The psychedelic drug psilocybin increase the connections between neurons


The psychedelic drug psilocybin, a naturally occurring compound found in some mushrooms, has been studied as a potential treatment for depression for years. But exactly how it works in the brain and how long beneficial results might last is still unclear.

In a new study, Yale researchers show that a single dose of psilocybin given to mice prompted an immediate and long-lasting increase in connections between neurons. The findings are published July 5 in the journal Neuron.

“We not only saw a 10% increase in the number of neuronal connections, but also they were on average about 10% larger, so the connections were stronger as well,” said Yale’s Alex Kwan, associate professor of psychiatry and of neuroscience and senior author of the paper.

Previous laboratory experiments had shown promise that psilocybin, as well as the anesthetic ketamine, can decrease depression. The new Yale research found that these compounds increase the density of dendritic spines, small protrusions found on nerve cells which aid in the transmission of information between neurons.

Chronic stress and depression are known to reduce the number of these neuronal connections.

Using a laser-scanning microscope, Kwan and first author Ling-Xiao Shao, a postdoctoral associate in the Yale School of Medicine, imaged dendritic spines in high resolution and tracked them for multiple days in living mice. They found increases in the number of dendritic spines and in their size within 24 hours of administration of psilocybin.

These changes were still present a month later. Also, mice subjected to stress showed behavioral improvements and increased neurotransmitter activity after being given psilocybin.

For some people, psilocybin, an active compound in “magic mushrooms,” can produce a profound mystical experience. The psychedelic was a staple of religious ceremonies among indigenous populations of the New World and is also a popular recreational drug.

It may be the novel psychological effects of psilocybin itself that spurs the growth of neuronal connections, Kwan said.

“It was a real surprise to see such enduring changes from just one dose of psilocybin,” he said. “These new connections may be the structural changes the brain uses to store new experiences.”

Preclinical research has demonstrated that psychedelic substances, including 2,5-dimethoxy-4-iodoamphetamine (DOI), lysergic acid diethylamide (LSD), N,N-dimethyltryptamine (DMT), and psilocybin, as well as alkaloids present in ayahuasca (harmine, tetrahydroharmine, and harmaline) affect neuroplasticity after acute and chronic administration.(1−5)

Catlow and colleagues, for example, demonstrated the increased formation of neurons (neurogenesis) in mice’ dentate gyrus after an average psilocybin dose of 3.5 μg/35 g bodyweight (intraperitoneal (i.p.)), while this was slightly decreased after a dose of 35 μg/35 g (psilocybin/bodyweight).(6)

Interestingly, when repeatedly given i.p. psilocybin four times interspersed with 1 week, a higher dose of 52 μg/35 g (psilocybin/bodyweight) increased neuroplasticity.(2) Chronic administration in rats of twice the ritualistic dose of ayahuasca (150 mL/70 kg bodyweight containing 0.26 mg/kg DMT) for 28 days resulted in increased in brain-derived neurotrophic factor (BDNF) levels in the hippocampus of the female rats, compared to that in control animals.(7)

A recent in vitro study in cultured cortical neurons of animals showed increased formation of new neurites, as expressed by the number of dendritic branches, the total length of the arbors, and formation of synapses, after extended (24 h) treatment with a range of psychedelics like DOI, LSD, and DMT.(1) While these effects were similar across psychedelic classes and the dissociative ketamine, LSD was the most potent, as shown via neuritogenesis assay.(1) Also in cultured human cortical neurons, the neuro-regenerative effects of DMT(8) and modulation of proteins involved in dendritic spine formation by 5-MeO-DMT have been shown.(9)

In light of the increased scientific interest in using low psychedelic doses,(10) also known as “microdosing”,(11) critical preclinical work with DMT has also shown that neuroplastic changes even take place after administration of low DMT doses that are considered to be subhallucinogenic.(1) Examples are morphological changes in the prefrontal cortex of adult rats and functional changes ex vivo.(1)

The practice of microdosing entails repeatedly taking low doses, which are usually one-tenth of a recreational dose that causes a psychedelic experience. For LSD, that would, for example, be between 10 and 20 μg.(12)
User claims suggest the effectivity of self-medication with low doses of psychedelics in the treatment of disorders related to neuroplasticity, including depression.(10)

Interestingly, depression has been linked with impairments in neuroplasticity, and pharmacologically induced symptom improvement is linked with increases in BDNF levels.(13,14) BDNF is highly expressed in limbic brain regions, which are involved in emotional processes, memory, and mood. Notably, Bershad et al. recently demonstrated connectivity changes in the limbic areas after a low dose of LSD (13 μg, tartrate).(15) These biological changes correlated positively with the enhanced mood in healthy volunteers.(15)

Together, these findings add scientific evidence to the idea that LSD in low doses could have therapeutic potential in mood-related disorders.(10) Given the interest in BDNF as a key player in several neurodegenerative and neuropsychiatric disorders(13,16,17) and preclinical data showing psychedelics-induced neuroplasticity even at low doses of psychedelics,(1) the present double-blind, placebo-controlled, within-subject (WS) study aimed to investigate whether LSD base in low doses (0, 5, 10, and 20 μg) affects BDNF plasma levels in healthy volunteers.

Blood samples were collected every 2 h over 6 h, and BDNF levels were determined afterward in blood plasma using ELISA.(18) Previously, it has been demonstrated that blood plasma BDNF concentrations reflect mammalian brain-tissue BDNF levels.(19)

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Provided by Yale University


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