Routes of Administration in Psychedelic Drug Research

Properties of psychedelics determine optimal routes of administration.

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The route of administration refers to the way in which medication is given and how users administer their drugs of choice.1 Psychedelics are commonly taken recreationally by oral or respiratory administration, but they can be taken in other ways as well, such as mucosally or intravenously. Understanding how the route of administration changes the effectiveness of a compound is important in the translational value of psychedelic research. Translational research typically means that what is learned through basic science can be translated to what is known clinically.

Why Does the Route Matter?

The way a drug is taken can alter its efficacy. Things like the size and molecular structure of a compound, as well as how the compound is absorbed and metabolized can determine the best way to administer it.1 

For example, LSD is highly potent and easily absorbed.2 The most common routes of administration are by mouth (oral) and under the tongue or mouth (sublingual or buccal, respectively)4 due to LSDs high oral availability and quick absorption through the stomach lining and mucous membranes in the mouth.2,3 LSD is mainly metabolized through enzymes in the liver and therefore taking it sublingually may provide higher absorption as it bypasses some liver-mediated metabolism.3

Another psychedelic compound DMT has a different chemical structure than LSD. The most common routes of administration are through smoking (inhalation) or by mouth.5 Due to its chemical structure, DMT  is rapidly metabolized in the brain by monoamine oxidase enzymes (MAOs) which is why its effects are so short-acting.5 MAOs are the enzymes mainly responsible for the degradation of amine neurotransmitters, like serotonin and dopamine, and many psychedelics.6 When taken orally, the compound is also rapidly metabolized by MAOs in the liver, so smoking the compound in combination with ß-carboline compounds (they block the action of MAOs) is the most popular route of administration.5,7

The Translational Value of Routes of Administration

Many basic science articles that focus on psychedelics use intraperitoneal injections, oral administration, or subcutaneous injections. Intraperitoneal injections refer to injecting an animal in the tissue that lines the abdominal wall.4 Subcutaneous refers to the injection of a compound just beneath the skin.

Humans don’t typically inject psychedelics into their abdominal cavity or under their skin, so are these routes translational? The answer is…kind of. One important thing to remember when reading basic science research is that it’s usually in an early stage of drug development, like discovery or characterization. In these stages, experiments are done to understand the basic pharmacology, targets, and effects a compound has in a system or a disease state.8 This research is usually done in small rodents or cells. 

Researchers need to make sure they understand the drug’s effects on a system before they can move forward to the formulation and drug delivery to determine the proper route of administration.8,9 A recent review on the use of intraperitoneal administration determined that using this route in rodent studies is the best way to evaluate target engagement and the behavioral effects of a compound.9 

Conclusion

It is important to determine the proper formulation of a drug and the appropriate route of administration for clinical success in drug development. Researchers are using the best routes possible in preclinical studies of psychedelics. By gaining an understanding of these compounds in the early stages, research can move forward to the next steps in drug development.

Alaina is a PhD student in pharmacology at Virginia Commonwealth University. Her research focuses on behavioral changes and circuitry of psychedelics involved in preclinical models of addiction and depression.

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