationships, connect, and experience a richer existence.
Abstract: Clinical studies have reported that the psychedelic lysergic acid diethylamide (LSD) enhances empathy and social behavior (SB) in humans, but its mechanism of action remains elusive. Using a multidisciplinary approach including in vivo electrophysiology, optogenetics, behavioral paradigms, and molecular biology, the effects of LSD on SB and glutamatergic neurotransmission in the medial prefrontal cortex (mPFC) were studied in male mice. Acute LSD (30 μg/kg) injection failed to increase SB. However, repeated LSD (30 μg/kg, once a day, for 7 days) administration promotes SB, without eliciting antidepressant/anxiolytic-like effects. Optogenetic inhibition of mPFC excitatory neurons dramatically inhibits social interaction and nullifies the prosocial effect of LSD. LSD potentiates the α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) and 5-HT2A, but not N-methyl-D-aspartate (NMDA) and 5- HT1A, synaptic responses in the mPFC and increases the phosphorylation of the serine-threonine protein kinases Akt and mTOR. In conditional knockout mice lacking Raptor (one of the structural components of the mTORC1 complex) in excitatory glutamatergic neurons (Raptorf/f:Camk2alpha-Cre), the prosocial effects of LSD and the potentiation of 5-HT2A/AMPA synaptic responses were nullified, demonstrating that LSD requires the integrity of mTORC1 in excitatory neurons to promote SB. Conversely, in knockout mice lacking Raptor in GABAergic neurons of the mPFC (Raptorf/f:Gad2- Cre), LSD promotes SB. These results indicate that LSD selectively enhances SB by potentiating mPFC excitatory transmission through 5-HT2A/AMPA receptors and mTOR signaling. The activation of 5-HT2A/AMPA/mTORC1 in the mPFC by psychedelic drugs should be explored for the treatment of mental diseases with SB impairments such as autism spectrum disorder and social anxiety disorder.
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