Microdosing

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"Microdose" redirects here; not to be confused with Microdose (album).

Microdosing, or micro-dosing, involves the administration of sub-therapeutic doses of drugs to study their effects in humans, aiming to gather preliminary data on safety, pharmacokinetics, and potential therapeutic benefits without producing significant physiological effects. This is called a "Phase 0 study" and is usually conducted before clinical Phase I to predict whether a drug is viable for the next phase of testing. Human microdosing aims to reduce the resources spent on non-viable drugs and the amount of testing done on animals. [1]

Less commonly, the term "microdosing" can be used to refer to precise dispensing of small amounts of a drug substance (e.g., a powder API) for a drug product (e.g., a capsule)[2] and, when the drug substance also happens to be liquid, this can potentially overlap with the term microdispensing (see: Psychedelic microdosing, for example).[3]

Techniques

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The basic approach is to label a candidate drug using the radio isotope carbon-14,[4] then administer the compound to human volunteers at levels typically about 100 times lower than the proposed therapeutic dosage (from around 1 to 100 micrograms but not above).[citation needed]

As only microdose levels of the drug are used, analytical methods are limited. Extreme sensitivity is needed. Accelerator mass spectrometry (AMS) is the most common method for microdose analysis. AMS was developed in the late 1970s from two distinct research threads with a common goal:[5] an improvement in radiocarbon dating that would make efficient use of datable material and that would extend the routine and maximum reach of radiocarbon dating. AMS is routinely used in geochronology and archaeology,[6] but biological applications began appearing in 1990 mainly due to the work of scientists at Lawrence Livermore National Laboratory. AMS service is now more accessible for biochemical quantitation from several private companies and non-commercial access to AMS is available at the National Institutes of Health (NIH) Research Resource at Lawrence Livermore National Laboratory,[7] or through the development of smaller affordable spectrometers. AMS does not measure the radioactivity of carbon-14 in microdose samples. AMS, like other mass spectrometry methods, measures ionic species according to mass-to-charge ratio.

Psychedelic

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Main article: Psychedelic microdosing

Davivid Rose (also known as jdyf333 and as Hank Exclamation Point) invented the word "microdose" in 1980 to describe a 5 microgram dose of LSD.

"If the story about 'Clearlight Brand "microdose" LSD' is true, then the origin of the term 'microdose' for very small doses of LSD precedes all other uses of the term, e.g. in pharmacology (since 1995), in agriculture (since 2005) and by Fadiman (2011)."

---German psychiatrist Torsten Passie, in his 2019 book The Science of Microdosing Psychedelics, published by Psychedelic Press. The book reproduces a page of the product information leaflet for "Clearlight brand 'microdose' LSD" that Davivid Rose wrote and distributed in early 1988.

("The name Clear Light was a promise about the mind-state the material itself produced: as a famously 'clean' form of LSD, its effects were described as limpid, even at high doses. In later decades, the first branded packaging of LSD microdoses [5 μg] were also named Clear Light."

---Erik Davis, on page 20 of his 2023 book Blotter-The Untold Story of an Acid Medium, published by The MIT Press. Davivid Rose is the person who produced the first branded packaging of 5 μg LSD microdoses mentioned by Davis.)

The first publicly published mention of microdose LSD was in "LSD Doodles--Catalogue Number One" by Hank Exclamation Point, a 1991 coloring book for adults that was published by Exploding Mandala Press in Berkeley, California in a very tightly-controlled limited edition. Each copy came with a set of color pencils, a pencil sharpener, and a packet containing 25 doses of Clearlight brand "Microdose" LSD. Each copy of the coloring book had a copy of the product insert that came with each packet ("Important Information for Potential Users of Clearlight-brand 'Microdose' LSD") bound into it.

(["Nowhere are Fadiman and Gruber’s words ‘being in the right mind at the right time’ more applicable than for the military fighter pilot. The world moving, quite literally, at Mach 1 creates an unforgiving cauldron where incoherent or incongruent thought yields catastrophic results. The difference between life and death depends on fighter pilots finding their mental best selves.”

---Buster Glosson, "three-star general, USAF [Ret.], author of War with Iraq", in a positive review on amazon dot com of Your Symphony of Selves: Discover and Understand More of Who We Are, a book written by James Fadiman and Jordan Gruber that was published in 2020.

["Davivid Rose—who invented the term 'Microdosing' and correctly implemented it in the early 80’s—is citing Jim and I in Symphony of Selves. Pretty cool."

---jordangruber123, 1.21. 2024, on Instagram dot com., commenting about something Davivid Rose posted on Flickr dot com. Jordan Gruber is the co-author of the book Microdosing for Healing, Health and Enhanced Performance by James Fadiman and Jordan Gruber, published by Macmillan in 2025.])

The first large batch of microdoses Davivid Rose produced were made in Berkeley in 1980 from LSD he illegally purchased from an underground source. He called them "Clearlight brand Mind Vitamin Tablets" and packaged them in labeled shrink-wrapped brown glass bottles, each containing 100 tablets. Each tablet contained 100 milligrams of ascorbic acid (vitamin C) and 5 micrograms of LSD. This first large batch of microdose LSD was given away, not sold

Davivid Rose manufactured a second labeled batch of microdoses in early 1988. Each 25-dose package of this second batch was distributed with a product information leaflet reading “Clearlight brand 'microdose' LSD". The LSD in this second labeled batch of microdoses was said to have been legally synthesized by a commercial lab for use as comparative samples by law enforcement and medical labs. Davivid Rose put it on perforated paper. More than 400,000 doses were manufactured. Most of this second batch was seized by Drug Enforcement Administration (DEA) agents in Oakland, California in early January 1993. No one was arrested. (The DEA has a strict policy of NOT giving the details of drug seizures, especially in cases where they have not arrested anyone. No one has been able to obtain written verification of this January 1993 seizure.) The portion of the second batch that was distributed was given away, not sold.


Psychedelic microdosing is the practice of using sub-threshold doses (microdoses) of serotonergic psychedelic drugs in an attempt to improve creativity, boost physical energy level, emotional balance, increase performance on problems-solving tasks and to treat anxiety, depression and addiction,[citation needed] though there is very little evidence supporting these purported effects as of 2019.[8]

Impact of psychedelic microdosing

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In 2021 it was reported in a study done that an increased conscientiousness was seen due to microdosing. [9] Microdosing was seen to have improved mental health after microdosing with psychedelics after 30 days.[10] More research is needed to ultimately decide whether or not microdosing helps those who suffer from depression and anxiety. [10] Microdosing has not seen to improve participants motor responses, attention, and cognitive problem-solving abilities.[10] Microdosing is still under investigation as to whether it works or not. Researchers are investigating into microdosing more and more, the placebo effect causes difficulties in research on this topic.[11]

In January 2006, the European Union Microdose AMS Partnership Programme (EUMAPP) was launched.[12] Ten organizations from five different countries (United Kingdom, Sweden, Netherlands, France, and Poland) will study various approaches to the basic AMS technique. The study is set to be published in 2009.[13]

One of the most meaningful potential outcomes of Phase-0/Microdosing studies is the early termination of development. In 2017, Okour et al published the first example in literature of a termination of an oral drug based on IV microdose data.[14]

See also

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References

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  1. ^ Burt T, Young G, Lee W, Kusuhara H, Langer O, Rowland M, et al. (November 2020). "Phase 0/microdosing approaches: time for mainstream application in drug development?". Nature Reviews. Drug Discovery. 19 (11): 801–818. doi:10.1038/s41573-020-0080-x. PMID 32901140.
  2. ^ Tablets & Capsules, March 2009. "Micro-dosing equipment fills niche in R&D, clinical trial materials".
  3. ^ Gregoire C (13 January 2016). "Everything You Wanted to Know About Microdosing (But Were Afraid to Ask)". The Huffington Post.
  4. ^ Babin V, Taran F, Audisio D (June 2022). "Late-Stage Carbon-14 Labeling and Isotope Exchange: Emerging Opportunities and Future Challenges". JACS Au. 2 (6): 1234–1251. doi:10.1021/jacsau.2c00030. PMC 9241029. PMID 35783167.
  5. ^ Kutschera W (2023). "An overview of world-wide AMS facilities". Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms. 538: 87–94. Bibcode:2023NIMPB.538...87K. doi:10.1016/j.nimb.2023.02.016.
  6. ^ "Accelerator Mass Spectrometry, C14 Dating, What is AMS?". Carbon Dating Service, AMS Miami - Beta Analytic. 2015-04-14. Retrieved 2023-05-31.
  7. ^ Broek TA, Ognibene TJ, McFarlane KJ, Moreland KC, Brown TA, Bench G (July 2021). "Conversion of the LLNL/CAMS 1 MV biological AMS system to a semi-automated natural abundance 14C spectrometer: system optimization and performance evaluation". Nuclear Instruments and Methods in Physics Research Section B: Beam Interactions with Materials and Atoms. 499 (published 2021-05-21): 124–132. Bibcode:2021NIMPB.499..124B. doi:10.1016/j.nimb.2021.01.022. PMC 10854407. PMID 38344059.
  8. ^ Anderson T, Petranker R, Christopher A, Rosenbaum D, Weissman C, Dinh-Williams LA, et al. (July 2019). "Psychedelic microdosing benefits and challenges: an empirical codebook". Harm Reduction Journal. 16 (1): 43. doi:10.1186/s12954-019-0308-4. PMC 6617883. PMID 31288862.
  9. ^ Dressler HM, Bright SJ, Polito V (2021-03-24). "Exploring the relationship between microdosing, personality and emotional insight: A prospective study". Journal of Psychedelic Studies. 5 (1): 9–16. doi:10.1556/2054.2021.00157.
  10. ^ a b c Rootman JM, Kiraga M, Kryskow P, Harvey K, Stamets P, Santos-Brault E, et al. (June 2022). "Psilocybin microdosers demonstrate greater observed improvements in mood and mental health at one month relative to non-microdosing controls". Scientific Reports. 12 (1): 11091. Bibcode:2022NatSR..1211091R. doi:10.1038/s41598-022-14512-3. PMC 9246852. PMID 35773270.
  11. ^ MD PG (2022-09-19). "The popularity of microdosing of psychedelics: What does the science say?". Harvard Health. Retrieved 2024-04-16.
  12. ^ "European Union Microdose AMS Partnership Programme". European Commission: CORDIS EU Research Results.
  13. ^ Burt T, Yoshida K, Lappin G, Vuong L, John C, de Wildt SN, et al. (April 2016). "Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development". Clinical and Translational Science. 9 (2): 74–88. doi:10.1111/cts.12390. PMC 5351314. PMID 26918865.
  14. ^ Okour M, Derimanov G, Barnett R, Fernandez E, Ferrer S, Gresham S, et al. (March 2018). "A human microdose study of the antimalarial drug GSK3191607 in healthy volunteers". British Journal of Clinical Pharmacology. 84 (3): 482–489. doi:10.1111/bcp.13476. PMC 5809343. PMID 29168205.

Further reading

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  • Lappin G, Garner RC (June 2005). "The use of accelerator mass spectrometry to obtain early human ADME/PK data". Expert Opinion on Drug Metabolism & Toxicology. 1 (1): 23–31. doi:10.1517/17425255.1.1.23. PMID 16922650.
  • Wilding IR, Bell JA (July 2005). "Improved early clinical development through human microdosing studies". Drug Discovery Today. 10 (13): 890–894. doi:10.1016/S1359-6446(05)03509-9. PMID 15993808.
  • Lappin G, Wagner CC, Langer O, van de Merbel N (May 2009). "New ultrasensitive detection technologies and techniques for use in microdosing studies". Bioanalysis. 1 (2): 357–66. doi:10.4155/bio.09.40. PMID 21083172.
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