Microdosing, or micro-dosing, is a technique for studying the behaviour of drugs in humans through the administration of doses so low ("sub-therapeutic") they are unlikely to produce whole-body effects, but high enough to allow the cellular response to be studied. 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" is also sometimes 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 what is termed microdispensing. For example, cannabis microdosing[3][4] and psychedelic microdosing.[5]

Techniques edit

The basic approach is to label a candidate drug using the radio isotope carbon-14,[6] 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).[7]

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:[8] 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,[9] 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,[10] 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 edit

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,[11] though there is very little evidence supporting these purported effects as of 2019.[12] In this context, microdosing is considered an application of hormesis.

Protocols edit

According to microdosify.com, there are 8 types of microdosing protocols or routines. Following are the types of microdosing protocols:[13]

  • Fadiman Protocol
  • Paul Stamets Stack
  • Two Days a Week Protocol
  • Every Other Day Microdosing Protocol
  • Nightcap Protocol
  • Intuitive Microdosing Protocol
  • The Asha Sultana Protocol
  • The 2:1 Protocol

Impact of use edit

In 2021 it was reported in a study done that an increased conscientiousness was seen due to microdosing. [14] Microdosing was seen to have improved mental health after microdosing with psychedelics after 30 days.[15] More research is needed to ultimately decide weather or not microdosing helps those who suffer from depression and anxiety. [15] Microdosing has not seen to improve participants motor responses, attention, and cognitive problem-solving abilities.[15] Microdosing is still under investigation as to weather it works or if it does not. Researchers are investigating into microdosing more and more, the placebo effect causes difficulties in research on this topic.[16]

It is reported that 15 of the 20 largest pharmaceutical companies have now used microdosing in drug development, and the use of the technique has been provisionally endorsed by both the European Medicines Agency and the Food and Drug Administration. It was once expected that by 2010, human microdosing would have gained a secure foothold at the discovery-preclinical interface, driven by early measurement of candidate drug behavior in humans and by irrefutable economic arguments.[citation needed]

In January 2006, the European Union Microdose AMS Partnership Programme (EUMAPP) was launched.[17] 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.[18]

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.[19] This study provides an example of the application of microdosing in circumstances where pre-clinical data were not sufficient to provide accurate information to guide first-in-human (FIH) study design.

See also edit

References edit

  1. ^ Burt, Tal; Young, Graeme; Lee, Wooin; Kusuhara, Hiroyuki; Langer, Oliver; Rowland, Malcolm; Sugiyama, Yuichi (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. ISSN 1474-1784. PMID 32901140.
  2. ^ Tablets & Capsules, March 2009. "Micro-dosing equipment fills niche in R&D, clinical trial materials".
  3. ^ "The Buzz without the High: Checkout this Popular Cannabis Trend in 2019". New England Leaf. Archived from the original on 2019-08-05. Retrieved 2019-08-05.
  4. ^ "Cannabis Microdosing - A Layman's Guide". House of Budz. Archived from the original on 2021-07-26. Retrieved 2017-04-10.
  5. ^ "Everything You Wanted to Know About Microdosing (But Were Afraid to Ask)". The Huffington Post. 13 January 2016.
  6. ^ Babin, Victor; Taran, Frédéric; Audisio, Davide (2022-06-27). "Late-Stage Carbon-14 Labeling and Isotope Exchange: Emerging Opportunities and Future Challenges". JACS Au. 2 (6): 1234–1251. doi:10.1021/jacsau.2c00030. ISSN 2691-3704. PMC 9241029. PMID 35783167.
  7. ^ [1] Animal Testing Perspectives: Microdosing
  8. ^ Kutschera, Walter (2022-05-11). "An overview of world-wide AMS facilities".
  9. ^ Miami, Beta Analytic 4985 S. W. 74th Court (2015-04-14). "Accelerator Mass Spectrometry, C14 Dating, What is AMS?". Carbon Dating Service, AMS Miami - Beta Analytic. Retrieved 2023-05-31.{{cite web}}: CS1 maint: numeric names: authors list (link)
  10. ^ Broek, Taylor; Ognibene, Ted; McFarlane, Karis; Moreland, Kimber; Brown, Tom; Bench, Graham (2021-07-15). "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. doi:10.1016/j.nimb.2021.01.022. PMC 10854407. PMID 38344059.
  11. ^ Fadiman, James (2016-01-01). "Microdose research: without approvals, control groups, double blinds, staff or funding". Psychedelic Press. XV.
  12. ^ Anderson, Thomas; Petranker, Rotem; Christopher, Adam; Rosenbaum, Daniel; Weissman, Cory; Dinh-Williams, Le-Anh; Hui, Katrina; Hapke, Emma (December 2019). "Psychedelic microdosing benefits and challenges: an empirical codebook". Harm Reduction Journal. 16 (1): 43. doi:10.1186/s12954-019-0308-4. ISSN 1477-7517. PMC 6617883. PMID 31288862.
  13. ^ Zoey, Roy (19 September 2023). "Ultimate Guide to Microdosing Protocols with Psilocybin (2023)". Microdosify.
  14. ^ Dressler, Hannah M.; Bright, Stephen J.; Polito, Vince (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.
  15. ^ a b c Rootman, Joseph M.; Kiraga, Maggie; Kryskow, Pamela; Harvey, Kalin; Stamets, Paul; Santos-Brault, Eesmyal; Kuypers, Kim P. C.; Walsh, Zach (2022-06-30). "Psilocybin microdosers demonstrate greater observed improvements in mood and mental health at one month relative to non-microdosing controls". Scientific Reports. 12 (1): 11091. doi:10.1038/s41598-022-14512-3. ISSN 2045-2322. PMC 9246852.
  16. ^ MD, Peter Grinspoon (2022-09-19). "The popularity of microdosing of psychedelics: What does the science say?". Harvard Health. Retrieved 2024-04-16.
  17. ^ "European Union Microdose AMS Partnership Programme". European Commission: CORDIS EU Research Results.
  18. ^ Burt, T; Lappin, G; Voung, L; John, C; Wildt, SN; Sugiyama, Y; Rowland, M (2016-03-30). "Microdosing and Other Phase 0 Clinical Trials: Facilitating Translation in Drug Development".
  19. ^ Okour, Malek; Derimanov, Geo; Barnett, Rodger; Fernandez, Esther; Ferrer, Santiago; Gresham, Stephanie; Hossain, Mohammad; Gamo, Francisco-Javier; Koh, Gavin; Pereira, Adrian; Rolfe, Katie; Wong, Deborah; Young, Graeme; Rami, Harshad; Haselden, John (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.
  • "The use of accelerator mass spectrometry to obtain early human ADME/PK data" G Lappin & R C Garner Expert Opinion in Pug Metabolite and Toxic (2005) 1(1):23-31
  • "Improved early clinical development through human microdosing studies" I Wilding & J Bell Drug Discovery Today 2005 July 1;10(13):890-4
  • "New ultrasensitive detection technologies and techniques for use in microdosing studies" G Lappin, C Wagner, O Langer & N van de Merbel Bioanalysis 2009 May 1(2):357–366 doi:10.4155/bio.09.40

External links edit