How psilocybin, the psychedelic in mushrooms, may rewire the brain to ease depression, anxiety and more

How psilocybin, the psychedelic in mushrooms, may rewire the brain to ease depression, anxiety and more
(CNN)Shrooms, Alice, tweezes, mushies, hongos, pizza toppings, magic mushrooms — everyday lingo for psychedelic mushrooms seems to grow with each generation. Yet leading mycologist Paul Stamets believes it’s time for fans of psilocybin mushrooms to leave such childish slang behind.
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Small clinical trials that have shown that one or two doses of psylocibin, given in a therapeutic setting, can make dramatic and long-lasting changes in people suffering from treatment-resistant major depressive disorder, which typically does not respond to traditional antidepressants.
Based on this research, the US Food and Drug Administration has described psilocybin as a breakthrough medicine, “which is phenomenal,” Stamets said.
Psilocybin, which the intestines convert into psilocin, a chemical with psychoactive properties, is also showing promise in combating cluster headaches, anxiety, anorexia, obsessive-compulsive disorder and various forms of substance abuse.
“The data are strong from depression to PTSD to cluster headaches, which is one of the most painful conditions I’m aware of,” said neurologist Richard Isaacson, director of the Alzheimer’s Prevention Clinic in the Center for Brain Health at Florida Atlantic University.
“I’m excited about the future of psychedelics because of the relatively good safety profile and because these agents can now be studied in rigorous double-blinded clinical trials,” Isaacson said. “Then we can move from anecdotal reports of ‘I tripped on this and felt better’ to ‘Try this and you will be statistically, significantly better.’”
Your brain on mushrooms
Classic psychedelics such as psilocybin and LSD enter the brain via the same receptors as serotonin, the body’s “feel good” hormone. Serotonin helps control body functions such as sleep, sexual desire and psychological states such as satisfaction, happiness and optimism.
People with depression or anxiety often have low levels of serotonin, as do people with post-traumatic stress disorder, cluster headaches, anorexia, smoking addiction and substance abuse. Treatment typically involves selective serotonin reuptake inhibitors, or SSRIs, which boost levels of serotonin available to brain cells. Yet it can take weeks for improvement to occur, experts say, if the drugs even work at all.
With psychedelics such as psilocybin and LSD, however, scientists can see changes in brain neuron connectivity in the lab “within 30 minutes,” said pharmacologist Brian Roth, a professor of psychiatry and pharmacology at the University of North Carolina at Chapel Hill.
“One of the most interesting things we’ve learned about the classic psychedelics is that they have a dramatic effect on the way brain systems synchronize, or move and groove together,” said Matthew Johnson, a professor in psychedelics and consciousness at Johns Hopkins Medicine.
“When someone’s on psilocybin, we see an overall increase in connectivity between areas of the brain that don’t normally communicate well,” Johnson said. “You also see the opposite of that — local networks in the brain that normally interact with each other quite a bit suddenly communicate less.”
It creates a “very, very disorganized brain,” ultimately breaking down normal boundaries between the auditory, visual, executive and sense-of-self sections of the mind — thus creating a state of “altered consciousness,” said David Nutt, director of the Neuropsychopharmacology Unit in the Division of Brain Sciences at Imperial College London.
And it’s that disorganization that is ultimately therapeutic, according to Nutt: “Depressed people are continually self-critical, and they keep ruminating, going over and over the same negative, anxious or fearful thoughts.
“Psychedelics disrupt that, which is why people can suddenly see a way out of their depression during the trip,” he added. “Critical thoughts are easier to control, and thinking is more flexible. That’s why the drug is an effective treatment for depression.”
The growth of brain cells
There’s more. Researchers say psychedelic drugs actually help neurons in the brain sprout new dendrites, which look like branches on a tree, to increase communication between cells.
“These drugs can increase neuronal outgrowth, they can increase this branching of neurons, they can increase synapses. That’s called neuroplasticity,” Nutt said.
That’s different from neurogenesis, which is the development of brand new brain cells, typically from stem cells in the body. The growth of dendrites helps build and then solidify new circuits in the brain, allowing us to, for example, lay down more positive pathways as we practice gratitude.
“Now our current thinking is this neuronal outgrowth probably doesn’t contribute to the increased connectivity in the brain, but it almost certainly helps people who have insights into their depression while on psilocybin maintain those insights,” Nutt said.
“You shake up the brain, you see things in a more positive way, and then you lay down those positive circuits with the neuroplasticity,” he added. “It’s a double whammy.”
Interestingly, SSRIs also increase neuroplasticity, a fact that science has known for some time. But in a 2022 double-blind phase 2 randomized controlled trial comparing psylocibin to escitalopram, a traditional SSRI, Nutt found the latter didn’t spark the same magic.
“The SSRI did not increase brain connectivity, and it actually did not improve well-being as much as psilocybin,” Nutt said. “Now for the first time you’ve got the brain science lining up with what patients say after a trip: ‘I feel more connected. I can think more freely. I can escape from negative thoughts, and I don’t get trapped in them.’ ”
Taking a psychedelic doesn’t work for everyone, Johnson stressed, “but when it works really well it’s like, ‘Oh my god, it’s a cure for PTSD or for depression.’ If people really have changed the way their brain is automatically hardwired to respond to triggers for anxiety, depression, smoking — that’s a real thing.”
How long do results last? In studies where patients were given just one dose of a psychedelic “a couple of people were better eight years later, but for the majority of those with chronic depression it creeps back after four or five months,” Nutt said.
“What we do with those people is unknown,” he added. “One possibility is to give another dose of the psychedelic — we don’t know if that would work or not, but it might. Or we could put them on an SSRI as soon as they’ve got their mood improved and see if that can hold the depression at bay.
“There are all sorts of ways we could try to address that question,” Nutt said, “but we just don’t know the answer yet.”

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