Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis; Vizeli et al. 2021
Journal Club #8
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Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis
Why they did it
Your body is constantly breaking down big molecules into small molecules. It either uses those small molecules to build other big molecules that it needs to live, or else it sends those small bois to your excretion centers for toilet time. The thousands of enzymes and pathways by which your enzymes break stuff down and build stuff up is called your metabolism.
Drug effects only last so long because over time, our body metabolizes them into different molecules. Sometimes those molecules still do fun stuff in our brains, like psilocin and noribogaine. Sometimes the drug is converted to an inert molecule, and so begins your comedown.
We still don’t know exactly how LSD is metabolized in our bodies, but it was recently discovered that a family of liver enzymes called the cytochrome p450 (CYP) enzymes are involved.
Enzymes are proteins, and proteins are encoded by genes in your DNA (via RNA). Genes are regions of DNA composed of a pattern of nucleotides. For some genes, different versions exist in a population of organisms. Slightly different genes will encode for slightly different proteins, sometimes causing noticeable differences in the proteins function.
DNA is transcribed into RNA, which is translated into proteins. This is the central dogma of molecular biology. There are different versions of the genes underlying some CYP enzymes. Specifically, an enzyme called CYP2D6 has two versions; one version codes for the fast-metabolizing CYP2D6 enzyme, and the other the slow-metabolizing CYP2D6 enzyme.
It has already been demonstrated that the version of CYP2D6 gene one has influences the metabolism of MDMA. Maybe it does the same for LSD 🤔
What they did
The authors set out to characterize how different CYP gene versions impact the metabolism and subjective effects (the trip) of LSD in human subjects.
They hypothesized that people with the slow-metabolizing version of CYP2D6 would have higher concentrations of LSD in their plasma for longer and experience stronger trips than people with the fast-metabolizing CYP2D6 version.
This study was run on 81 subjects (41 women) of European descent pooled from four different LSD studies that each used the same industry standard, randomized, double-blind, placebo-controlled, crossover design. Each study was pre-registered at ClinicalTrials.gov and were run in the same laboratory (The Leichti Lab at University Hospital Basel).
Each study had a slightly different dosing regimen, but each participant consumed either a gelatin capsule or liquid solution of LSD, experienced the trip under supervision while reclined in a hospital bed, most often while listening to music.
The researchers collected four sets of data:
Pharmacokinetic analysis (Pharmaco = drug, kinetic = movement)
Researchers took repeated blood samples from subjects during their trip to assess the concentration of LSD circulating in their bodies
Per subject, LSD concentration over time was plotted as a curve. The area under the curve (AUC) is a pharmacokinetic measurement used to understand the total exposure of a drug to a body over time.
Larger area under the curve = higher total exposure to LSD
Important parameters related to AUC:
Cmax: Maximum concentration in plasma
Tmax: Time of maximum concentration
t1/2 or half-life: Time required to reduce the plasma concentration to one-half of its initial value
Physiological effects
They took blood pressure, heart rate, and body temperature measurements throughout the trip.
Standard way to make sure everything is going okay, and also important to know if any abnormal physiological effects occur which could explain data
Subjective effects
Assessed in two ways:
Visual analog scales (VAS): A visual measurement system quantify symptoms with continuous rather than discrete values. For example, pain can be more accurately categorized on a scale of 0-100%, rather than as “low”, “mild”, or “intense”.
Subjects were repeatedly presented three VAS’s measuring “Any drug effect”, “good drug effect” and “bad drug effect”, rated from “not at all” to “extremely”.
5 Dimensions of Altered States of Consciousness (5D-ASC) scale: A standard questionnaire given to subjects after their trip. The three main subscales that describe altered consciousness are Oceanic Boundlessness (OB), Anxious Ego Dissolution (AED), and Visionary Restructuring (VR).
Genotyping
The researchers deployed single-nucleotide polymorphism (SNP) genotyping to determine what versions of CYP enzymes the subjects had.
A SNP is a specific location within a gene where one nucleotide has been substituted by another. These small changes are what causes people to have the same enzymes but with different functions.
Different human populations tend to have different frequencies of specific SNP’s, so they focused on the SNP’s of CYP genes most common to individuals with European ancestry, as this is where their subject pool is from.
To assess CYP genotypes, the researchers took blood samples from each subject, extracted and purified DNA from the samples, and then ran the purified DNA through a real time polymerase chain reaction (PCR) procedure. This procedure attaches a signal to specific polymorphisms, and then amplifies that signal so that we can “read” which polymorphisms are present in a given DNA sample.
What they found
The results are fairly simple: People with the slow-metabolizing version of CYP2D6 have higher LSD exposure, and experience stronger subjective effects.
There was no difference in Cmax between both fast- and slow-metabolizers, i.e. their maximum concentration of LSD was no different. However, the slow-metabolizers had longer t1/2 values, which means that the LSD was circulating at higher levels for longer. This expands the plasma LSD concentration vs. time curve for this group, thereby increasing the AUC. Remember: Larger area under the curve = higher total exposure to LSD
Slow metabolizers had a longer duration of reported subjective effects, and consistently ranked these effects stronger the the fast metabolizers. Specifically, they rated higher on the total 5D-ASC scale, and the AED and VR subscales.
It should be noted that only 7 of the 81 subjects had the slow-metabolizing version of the gene.
The other CYP enzymes studied did not have any association with pharmacokinetic and subjective effects of LSD. It seems like of this enzyme class, CYPD26 is the most important for understanding LSD metabolism.
My Take
This study was conducted using data from subjects originally enrolled in four separate but similar Phase 1 studies on the effects of LSD in human subjects. Recruiting human subjects is challenging and expensive, and so researchers try to collect as much data as they can while they got ‘em. The four original studies are pretty boring, but in a good way. They report fundamental details about the fate and effects of LSD in humans. This study takes this line of study a step further down the human rabbit hole, straight into our genetics.
If all of the CYP enzymes played a role in LSD metabolism, it would be less interesting than what they did find: There is a CYP enzyme with multiple versions, and the version one has can explain why they might experience LSD differently than someone else. Further, CYP2D6 also plays a role in the metabolism of MDMA and ibogaine (the latter an interesting connection not mentioned in the paper). The drug you take and the set and setting present when you take it will always be important, but now we can see how our individual genetics can play a role too.
Finally, from a medical standpoint, the ability to predict an individual’s reaction to a psychedelic is useful for customizing treatment. Overdose is not really an issue with LSD, but there are doses that are optimal for LSD’s therapeutic benefit. In this context, someone who has the slow-metabolizing version of CYP2D6 might need less LSD for their ideal dose, while the fast-metabolizing people could benefit more from a higher dose. The ability to maximize the benefit one receives from LSD seems like a net good, and I assume the FDA agrees.
These studies were funded by Swiss National Science Foundation grants to Dr. Matthias Leichti to study the pharmacology of serotonergic substances and their effects on human emotional processing. Dr. Leichti is also a consultant for MindMed. MindMed licensed this knowledge upon publication for use in developing personalized LSD dosing products.
I appreciate your feedback on how I did breaking down this science. Let me know in the comments:
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📃 Here’s the paper:
Vizeli, P. et al. Genetic influence of CYP2D6 on pharmacokinetics and acute subjective effects of LSD in a pooled analysis. Sci. Rep.11, 1–9 (2021).
Tunes for your next flow state
🔥 Luttrell - Music for My Memories EP Pt. II
🍯 The Touré-Raichel Collective - The Paris Session
Very interesting! I've always found LSD to be very underwhelming while my counterparts are, as we say "tripping balls" - perhaps this is why. Thanks Tyler!
Hey Tyler, this is Jordan. Great write up and fascinating to learn. Congrats you and Kassi on the house and keep the good studies rolling! Cheers bud!