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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, psychedelic microdosing. [3]
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 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, [8] though there is very little evidence supporting these purported effects as of 2019. [9]
In 2021 it was reported in a study done that an increased conscientiousness was seen due to microdosing. [10] Microdosing was seen to have improved mental health after microdosing with psychedelics after 30 days. [11] More research is needed to ultimately decide whether or not microdosing helps those who suffer from depression and anxiety. [11] Microdosing has not seen to improve participants motor responses, attention, and cognitive problem-solving abilities. [11] 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. [12]
In January 2006, the European Union Microdose AMS Partnership Programme (EUMAPP) was launched. [13] 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. [14]
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. [15]
Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states and an expansion of consciousness. Also referred to as classic hallucinogens or serotonergic hallucinogens, the term psychedelic is sometimes used more broadly to include various types of hallucinogens, such as those which are atypical or adjacent to psychedelia like salvia and MDMA, respectively.
Mass spectrometry (MS) is an analytical technique that is used to measure the mass-to-charge ratio of ions. The results are presented as a mass spectrum, a plot of intensity as a function of the mass-to-charge ratio. Mass spectrometry is used in many different fields and is applied to pure samples as well as complex mixtures.
Electrospray ionization (ESI) is a technique used in mass spectrometry to produce ions using an electrospray in which a high voltage is applied to a liquid to create an aerosol. It is especially useful in producing ions from macromolecules because it overcomes the propensity of these molecules to fragment when ionized. ESI is different from other ionization processes since it may produce multiple-charged ions, effectively extending the mass range of the analyser to accommodate the kDa-MDa orders of magnitude observed in proteins and their associated polypeptide fragments.
In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation.
Tandem mass spectrometry, also known as MS/MS or MS2, is a technique in instrumental analysis where two or more stages of analysis using one or more mass analyzer are performed with an additional reaction step in between these analyses to increase their abilities to analyse chemical samples. A common use of tandem MS is the analysis of biomolecules, such as proteins and peptides.
Metabolomics is the scientific study of chemical processes involving metabolites, the small molecule substrates, intermediates, and products of cell metabolism. Specifically, metabolomics is the "systematic study of the unique chemical fingerprints that specific cellular processes leave behind", the study of their small-molecule metabolite profiles. The metabolome represents the complete set of metabolites in a biological cell, tissue, organ, or organism, which are the end products of cellular processes. Messenger RNA (mRNA), gene expression data, and proteomic analyses reveal the set of gene products being produced in the cell, data that represents one aspect of cellular function. Conversely, metabolic profiling can give an instantaneous snapshot of the physiology of that cell, and thus, metabolomics provides a direct "functional readout of the physiological state" of an organism. There are indeed quantifiable correlations between the metabolome and the other cellular ensembles, which can be used to predict metabolite abundances in biological samples from, for example mRNA abundances. One of the ultimate challenges of systems biology is to integrate metabolomics with all other -omics information to provide a better understanding of cellular biology.
Accelerator mass spectrometry (AMS) is a form of mass spectrometry that accelerates ions to extraordinarily high kinetic energies before mass analysis. The special strength of AMS among the different methods of mass spectrometry is its ability to separate a rare isotope from an abundant neighboring mass. The method suppresses molecular isobars completely and in many cases can also separate atomic isobars. This makes possible the detection of naturally occurring, long-lived radio-isotopes such as 10Be, 36Cl, 26Al and 14C.
In mass spectrometry, matrix-assisted laser desorption/ionization (MALDI) is an ionization technique that uses a laser energy-absorbing matrix to create ions from large molecules with minimal fragmentation. It has been applied to the analysis of biomolecules and various organic molecules, which tend to be fragile and fragment when ionized by more conventional ionization methods. It is similar in character to electrospray ionization (ESI) in that both techniques are relatively soft ways of obtaining ions of large molecules in the gas phase, though MALDI typically produces far fewer multi-charged ions.
Liquid chromatography–mass spectrometry (LC–MS) is an analytical chemistry technique that combines the physical separation capabilities of liquid chromatography with the mass analysis capabilities of mass spectrometry (MS). Coupled chromatography – MS systems are popular in chemical analysis because the individual capabilities of each technique are enhanced synergistically. While liquid chromatography separates mixtures with multiple components, mass spectrometry provides spectral information that may help to identify each separated component. MS is not only sensitive, but provides selective detection, relieving the need for complete chromatographic separation. LC–MS is also appropriate for metabolomics because of its good coverage of a wide range of chemicals. This tandem technique can be used to analyze biochemical, organic, and inorganic compounds commonly found in complex samples of environmental and biological origin. Therefore, LC–MS may be applied in a wide range of sectors including biotechnology, environment monitoring, food processing, and pharmaceutical, agrochemical, and cosmetic industries. Since the early 2000s, LC–MS has also begun to be used in clinical applications.
Isotope-ratio mass spectrometry (IRMS) is a specialization of mass spectrometry, in which mass spectrometric methods are used to measure the relative abundance of isotopes in a given sample.
Pharmacokinetics, sometimes abbreviated as PK, is a branch of pharmacology dedicated to describing how the body affects a specific substance after administration. The substances of interest include any chemical xenobiotic such as pharmaceutical drugs, pesticides, food additives, cosmetics, etc. It attempts to analyze chemical metabolism and to discover the fate of a chemical from the moment that it is administered up to the point at which it is completely eliminated from the body. Pharmacokinetics is based on mathematical modeling that places great emphasis on the relationship between drug plasma concentration and the time elapsed since the drug's administration. Pharmacokinetics is the study of how an organism affects the drug, whereas pharmacodynamics (PD) is the study of how the drug affects the organism. Both together influence dosing, benefit, and adverse effects, as seen in PK/PD models.
MALDI mass spectrometry imaging (MALDI-MSI) is the use of matrix-assisted laser desorption ionization as a mass spectrometry imaging technique in which the sample, often a thin tissue section, is moved in two dimensions while the mass spectrum is recorded. Advantages, like measuring the distribution of a large amount of analytes at one time without destroying the sample, make it a useful method in tissue-based study.
In the field of pharmacokinetics, the area under the curve (AUC) is the definite integral of the concentration of a drug in blood plasma as a function of time. In practice, the drug concentration is measured at certain discrete points in time and the trapezoidal rule is used to estimate AUC. In pharmacology, the area under the plot of plasma concentration of a drug versus time after dosage gives insight into the extent of exposure to a drug and its clearance rate from the body.
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases start with testing for drug safety in a few human subjects, then expand to many study participants to determine if the treatment is effective. Clinical research is conducted on drug candidates, vaccine candidates, new medical devices, and new diagnostic assays.
Mass spectrometric immunoassay (MSIA) is a rapid method is used to detect and/ or quantify antigens and or antibody analytes. This method uses an analyte affinity isolation to extract targeted molecules and internal standards from biological fluid in preparation for matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS). This method allows for "top down" and "bottom up" analysis. This sensitive method allows for a new and improved process for detecting multiple antigens and antibodies in a single assay. This assay is also capable of distinguishing mass shifted forms of the same molecule via a panantibody, as well as distinguish point mutations in proteins. Each specific form is detected uniquely based on their characteristic molecular mass. MSIA has dual specificity because of the antibody-antigen reaction coupled with the power of a mass spectrometer.
Aerosol mass spectrometry is the application of mass spectrometry to the analysis of the composition of aerosol particles. Aerosol particles are defined as solid and liquid particles suspended in a gas (air), with size range of 3 nm to 100 μm in diameter and are produced from natural and anthropogenic sources, through a variety of different processes that include wind-blown suspension and combustion of fossil fuels and biomass. Analysis of these particles is important owing to their major impacts on global climate change, visibility, regional air pollution and human health. Aerosols are very complex in structure, can contain thousands of different chemical compounds within a single particle, and need to be analysed for both size and chemical composition, in real-time or off-line applications.
Jennifer S. Brodbelt is an American chemist known for her research using mass spectrometry to characterize organic compounds, especially biopolymers and proteins.
Psychedelic microdosing involves consuming sub-threshold doses (microdoses) of serotonergic psychedelic drugs like LSD and psilocybin to potentially enhance creativity, energy, emotional balance, problem-solving abilities, and to address anxiety, depression, and addiction. This practice has gained popularity in the 21st century.
Mind Medicine Inc., also known as MindMed, is a New York-based psychedelic medicine biotech company that develops psychedelic-inspired medicines known as psychoplastogens and therapies to address addiction and mental illness.
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