Tag Archives: ayahuasca

Hallucinogenic molecules and the brain

Psychedelic drugs seems to be enjoying a ‘moment’. After decades of being vilified and  declared illegal (in many jurisdictions), psychedelic (or hallucinogenic) drugs are once again being tested for use in therapy. A Sept. 1, 2017 article by Diana Kwon for The Scientist describes some of the latest research (I’ve excerpted the section on molecules; Note: Links have been removed),

Mind-bending molecules

© SEAN MCCABE

All the classic psychedelic drugs—psilocybin, LSD, and N,N-dimethyltryptamine (DMT), the active component in ayahuasca—activate serotonin 2A (5-HT2A) receptors, which are distributed throughout the brain. In all likelihood, this receptor plays a key role in the drugs’ effects. Krähenmann [Rainer Krähenmann, a psychiatrist and researcher at the University of Zurich]] and his colleagues in Zurich have discovered that ketanserin, a 5-HT2A receptor antagonist, blocks LSD’s hallucinogenic properties and prevents individuals from entering a dreamlike state or attributing personal relevance to the experience.12,13

Other research groups have found that, in rodent brains, 2,5-dimethoxy-4-iodoamphetamine (DOI), a highly potent and selective 5-HT2A receptor agonist, can modify the expression of brain-derived neurotrophic factor (BDNF)—a protein that, among other things, regulates neuronal survival, differentiation, and synaptic plasticity. This has led some scientists to hypothesize that, through this pathway, psychedelics may enhance neuroplasticity, the ability to form new neuronal connections in the brain.14 “We’re still working on that and trying to figure out what is so special about the receptor and where it is involved,” says Katrin Preller, a postdoc studying psychedelics at the University of Zurich. “But it seems like this combination of serotonin 2A receptors and BDNF leads to a kind of different organizational state in the brain that leads to what people experience under the influence of psychedelics.”

This serotonin receptor isn’t limited to the central nervous system. Work by Charles Nichols, a pharmacology professor at Louisiana State University, has revealed that 5-HT2A receptor agonists can reduce inflammation throughout the body. Nichols and his former postdoc Bangning Yu stumbled upon this discovery by accident, while testing the effects of DOI on smooth muscle cells from rat aortas. When they added this drug to the rodent cells in culture, it blocked the effects of tumor necrosis factor-alpha (TNF-α), a key inflammatory cytokine.

“It was completely unexpected,” Nichols recalls. The effects were so bewildering, he says, that they repeated the experiment twice to convince themselves that the results were correct. Before publishing the findings in 2008,15 they tested a few other 5-HT2A receptor agonists, including LSD, and found consistent anti-inflammatory effects, though none of the drugs’ effects were as strong as DOI’s. “Most of the psychedelics I have tested are about as potent as a corticosteroid at their target, but there’s something very unique about DOI that makes it much more potent,” Nichols says. “That’s one of the mysteries I’m trying to solve.”

After seeing the effect these drugs could have in cells, Nichols and his team moved on to whole animals. When they treated mouse models of system-wide inflammation with DOI, they found potent anti-inflammatory effects throughout the rodents’ bodies, with the strongest effects in the small intestine and a section of the main cardiac artery known as the aortic arch.16 “I think that’s really when it felt that we were onto something big, when we saw it in the whole animal,” Nichols says.

The group is now focused on testing DOI as a potential therapeutic for inflammatory diseases. In a 2015 study, they reported that DOI could block the development of asthma in a mouse model of the condition,17 and last December, the team received a patent to use DOI for four indications: asthma, Crohn’s disease, rheumatoid arthritis, and irritable bowel syndrome. They are now working to move the treatment into clinical trials. The benefit of using DOI for these conditions, Nichols says, is that because of its potency, only small amounts will be required—far below the amounts required to produce hallucinogenic effects.

In addition to opening the door to a new class of diseases that could benefit from psychedelics-inspired therapy, Nichols’s work suggests “that there may be some enduring changes that are mediated through anti-inflammatory effects,” Griffiths [Roland Griffiths, a psychiatry professor at Johns Hopkins University] says. Recent studies suggest that inflammation may play a role in a number of psychological disorders, including depression18 and addiction.19

“If somebody has neuroinflammation and that’s causing depression, and something like psilocybin makes it better through the subjective experience but the brain is still inflamed, it’s going to fall back into the depressed rut,” Nichols says. But if psilocybin is also treating the inflammation, he adds, “it won’t have that rut to fall back into.”

If it turns out that psychedelics do have anti-inflammatory effects in the brain, the drugs’ therapeutic uses could be even broader than scientists now envision. “In terms of neurodegenerative disease, every one of these disorders is mediated by inflammatory cytokines,” says Juan Sanchez-Ramos, a neuroscientist at the University of South Florida who in 2013 reported that small doses of psilocybin could promote neurogenesis in the mouse hippocampus.20 “That’s why I think, with Alzheimer’s, for example, if you attenuate the inflammation, it could help slow the progression of the disease.”

For anyone who was never exposed to the anti-hallucinogenic drug campaigns, this turn of events is mindboggling. There was a great deal of concern especially with LSD in the 1960s and it was not entirely unfounded. In my own family, a distant cousin, while under the influence of the drug, jumped off a building believing he could fly.  So, Kwon’s story opening with a story about someone being treated successfully for depression with a psychedelic drug was surprising to me . Why these drugs are being used successfully for psychiatric conditions when so much damage was apparently done under the influence in decades past may have something to do with taking the drugs in a controlled environment and, possibly, smaller dosages.

Tune in, turn on, and drop out—LSD and psychedelic talk at Vancouver’s (Canada) Café Scientifique on March 31, 2015

There seems to be a lot of interest in psychedelics these days and not least here in Vancouver. Next Tuesday, March 31, 2015 Cafe Scientifique, held in the back room of The Railway Club (2nd floor of 579 Dunsmuir St. [at Seymour St.], will be hosting a talk on LSD (from the March 16, 2015 announcement,

Our speaker for the evening will be Dr. Michael Hughesa Research Associate in the Department of Medical Genetics at UBC (University of British Columbia) …

Psychedelic Medicine: The History & Science of LSD in the Clinic

Ergot is a fungus that grows on rye and other grains that has been blamed (rightly or wrongly) for episodes of mass hysteria throughout history. Lysergic acid diethylamide (LSD) was first synthesized from ergot in 1938 by a Swiss chemist named Albert Hoffman, who, at the height of World War II, also discovered (somewhat mysteriously) its psychedelic properties. LSD soon came to the attention of the U.S. Army who quickly proceeds to buy up all the supply – primarily to keep it out of the hands of its enemies. Throughout the Cold War, elements in U.S. defense and security agencies engage in experiments by secretly slipping LSD to citizens with dangerous (and sometimes comical) consequences with the goal of perfecting brainwashing and mind control. Canadian scientists at McGill participated in some of these studies, thinking they could use LSD to cure psychoses. These unethical and largely unscientific experiments were akin to psychological torture. Meanwhile, the public discovered the recreational benefits of LSD and the hippie movement adopted the drug as a symbol and vehicle to enlightenment. Largely for this reason, in the early ‘70s LSD was classified as a Schedule-1 drug in the U.S. restricted legal access stopped most research and hopes of the clinical benefits of LSD was abandoned and all but forgotten. Recently, scientists, mostly working outside of the U.S. and Canada, have rediscovered LSD’s efficacy for the treatment of psychiatric disorders including post-traumatic stress syndrome (PTSD) and existential fear in terminally ill patients. Are we ready for a new wave of ethical human research to (re)-discover the clinical benefits of LSD? Take a journey through the strange history of LSD research and learn about its potential applications in medicine. What a long, strange trip it’s been.

Hughes works as a team member in the Hematopoietic Cell Development laboratory at the University of British Columbia’s (UBC) Biomedical Research Centre.

Last week on March 18, 2015, The UBC Neuroscience Graduate Student Association hosted a screening of Neurons to Nirvana: Understanding Psychedelic Medicines at the Pacific Cinematheque theatre in Vancouver (Note: Links have been removed),

A thought-provoking and visually-stunning documentary that explores the potential of five powerful psychedelic substances (LSD, psilocybin, MDMA, ayahuasca, and cannabis) as psychotherapeutic medicines. Despite the potential promise shown by such drugs in research conducted in the 1950s, the increasingly restrictive anti-drug policies of successive governments effectively shut down further enquiry. As one of the many world-renowned researchers, writers, psychologists, and scientists interviewed in the film says: “The government does not allow this research to take place, and then says there’s no research to support it. It’s beyond hypocrisy.” The film is a cogent call to put irrational, fear-based beliefs aside in order to allow clinical, evidence-based research into psychedelics in areas such as addictions, PTSD, anxiety, depression, and end-of-life care.

– – – – – – – – – – – – – – – – – –

Post-screening discussion with co-director Oliver Hockenhull and Mark Haden.

A teacher and essayist as well as a filmmaker, Oliver Hockenhull has presented at numerous universities in Canada, the US, and Europe. He has blended the documentary, essay, and experimental genres in such previous works as Aldous Huxley: The Gravity of Light (1996), Building Heaven, Remembering Earth (1999), and Evo (2002).

Mark Haden worked for Vancouver Coastal Health Addiction Services for 28 years and is now an Adjunct Professor at the UBC School of Population and Public Health. He is a pivotal voice in the drug policy reform movement, providing viable models for reforming drug education and regulating markets for currently illegal substances. Mark is also the Chair of the Board of MAPS Canada (Multidisciplinary Association for Psychedelic Studies).

Moderated by Dr. Harry Karlinsky, Clinical Professor, Department of Psychiatry, University of British Columbia.

Perhaps popular demand will lead to another showing. In the meantime, there’s Hughes’ talk and if his description is indicative it should be fascinating.

For anyone who did not recognize it,  ‘tune in, turn on, and drop out’, is a phrase that Timothy Leary, the high priest of psychedelics, psychologist, and former lecturer at Harvard University popularized during the 1960s and 70s. According to the ‘tune in, turn on, and drop out‘ entry in Wikipedia, the phrase was given to Leary by Canadian media theorist, Marshall McLuhan.

ETA March 27, 2015 at 1610 PDT: I just received a newsletter from Canada’s National Film Board where the feature item is this,

All About Acid: Hofmann’s Potion

Open your mind with this powerful feature documentary that retraces the history of LSD, a substance first used to treat addiction and mental illness that became the self-understanding tool of a generation.

For more on Hofmann’s Potion, read Meet the Lab Coat-Clad Granddaddies of LSD on the NFB/ blog.

Watch Now

* ‘tun’ changed to ‘turn’ (sigh) March 27, 2015 at 1615 PDT