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Anti-inflammatory

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Anti-inflammatory or antiphlogistic is the property of a substance or treatment that reduces inflammation or swelling. Anti-inflammatory drugs, also called anti-inflammatories, make up about half of analgesics. These drugs remedy pain by reducing inflammation as opposed to opioids, which affect the central nervous system to block pain signaling to the brain.

Nonsteroidal anti-inflammatory drugs

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Main article: Nonsteroidal anti-inflammatory drug

Nonsteroidal anti-inflammatory drugs (NSAIDs) alleviate pain by counteracting the cyclooxygenase (COX) enzyme.[1] On its own, COX enzyme synthesizes prostaglandins, creating inflammation. In whole, the NSAIDs prevent the prostaglandins from ever being synthesized, reducing or eliminating the inflammation and resulting pain.[citation needed]

Some common examples of NSAIDs are aspirin, ibuprofen, and naproxen. The newer specific COX-inhibitors are not classified together with the traditional NSAIDs, even though they presumably share the same mode of action.

On the other hand, there are analgesics that are commonly associated with anti-inflammatory drugs but that have no anti-inflammatory effects. An example is paracetamol (known as acetaminophen in the U.S). Contrary to NSAIDs, which reduce pain and inflammation by inhibiting COX enzymes, paracetamol has—as early as 2006—been shown to block the reuptake of endocannabinoids,[2][3] which only reduces pain, likely explaining why it has minimal effect on inflammation; paracetamol is sometimes combined with an NSAID (in place of an opioid) in clinical practice to enhance the pain relief of the NSAID, while still receiving the injury/disease modulating effect of NSAID-induced inflammation reduction (which is not received from opioid/paracetamol combinations).[4]

Side effects

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Long-term use of NSAIDs can cause gastric erosions, which can become stomach ulcers and in extreme cases can cause severe haemorrhage, resulting in death. The risk of death as a result of GI bleeding caused by the use of NSAIDs is 1 in 12,000 for adults aged 16–45.[5] The risk increases almost twentyfold for those over 75.[5] Other dangers of NSAIDs are exacerbating asthma and causing kidney damage.[5] Apart from aspirin, prescription and over-the-counter NSAIDs also increase the risk of heart attack and stroke.[6]

Corticosteroids

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Corticosteroids, specifically glucocorticoids or glucocorticoid receptor agonists, are powerful anti-inflammatory agents, but they are also powerful immunosuppressants and are associated with various toxicities, which constrains their use.[7][8]

Antileukotrienes

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Main article: Antileukotriene

Antileukotrienes are anti-inflammatory agents which function as leukotriene-related enzyme inhibitors (arachidonate 5-lipoxygenase) or leukotriene receptor antagonists (cysteinyl leukotriene receptors), and consequently oppose the function of these inflammatory mediators. Although they are not used for analgesic benefits, they are widely utilized in the treatment of diseases related to inflammation of the lungs, such as asthma and COPD, as well as sinus inflammation in allergic rhinitis.[9][10] They are also being investigated for use in diseases and injuries involving inflammation of the brain (e.g., Parkinson's disease).[11][12]

Serotonergic psychedelics

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Various serotonergic psychedelics, acting as serotonin 5-HT2A receptor agonists, have been found to be powerful and highly potent anti-inflammatory and immunomodulatory agents.[13][14][15][16][17][18][19] In contrast to corticosteroids however, psychedelics with anti-inflammatory effects do not suppress the immune system.[13][14] Some psychedelics are far more potent in their anti-inflammatory effects than in their psychedelic effects.[15][16] For instance, (R)-DOI is 30- to >50-fold more potent in producing anti-inflammatory effects than in producing psychedelic-like behavioral effects in preclinical research.[15][16][14] Psilocin, the active form of psilocybin, has similar anti-inflammatory potency as (R)-DOI.[14][15][14][19]

The potencies of psychedelics and other serotonin 5-HT2A receptor agonists as anti-inflammatory drugs vary, with 2C-I, DOIB, 2C-B, 4-HO-DiPT, DOI, 2,5-DMA, DOET, DOM, psilocin, and 2C-H being highly potent and fully efficacious anti-inflammatories; TMA-2, 2C-B-Fly, TCB-2, ETH-LAD, LSD, and 2C-T-33 being partially efficacious anti-inflammatories; and lisuride, 1-methylpsilocin, 5-MeO-DMT, and DMT having negligible efficacy.[14][19]

Both non-hallucinogenic agents with full anti-inflammatory effects, such as 2,5-DMA, and non-anti-inflammatory agents with full psychedelic effects, such as DOTFM, are known.[19][20][21][22] Hence, the psychedelic and anti-inflammatory effects of serotonin 5-HT2A receptor agonists appear to be fully dissociable.[20] These effects appear to be mediated by different intracellular signaling pathways, although the exact pathways are still under study.[22]

Serotonin 5-HT2A receptor agonists with anti-inflammatory effects but reduced psychedelic effects, such as 2C-iBu (ELE-02), are under development for the treatment of inflammatory conditions.[23][24][25] They may also have applications in the treatment of neuroinflammation.[13][16] The anti-inflammatory effects of psychedelics may be involved in the effects of psychedelic microdosing.[26][27] Relatedly, LSD microdosing is being studied in the treatment of Alzheimer's disease for its anti-inflammatory effects.[28][29]

Although some psychedelics have anti-inflammatory effects, many psychedelics are also potent serotonin 5-HT2B receptor agonists.[30] This action, with repeated long-term use, has been implicated in the development of cardiac fibrosis and valvulopathy.[31][32][33][34][35] This may also be the case with microdosing.[31][32][33] However, the risks are theoretical, and more research is needed to see if these complications can actually occur with psychedelics.[31][34] A preliminary animal study found that chronic microdosing of LSD did not result in heart structure changes or valvulopathy in rodents.[36] Research appears to be mixed on whether LSD and psilocin are potent serotonin 5-HT2B receptor agonists or not.[30]

References

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  1. ^ Knights KM, Mangoni AA, Miners JO (November 2010). "Defining the COX inhibitor selectivity of NSAIDs: implications for understanding toxicity". Expert Rev Clin Pharmacol. 3 (6): 769–76. doi:10.1586/ecp.10.120. PMID 22111779. S2CID 207209534.
  2. ^ Ottani, Alessandra; Leone, Sheila; Sandrini, Maurizio; Ferrari, Anna; Bertolini, Alfio (February 15, 2006). "The analgesic activity of paracetamol is prevented by the blockade of cannabinoid CB1 receptors". European Journal of Pharmacology. 531 (1–3): 280–281. doi:10.1016/j.ejphar.2005.12.015. hdl:11380/613413. PMID 16438952.
  3. ^ Dani, Mélina; Guindon, Josée; Lambert, Chantal; Beaulieu, Pierre (November 14, 2007). "The local antinociceptive effects of paracetamol in neuropathic pain are mediated by cannabinoid receptors". European Journal of Pharmacology. 573 (1–3): 214–215. doi:10.1016/j.ejphar.2007.07.012. PMID 17651722.
  4. ^ Merry AF, Gibbs RD, Edwards J, Ting GS, Frampton C, Davies E, Anderson BJ (January 2010). "Combined acetaminophen and ibuprofen for pain relief after oral surgery in adults: a randomized controlled trial". British Journal of Anaesthesia. 104 (1): 80–8. doi:10.1093/bja/aep338. PMC 2791549. PMID 20007794.
  5. ^ a b c "Table 7". NSAIDs and adverse effects. Bandolier. Archived from the original on February 18, 2012. Retrieved December 20, 2012.
  6. ^ Trelle, Sven; Reichenbach, Stephan; Wandel, Simon; Hildebrand, Pius; Tschannen, Beatrice; Villiger, Peter M.; Egger, Matthias; Jüni, Peter (11 January 2011). "Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis". British Medical Journal (Clinical Research Ed.). 342: c7086. doi:10.1136/bmj.c7086. PMC 3019238. PMID 21224324.
  7. ^ Ingawale DK, Mandlik SK (April 2020). "New insights into the novel anti-inflammatory mode of action of glucocorticoids". Immunopharmacol Immunotoxicol. 42 (2): 59–73. doi:10.1080/08923973.2020.1728765. PMID 32070175.
  8. ^ Escoter-Torres L, Caratti G, Mechtidou A, Tuckermann J, Uhlenhaut NH, Vettorazzi S (2019). "Fighting the Fire: Mechanisms of Inflammatory Gene Regulation by the Glucocorticoid Receptor". Front Immunol. 10: 1859. doi:10.3389/fimmu.2019.01859. PMC 6693390. PMID 31440248.
  9. ^ Dvorak J, Feddermann N, Grimm K (July 2006). "Glucocorticosteroids in football: use and misuse". British Journal of Sports Medicine. 40 (Suppl 1): i48–54. doi:10.1136/bjsm.2006.027599. PMC 2657490. PMID 16799104.
  10. ^ Scott JP, Peters-Golden M (September 2013). "Antileukotriene agents for the treatment of lung disease". Am. J. Respir. Crit. Care Med. 188 (5): 538–544. doi:10.1164/rccm.201301-0023PP. PMID 23822826.
  11. ^ Hamzelou, Jessica (23 October 2015). "Old rat brains rejuvenated and new neurons grown by asthma drug". New Scientist. Retrieved 28 October 2015.
  12. ^ Yirka, Bob. "Asthma drug found to rejuvenate older rat brains". medicalxpress.com. Retrieved 3 November 2015.
  13. ^ a b c Nichols DE, Johnson MW, Nichols CD (February 2017). "Psychedelics as Medicines: An Emerging New Paradigm". Clin Pharmacol Ther. 101 (2): 209–219. doi:10.1002/cpt.557. PMID 28019026.
  14. ^ a b c d e f Flanagan TW, Nichols CD (2022). "Psychedelics and Anti-inflammatory Activity in Animal Models". Disruptive Psychopharmacology. Current Topics in Behavioral Neurosciences. Vol. 56. pp. 229–245. doi:10.1007/7854_2022_367. ISBN 978-3-031-12183-8. PMID 35546383.
  15. ^ a b c d Nichols CD (November 2022). "Psychedelics as potent anti-inflammatory therapeutics". Neuropharmacology. 219: 109232. doi:10.1016/j.neuropharm.2022.109232. PMID 36007854.
  16. ^ a b c d Flanagan TW, Nichols CD (August 2018). "Psychedelics as anti-inflammatory agents" (PDF). Int Rev Psychiatry. 30 (4): 363–375. doi:10.1080/09540261.2018.1481827. PMID 30102081.
  17. ^ Thompson C, Szabo A (December 2020). "Psychedelics as a novel approach to treating autoimmune conditions". Immunol Lett. 228: 45–54. doi:10.1016/j.imlet.2020.10.001. hdl:10852/80687. PMID 33035575.
  18. ^ Low ZX, Ng WS, Lim ES, Goh BH, Kumari Y (September 2024). "The immunomodulatory effects of classical psychedelics: A systematic review of preclinical studies". Prog Neuropsychopharmacol Biol Psychiatry. 136: 111139. doi:10.1016/j.pnpbp.2024.111139. PMID 39251080.
  19. ^ a b c d Flanagan TW, Billac GB, Landry AN, Sebastian MN, Cormier SA, Nichols CD (April 2021). "Structure-Activity Relationship Analysis of Psychedelics in a Rat Model of Asthma Reveals the Anti-Inflammatory Pharmacophore". ACS Pharmacol Transl Sci. 4 (2): 488–502. doi:10.1021/acsptsci.0c00063. PMC 8033619. PMID 33860179.
  20. ^ a b Hamilton Morris (14 November 2021). "PODCAST 33: An interview with Dr. Charles D. Nichols". The Hamilton Morris Podcast (Podcast). Patreon. Event occurs at 48:22–53:56. Retrieved 20 January 2025.
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  22. ^ a b Flanagan TW, Foster TP, Galbato TE, Lum PY, Louie B, Song G, et al. (February 2024). "Serotonin-2 Receptor Agonists Produce Anti-inflammatory Effects through Functionally Selective Mechanisms That Involve the Suppression of Disease-Induced Arginase 1 Expression". ACS Pharmacology & Translational Science. 7 (2): 478–492. doi:10.1021/acsptsci.3c00297. PMC 10863441. PMID 38357283. The effects of (R)-DOTFM were examined in the head-twitch response (HTR) assay. (R)-DOTFM produced a strong HTR with a potent ED 50 of 0.60 μmol/kg. These values are equivalent to (R)-DOI, as previously determined.
  23. ^ Newvine, Colleen (8 July 2020). "Eleusis Draws on Research Into Psychedelics To Develop New Medicines for Inflammation". Lucid News - Psychedelics, Consciousness Technology, and the Future of Wellness. Retrieved 16 February 2025.
  24. ^ Shlomi Raz, Eleusis (February 2020). Eleusis Drug Development Overview. LSX World Congress 2020.
  25. ^ WO published 2020210823, Charles D. Nichols; Gerald Billac & David E. Nichols, "Compounds and methods for treating inflammatory disorders", published 15 October 2020 
  26. ^ Kuypers KP, Ng L, Erritzoe D, Knudsen GM, Nichols CD, Nichols DE, Pani L, Soula A, Nutt D (September 2019). "Microdosing psychedelics: More questions than answers? An overview and suggestions for future research". J Psychopharmacol. 33 (9): 1039–1057. doi:10.1177/0269881119857204. PMC 6732823. PMID 31303095.
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  28. ^ Kozlowska U, Nichols C, Wiatr K, Figiel M (July 2022). "From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders". J Neurochem. 162 (1): 89–108. doi:10.1111/jnc.15509. PMID 34519052.
  29. ^ Family N, Maillet EL, Williams LT, Krediet E, Carhart-Harris RL, Williams TM, Nichols CD, Goble DJ, Raz S (March 2020). "Safety, tolerability, pharmacokinetics, and pharmacodynamics of low dose lysergic acid diethylamide (LSD) in healthy older volunteers". Psychopharmacology (Berl). 237 (3): 841–853. doi:10.1007/s00213-019-05417-7. PMC 7036065. PMID 31853557.
  30. ^ a b Luethi, Dino; Liechti, Matthias E. (2021). "Drugs of Abuse Affecting 5-HT2B Receptors". 5-HT2B Receptors. Vol. 35. Cham: Springer International Publishing. pp. 277–289. doi:10.1007/978-3-030-55920-5_16. ISBN 978-3-030-55919-9.
  31. ^ a b c Tagen M, Mantuani D, van Heerden L, Holstein A, Klumpers LE, Knowles R (September 2023). "The risk of chronic psychedelic and MDMA microdosing for valvular heart disease". J Psychopharmacol. 37 (9): 876–890. doi:10.1177/02698811231190865. PMID 37572027.
  32. ^ a b Rouaud A, Calder AE, Hasler G (March 2024). "Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins". J Psychopharmacol. 38 (3): 217–224. doi:10.1177/02698811231225609. PMC 10944580. PMID 38214279.
  33. ^ a b Nahlawi A, Ptaszek LM, Ruskin JN (February 2025). "Cardiovascular effects and safety of classic psychedelics". Nat Cardiovasc Res. 4 (2): 131–144. doi:10.1038/s44161-025-00608-2. PMID 39910289.
  34. ^ a b Wsół A (December 2023). "Cardiovascular safety of psychedelic medicine: current status and future directions". Pharmacol Rep. 75 (6): 1362–1380. doi:10.1007/s43440-023-00539-4. PMC 10661823. PMID 37874530.
  35. ^ McIntyre RS (2023). "Serotonin 5-HT2B receptor agonism and valvular heart disease: implications for the development of psilocybin and related agents". Expert Opin Drug Saf. 22 (10): 881–883. doi:10.1080/14740338.2023.2248883. PMID 37581427.
  36. ^ Effinger D, King J, Calderon J, Strong J, Thompson S (December 2024). "ACNP 63rd Annual Meeting: Poster Abstracts P609-P914: P680. Assessing the Potential Cardiovascular Risk of Microdosing Lysergic Acid Diethylamide in Mice". Neuropsychopharmacology. 49 (Suppl 1): 418–594 (459–459). doi:10.1038/s41386-024-02013-y. PMID 39643635.
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