Category Archives: pharmacology

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.

‘Hunting’ pharmaceuticals and removing them from water

Pharmaceuticals are not the first pollutants people think of when discussing water pollution but, for those who don’t know, it’s a big issue and scientists at the University of Surrey (UK) have developed a technology they believe will help to relieve the contamination. From an April 10, 2017 University of Surrey press release (also on EurekAlert),

The research involves the detection and removal of pharmaceuticals in or from water, as contamination from pharmaceuticals can enter the aquatic environment as a result of their use for the treatment of humans and animals. This contamination can be excreted unchanged, as metabolites, as unused discharge or by drug manufacturers.

The research has found that a new type of ‘supermolecule’, calix[4], actively seeks certain pharmaceuticals and removes them from water.

Contamination of water is a serious concern for environmental scientists around the world, as substances include hormones from the contraceptive pill, and pesticides and herbicides from allotments. Contamination can also include toxic metals such as mercury, arsenic, or cadmium, which was previously used in paint, or substances that endanger vital species such as bees.

Professor Danil de Namor, University of Surrey Emeritus Professor and leader of the research, said: “Preliminary extraction data are encouraging as far as the use of this receptor for the selective removal of these drugs from water and the possibility of constructing a calix[4]-based sensing devices.

“From here, we can design receptors so that they can bind selectively with pollutants in the water so the pollutants can be effectively removed. This research will allow us to know exactly what is in the water, and from here it will be tested in industrial water supplies, so there will be cleaner water for everyone.

“The research also creates the possibility of using these materials for on-site monitoring of water, without having to transport samples to the laboratory.”

Dr Brendan Howlin, University of Surrey co-investigator, said: “This study allows us to visualise the specific receptor-drug interactions leading to the selective behaviour of the receptor. As well as the health benefits of this research, molecular simulation is a powerful technique that is applicable to a wide range of materials.

“We were very proud that the work was carried out with PhD students and a final year project student, and research activities are already taking place with the Department of Chemical and Processing Engineering (CPI) and the Advanced Technology Institute (ATI).

“We are also very pleased to see that as soon as the paper was published online by the European Journal of Pharmaceutical Sciences, we received invitations to give keynote lectures at two international conferences on pharmaceuticals in Europe later this year.”

That last paragraph is intriguing and it marks the first time I’ve seen that claim in a press release announcing the publication of a piece of research.

Here’s a link to and a citation for the paper,

A calix[4]arene derivative and its selective interaction with drugs (clofibric acid, diclofenac and aspirin) by Angela F Danil de Namor, Maan Al Nuaim, Jose A Villanueva Salas, Sophie Bryant, Brendan Howlin. European Journal of Pharmaceutical Sciences Volume 100, 30 March 2017, Pages 1–8 https://doi.org/10.1016/j.ejps.2016.12.027

This paper is behind a paywall.

Greener catalysts with iron nanoparticles

A research team at the University of Toronto has announced the discovery of a possible ‘green’ alternative to commonly used catalysts in the food, drug, and fragrance industries. From the March 27, 2012 news item on Nanowerk,

A chemistry team at the University of Toronto has discovered environmentally-friendly iron-based nanoparticle catalysts that work as well as the expensive, toxic, metal-based catalysts that are currently in wide use by the drug, fragrance and food industry.

“It is always important to strive to make industrial syntheses more green, and using iron catalysts is not only much less toxic, but it is also much more cost effective,” said Jessica Sonnenberg, a PhD student and lead author of a paper published this week in the Journal of the American Chemical Society (“Iron Nanoparticles Catalyzing the Asymmetric Transfer Hydrogenation of Ketones”).

The March 27, 2012 University of Toronto news release provides a quote from Sonnenberg which suggests there’s still a lot more work to be done before the toxic metal-based catalysts currently being used could be replaced,

… “Catalysts, even cheap iron ones developed for these types of reaction, still suffer one major downfall,” explained Sonnenberg.  “They require a one-to-one ratio of very expensive organic ligands – the molecule that binds to the central metal atom of a chemical compound – to yield catalytic activity. Our discovery of functional surface nanoparticles opens the door to using much smaller ratios of these expensive compounds relative to the metal centres.  This drastically reduces the overall cost of the transformations.”

This work at the University of Toronto reminded me of another team also working on green catalysts for chemical reactions and also based in Canada, this time at McGill University. The McGill team lead by Chao-Jun Li was mentioned most recently here in a Jan. 10, 2011 posting where their ‘nanomagnetics’ technology to replace the current toxic catalysts  is described.

Nanobiotechnology research cooperation between India and Australia

The Nov. 28, 2010 news item on Nanowerk features a nanotechnology project which seems to have been 120 years in the making,

Professor Den Hollander Vice-Chancellor and President of Deakin University was excited as well about this partnership and said, ‘Alfred Deakin first recognized the possibilities of India and Australia working together nearly 120 years ago. It is pleasing for everyone at Deakin and TERI [The Energy and Resources Institute] to be involved in a partnership that not only fulfils his prophecies but which has mutual benefits for both nations,” She further added, ‘For Deakin to be partnered with such an organization led by a man of Dr. Pachauri’s [TERI, Director-General] standing is a massive complement. We hope to use the agreement with TERI as a model for other partners.’

Dr. R. K. Pachauri is a world-renowned economist and the head of the Nobel Prize winning UN Climate panel. TERI, The Energy and Resources Institute in India, and Deakin University in Australia have recently signed a memorandum of understanding,

The Energy and Resources Institute (TERI), India and Deakin University, Australia signed a memorandum of understanding (MOU) to announce the setting up of a Centre of Excellence, the TERI-Deakin Nano Biotechnology Research Centre in the field of Nano Biotechnology in India. This development is an outcome of TERI’s core capability of knowledge creation and development of efficient, environment friendly technologies and Deakin’s India Research Initiative (DIRI) which is committed towards establishing a lasting association with industry partners in India to chart a vibrant culture of research and scholastic excellence.

The initiative is also aimed at bridging the gap between industry and academia through research and collaboration of world leading experts, which will enable efficiency, effectiveness and provide solutions for a sustainable future through the utilization of biotechnology. The TERI- Deakin Nano Biotechnology Research Centre will bring to the fore Deakin’s expertise in the design and characterization of novel nanomaterials while TERI’s Biotechnology and Management of Bioresource Division (BMBD) will bring their wealth of experience in biotech applications in pharmacology, food, agriculture and environmental areas.