Computational modeling showed that human serum albumin, the most abundant blood protein, avidly binds multiple cannabinoid drugs, potentially acting as a key determinant of their effectiveness and dosing.
Read this if you are interested in how cannabinoid drugs travel through the body and why people respond differently to the same dose.
HSA binds cannabinoid drugs with energies of -5.4 to -10.9 kcal/mol at blood concentrations of 750 micromolar
What the researchers found
This study investigated whether human serum albumin (HSA), the most abundant protein in blood plasma, serves as a major transporter for cannabinoid drugs.
Using computational docking methods, the researchers found that HSA binds strongly to a wide range of cannabinoid compounds: indirect agonists (URB597, AM5206, JZL184, JZL195, AM404), direct agonists (WIN55,212-2, CP55,940), and the antagonist/inverse agonist SR141716 (rimonabant).
Binding energies ranged from -5.4 to -10.9 kcal/mol. Given the high concentration of HSA in blood (~750 micromolar), the modeling suggests these complexes would form readily under physiological conditions.
Since HSA already binds the natural endocannabinoid anandamide and THC, it appears to be a universal carrier for cannabinoid compounds. This has practical implications: the amount of HSA in a patient's blood could significantly affect how much "free" (active) cannabinoid drug is available to produce effects.
Why it matters
If HSA is a major determinant of cannabinoid drug levels in the blood, it could explain why cannabis and cannabinoid drugs affect people differently. Patients with lower albumin levels (liver disease, malnutrition, elderly) might experience stronger effects from the same dose, while those with higher albumin might need more.
The numbers in context
Binding energies: -5.4 to -10.9 kcal/mol across 8 cannabinoid drugs. HSA blood concentration: ~750 micromolar. THC and anandamide are already known to bind HSA.
How the study worked
In silico molecular docking study using computational methods to model the binding interactions between HSA and eight different cannabinoid drugs. Free energy calculations estimated binding strength. Results were contextualized against known HSA concentration in human blood.
What this study cannot tell us
Computational (in silico) modeling only, without experimental confirmation of binding affinities or biological relevance. Docking scores do not always accurately predict real binding behavior. The study does not address whether HSA binding changes cannabinoid drug activity in living systems.
How to read the evidence
Computational modeling study without experimental validation. Preliminary but raises important pharmacokinetic questions.
When this study was published
Published in 2017.
The bigger picture
Drug-protein binding is a fundamental concept in pharmacology that has been largely unexplored for cannabinoids. If HSA binding significantly affects cannabinoid bioavailability, it could influence dosing guidelines, explain individual variation in response, and become a factor in drug interaction predictions.
Questions still open
- Do patients with low albumin (liver disease, malnutrition) experience stronger cannabis effects? Could HSA binding explain some drug interactions between cannabinoids and other highly protein-bound drugs? Would measuring albumin levels help personalize cannabinoid dosing?
Common questions
Why do people respond differently to the same cannabis dose?
What is human serum albumin?
Read the original research
Human serum albumin: A modulator of cannabinoid drugs.
IUBMB life, 69(11), 834-840
Citation
Leboffe, Loris; di Masi, Alessandra; Trezza, Viviana; Polticelli, Fabio; Ascenzi, Paolo. (2017). Human serum albumin: A modulator of cannabinoid drugs.. IUBMB life, 69(11), 834-840. https://doi.org/10.1002/iub.1682
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