We’ve previously discussed the potential benefits of consuming psilocybin in oral strips, one version of which is currently being developed by the Toronto-based Cybin. Cybin’s work also includes novel tryptamine analogs. Specifically, they have demonstrated proof-of-concept for CYB003 and CYB004, which are deuterated analogs of tryptamines. What does it mean to say that a drug is deuterated, and how might it affect the clinical action of the finished product?
In the plainest terms possible, when you deuterate a molecule, you are replacing selected hydrogen atoms with deuterium atoms. Deuterium is one of three possible isotopes of hydrogen, along with protium and tritium.
For those who need a bit of a chemistry refresher, isotopes are analogs of a particular element that differ from their base elements by mass thanks to the number of neutrons in each atom’s nucleus. Protium has one proton and no neutrons, deuterium has one proton and one neutron, and tritium has one proton and two neutrons, with each of these being consecutively heavier than the last. Deuterium is found naturally in water in low amounts, usually at around a 1:6400 ratio to protium atoms. When fully extracted from ordinary water, the resulting liquid that contains only deuterium is known as “heavy water”.
Deuterium may be used in pharmacology for reasons we’re about to discuss, but it’s also used, along with tritium, in fusion reactions. Among fusion reactions, the reaction involving deuterium and tritium is the easiest to achieve and is currently the most viable means of producing fusion energy. Unlike deuterium, which is stable, tritium is radioactive — so we probably don’t want that in our drugs for now. If you aren’t a biochemist and you’ve heard of tritium before, but can’t quite remember how, the video below will likely remind you:
Deuterium, Where’s My Carbon?
So where’s the value in deuterating the molecules of certain drugs by replacing the hydrogen atoms with deuterium? For one thing, that extra neutron helps to form stronger bonds between deuterium and carbon atoms, compared to the same bonds with hydrogen. This has a host of different effects depending on the molecule, as well as the position of the deuterium within it. One of the main impacts is in altering the way that our bodies metabolize the drug, since it is harder to break down the chemical bonds through enzymatic action. In some cases, if it slows down the half-life of the active compound, it can mean a less frequent dosing schedule for ongoing drug therapies. In other instances, it can decrease toxic side effects by slowing down the production of toxic metabolites when your body breaks down the molecules. Deuteration has shown to improve pharmacokinetic qualities of some medications, thereby improving clinical efficacy — which is what Cybin is hoping to offer with their deuterated tryptamines.
The first patent for a deuterated version of an existing drug was filed in 1976, then another in 1978. Several patents were filed for deuterated volatile anaesthetics in the 90s. Since then, the practice of filing patents for deuterated versions of existing drugs has been gaining traction —to the point where big pharmaceutical companies have begun including deuterated versions of medications within their patents. As of 2019, 20 deuterated drugs were in development and 6 had reached Phase III clinical trials.
Deuterated drug analogs can offer many changes in how our bodies process the medicine we take. Cybin hopes to take advantage of changes to the pharmacokinetic profile of tryptamines (where and how fast they travel through our bodies) in order to offer psychedelic therapies with shorter or longer trip durations. Their oral thin strip technology offers similar benefits by altering the speed of onset of the psychedelic trip, altogether bypassing digestive metabolic processes. Using the CEREP 5-HT selectivity panel to examine serotonin agonist effects, Cybin has confirmed that these tryptamines retain their therapeutic pharmacology.
In April, Cybin confirmed treatment of alcohol use disorder as the indication of choice for CYB003 —a problem that has become more prevalent due to the realities of the Covid-19 pandemic. Earlier, in March, Cybin signed an agreement with Catalent Inc. to produce CYB003 in the form of freeze-dried, orally disintegrating tablets that can be taken without water. This means that it can be taken in a similar fashion to oral thin strips, which may add a further twist to the changes in its metabolic interactions.