|Injection, oral, eyedrops|
|CompTox Dashboard (EPA)|
|Chemical and physical data|
|Molar mass||414.630 g·mol−1|
|3D model (JSmol)|
|(what is this?)|
HU-308 (also known as HU308, PPP-003 and ARDS-003) is a cannabidiol (CBD)-derivative drug that acts as a potent cannabinoid agonist. It is highly selective for the cannabinoid-2 receptor (CB2 receptor) subtype, with a selectivity more than 5,000 times greater for the CB2 receptor than the CB1 receptor. The synthesis and characterization of HU-308 took place in the laboratory of Raphael Mechoulam at the Hebrew University of Jerusalem (the HU in HU-308) in the late 1990s. The pinene dimethoxy-DMH-CBD derivative HU-308 was identified as a potent peripheral CB2-selective agonist in studies in 1990 and 1999.
HU-308 has shown interesting properties such as anti-inflammatory, analgesic, neuroprotective, antitumor and anti-osteoporitic (anti-bone-loss) effects, and has been used as a pharmacological tool in numerous cannabinoid studies in this field. The US National Institutes of Health (NIH) database notes it for being pivotal to the advance of findings in attenuating oxidative stress, inflammatory response, and apoptosis (programmed cell death). HU-308 is also classified as a non-steroidal anti-inflammatory drug (NSAID).
Cannabinoid receptors were first implicated in the regulation of bone mass in 2004, when cannabinoid-2 (CB2) knockout mice were found to have markedly accelerated age-related trabecular bone loss and cortical expansion accompanied by increased activity of trabecular osteoblasts, increased numbers of osteoclasts, and decreased numbers of diaphyseal osteoblast precursors. CB2 receptors were expressed in osteoblasts, osteocytes, and osteoclasts. The selective CB2 agonist HU-308, but not the CB1 receptor agonist noladin ether, attenuated ovariectomy-induced bone loss and markedly stimulated cortical thickness through the suppression of osteoclast number and stimulation of endocortical bone formation. Furthermore, HU-308 dose dependently increased the number and activity of endocortical osteoblasts and restrained trabecular osteoclastogenesis by inhibiting proliferation of osteoclast precursors. These results, coupled with CB2 but not CB1 receptor mRNA expression during osteoblastic differentiation, suggested a role for CB2 receptors in bone remodeling. Such a role of CB2 but not CB1 receptors is also supported by a 2005 systematic genetic association study overseen by molecular biologist Meliha Karsak in postmenopausal osteoporosis patients, which found a statistically significant association of single polymorphisms (P=0.0014) and haplotypes (P=0.0001) that encompassed the CNR2 gene on human chromosome 1p36, while finding no convincing association for the psychotropic CNR1 gene. It is the non-psychotropic cannabinoid receptor type 2 gene that is found to be so strongly associated with human osteoporosis as P value of 0.0001.
HU308 promotes neural progenitor (NP) proliferation and neurogenesis of neural stem cells, promotes neuroprotection and neurorepair, activates phosphatidylinositol, and has important implications for neuronal survival under neuroinflammatory conditions occurring in animal models of neurodegenerative diseases, such as multiple sclerosis, Alzheimer disease, and Huntington's disease, and upon acute ischemic brain injury. Attenuation of the inflammatory response in the brain has also been reported by activation of CB2 receptors in a study of pial vessels forming the blood–brain barrier, using a model of lipopolysaccharide-induced encephalitis, wherein activation of CB2 receptors decreased adhesion molecules in the brain tissue and leukocyte-endothelial adhesion in the pial vessels. HU-308 protects both liver and blood vessel tissues against hepatic ischemia and reperfusion (blood circulatory system) injury by attenuating oxidative stress, inflammatory response and apoptosis via inhibition of TNF-α. The role of CB2 receptors in endothelial cell activation and endothelial/inflammatory cell interactions, being critical steps not only in reperfusion injury, but also atherosclerosis and other inflammatory disorders, is very important, because selective CB2 cannabinoid agonist HU-308 decreased TNF-α-induced ICAM-1 and VCAM-1 expression in human liver sinusoidal endothelial cells (HLSECs) expressing CB2 receptors, as well as the adhesion of human neutrophils to HLSECs in vitro. HU-308 reduces blood pressure, blocks defecation, and elicits anti-inflammatory and peripheral analgesic activity. Cannabidiol (CBD) and its potent derivatives (like HU-308) are generating considerable interest due to their beneficial neuroprotective, antiepileptic, anxiolytic, antipsychotic, anti-inflammatory and pain-relieving properties, and the CBD scaffold has become of increasing interest for medicinal chemists.
Inflammation and immune modulation
HU-308 has an important functional outcome regarding the secretion of interleukin 6 (IL-6) and interleukin 10 (IL-10) with therapeutic immunomodulatory properties in vitro. There is evidence that IL-6 may be used as an inflammatory marker for the more severe COVID-19 infections that have a poor prognosis for a favorable outcome because raised levels of IL-6 as well as troponin are associated with a poor prognosis in COVID-19. Researchers have shown that HU-308 also mediates immune modulation in sepsis, and displays antiallodynic activity (alleviates allodynic pain) in the rat hindpaw incision model of post-operative pain, is neuroprotective and improves motor performance in a mouse model of Huntington's disease. A study has also shown that HU-308 dramatically fights the cytokine release syndrome (CRS, also called cytokine release storm) that is seen in many diseases and conditions, including acute respiratory distress syndrome (ARDS), COVID-19, sepsis, septic shock, systemic inflammatory response syndrome (SIRS), cytokine storm syndrome (CSS), multi-organ dysfunction syndrome (MODS), pneumonia, uveitis, corneal neuropathic pain hyperalgesia, photo-allodynia, burning, stinging, dryness and inflammation. The antinociceptive and anti-inflammatory effects of HU-308, but not Δ8THC or CBD, were mediated through CB2R, and reduces cytokine storms in the eye, where corneal damage can result in an inflammatory response involving the production of proinflammatory cytokines, neovascularization, recruitment of leukocytes, and release of neuropeptides producing inflammatory pain. A CB2R agonist was first demonstrated to reduce corneal pain in a 2018 study on HU-308. HU-308 is a selective and highly potent agonist at CB2R and has been shown to reduce lipopolysaccharide-induced intraocular inflammation.
Multi-organ dysfunction and damage
While CB2 knockout mice developed enhanced inflammation and tissue injury from cisplatin-induced kidney damage, HU-308, working through the endocannabinoid system and the CB2 receptor, protected against cisplatin-induced kidney damage by attenuating inflammation and oxidative or nitrosative stress. Such selective CB2 agonists may represent a novel approach to prevent this complication of chemotherapy. Activation of the CB2 receptors (expressed predominantly in immune cells and to a much lesser extent in other cell types [e.g., endothelial and parenchymal cells]) by recently recognized endogenous lipid mediators (the endocannabinoids) produced and present in virtually all tissues/organ systems, or by selective synthetic CB2 agonists such as HU-308, has been shown to protect against tissue damage in various experimental models of ischemic-reperfusion injury, atherosclerosis/cardiovascular inflammation, and neurodegenerative, gastrointestinal and other disorders by limiting inflammatory cell chemotaxis/infiltration, activation and interrelated oxidative/nitrosative stress. In vivo, HU-308 treatment attenuated DSS-induced colitis mice associated with reduced colon inflammation and inhibited NLRP3 inflammasome activation in wild-type mice. Furthermore, CB2 receptors are over-expressed in a variety of cancers, and CB2 activation may decrease the proliferation and growth of various cancer cells and tumors. HU-308 was shown to reduce swelling, synovial joint inflammation and destruction, and lower circulating antibodies against Collagen I.
HU-308 is also known as ARDS-03 for its ARDS-fighting abilities. A collaboration study at the US National Institutes of Health (NIH) at George Mason University's (GMU's) National Center for Biodefense and Infectious Diseases Biomedical Research Laboratory (BRL) is examining ways to prevent lethal ARDS seen in COVID-19 patients. Regulatory filings show that in late 2020, Tetra Bio-Pharma and Targeted Pharmaceutical designed short-to-mid-term studies to gather additional data on the benefits of ARDS-003 in SARS-CoV-2 infected animal models for the prevention of ARDS in COVID-19. A former NIH deputy director is heading the GMU research on ARDS-003, which is a novel, sterile, injectable, optimized, nanoemulsion form of HU-308 that has successfully undergone safety and toxicology studies in accordance with USFDA oversight, which were required before submitting an investigational new drug (IND) application in the US and a clinical trial application (CTA) in Canada for a Phase 1 research study through the SARS-CoV-2 regulatory fast-track pathway. The toxicology program was designed to the standards of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) for enabling a first-in-human clinical trial; and included general toxicology data for two species-specific studies to assess toxicity in major organ systems (cardiovascular, respiratory, and nervous system) and genotoxicity, as well as the metabolism and pharmacokinetic distribution of the drug. Tetra Bio-Pharma is the first endocannabinoid system (ECS) biotechnology company researching a cannabinoid treatment for ARDS and sepsis linked to COVID-19, pneumonia and other critical conditions, The ARDS-003 pharmaceutical drug gained FDA approval to begin Phase I and Phase II clinical trials in human subjects for the reduction of cytokine storm, sepsis, and ARDS in COVID-19. GMU researchers are conducting three studies to assess the therapeutic efficacy of candidate interventions for COVID-19 in mouse models of angiotensin-converting enzyme 2 (ACE2) animals infected intranasally with SARS-CoV-2 to determine the survival advantage conferred by a therapeutic if an alternate course or dosing strategy needs to be followed, and to determine viral levels on day-three post-infection when viral load in the lungs is expected to peak. Dalton Pharma is producing the injectable drug for the GMU effort.
HU-308 is non-psychoactive and not scheduled at the federal level in the United States. It is a Schedule I controlled substance in the state of Florida making it illegal to buy, sell, or possess there.
- Mechoulam R, Lander N, Breuer A, Zahalka J (1990-04-11). "Synthesis of the individual, pharmacologically distinct enantiomers of a tetrahydrocannabinol derivative". Tetrahedron Asymmetry. 1 (5): 315–318. doi:10.1016/S0957-4166(00)86322-3.
- Hanus L, Breuer A, Tchilibon S, Shiloah S, Goldenberg D, Horowitz M, Pertwee RG, Ross RA, Mechoulam R, Fride E (December 1999). "HU-308: a specific agonist for CB(2), a peripheral cannabinoid receptor". Proceedings of the National Academy of Sciences of the United States of America. 96 (25): 14228–33. Bibcode:1999PNAS...9614228H. doi:10.1073/pnas.96.25.14228. PMC 24419. PMID 10588688.
- "Properties of HU-308 ~ Formula C27H42O3". Pitt Quantum Repository. University of Pittsburgh Department of Chemistry.
- Rajesh M, Pan H, Mukhopadhyay P, Bátkai S, Osei-Hyiaman D, Haskó G, et al. (December 2007). "Pivotal Advance: Cannabinoid-2 receptor agonist HU-308 protects against hepatic Ischemia-reperfusion injury by attenuating oxidative stress, inflammatory response, and apoptosis". Journal of Leukocyte Biology. 82 (6): 1382–9. doi:10.1189/jlb.0307180. PMC 2225476. PMID 17652447.
- Lynch, Mary; Kelly, Melanie. "Spanish Patent ES2784229T3 HU-308, HU-433, CBD-DMH Compositions and procedures for the treatment of eye inflammation and pain". Google Patents. Panag Pharma. Retrieved 22 February 2021.
A61P29/00 Non-central analgesic, antipyretic or anti-inflammatory agents, e.g antirheumatic agents; Non-steroidal anti-inflammatory drugs (NSAIDs)
- Karsak M, Ofek O, Fogel M, Wright K, Tam J, Gabet Y, Birenboim R, Attar-Namdar M, Müller R, Cohen-Solal M (October 2004). "The cannabinoid CB2 receptor: a potential target for the treatment of osteoporosis". Journal of Bone and Mineral Research. 19 (S1): S383. doi:10.1002/jbmr.5650191306.
- Ofek O, Karsak M, Leclerc N, Fogel M, Frenkel B, Wright K, Tam J, Attar-Namdar M, Kram V, Shohami E, Mechoulam R, Zimmer A, Bab I (2006-01-17). "Peripheral cannabinoid receptor, CB2, regulates bone mass". Proc Natl Acad Sci U S A. 103 (3): 696–701. doi:10.1073/pnas.0504187103. PMC 1334629. PMID 16407142.
- Karsak M, Cohen-Solal M, Freudenberg J, Ostertag A, Morieux C, Kornak U, Essig J, Erxlebe E, Bab I, Kubisch C, de Vernejoul MC, Zimmer A (15 November 2005). "Cannabinoid receptor type 2 gene is associated with human osteoporosis". Human Molecular Genetics. 14 (22): 3389–96. doi:10.1093/hmg/ddi370. PMID 16204352.
- Palazuelos J, Aguado T, Egia A, Mechoulam R, Guzmán M, Galve-Roperh I (November 2006). "Non-psychoactive CB2 cannabinoid agonists stimulate neural progenitor proliferation". FASEB Journal. 20 (13): 2405–7. doi:10.1096/fj.06-6164fje. PMID 17015409. S2CID 4885167.
- Fernández-Ruiz J, González S, Romero J, Ramos JA (2005). "Cannabinoids in Neurodegeneration and Neuroprotection". In: Mechoulam, R.(Ed.), Cannabinoids as Therapeutics (MDT) Birkhaüser Verlag; Switzerland: 79–109.
- Fernández-Ruiz J, Romero J, Velasco G, Tolón RM, Ramos JA, Guzmán M (Jan 2007). "Cannabinoid CB2 receptor: a new target for the control of neural cell survival". Trends Pharmacol Sci. 28 (1): 39–45. doi:10.1016/j.tips.2006.11.001. PMID 17141334.
- Esposito G, Scuderi C, Savani C, Steardo L, Jr, De Filippis D, Cottone P, Iuvone T, Cuomo V, Steardo L (Aug 2007). "Cannabidiol in vivo blunts beta-amyloid induced neuroinflammation by suppressing IL-1beta and iNOS expression". British Journal of Pharmacology. 151 (8): 1272–1279. doi:10.1038/sj.bjp.0707337. PMC 2189818. PMID 17592514.
- Fernández-López D, Pazos MR, Tolón RM, Moro MA, Romero J, Lizasoain I, Martínez-Orgado J (Sep 2007). "The cannabinoid agonist WIN55212 reduces brain damage in an in vivo model of hypoxic-ischemic encephalopathy in newborn rats". Pediatric Research. 62 (3): 255–60. doi:10.1203/PDR.0b013e318123fbb8. PMID 17622949.
- Palazuelos J, Ortega Z, Díaz-Alonso J, Guzmán M, and Galve-Roperh I (January 2012). "CB2 Cannabinoid Receptors Promote Neural Progenitor Cell Proliferation via mTORC1 Signaling". Journal of Biological Chemistry. 287 (2): 1198–1209. doi:10.1074/jbc.M111.291294. PMC 3256884. PMID 22102284.
- Ramirez SH, Haskó J, Skuba A, Fan S, Dykstra H, McCormick R, Reichenbach N, Krizbai I, Mahadevan A, Zhang M, Tuma R, Son YJ, Persidsky Y (21 March 2012). "Activation of cannabinoid receptor 2 attenuates leukocyte-endothelial cell interactions and blood-brain barrier dysfunction under inflammatory conditions". Journal of Neuroscience. 32 (12): 4000–16. doi:10.1523/JNEUROSCI.4628-11.2012. PMC 3325902. PMID 22442067.
- Rajesh M, Mukhopadhyay P, Batkai S, Hasko G, Liaudet L, Huffman JW, et al. (2007-10-01). "CB2-receptor stimulation attenuates TNF-alpha-induced human endothelial cell activation, transendothelial migration of monocytes, and monocyte-endothelial adhesion". American Journal of Physiology. Heart & Circulatory Physiology. 293 (4): H2210–H2218. doi:10.1152/ajpheart.00688.2007. PMC 2229632. PMID 17660390.
- Pacher P, Gao B (Apr 2008). "Endocannabinoids and Liver Disease. III. Endocannabinoid effects on immune cells: implications for inflammatory liver diseases". Am J Physiol Gastrointest Liver Physiol. 294 (4): G850–G854. doi:10.1152/ajpgi.00523.2007. PMC 2376822. PMID 18239059.
- LaBuda CJ, Koblish M, Little PJ (December 2005). "Cannabinoid CB2 receptor agonist activity in the hindpaw incision model of postoperative pain". European Journal of Pharmacology. 527 (1–3): 172–4. doi:10.1016/j.ejphar.2005.10.020. PMID 16316653.
- Morales P, Reggio PH, Jagerovic N (2017-06-28). "An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol". Frontiers in Pharmacology. 8: 422. doi:10.3389/fphar.2017.00422. PMC 5487438. PMID 28701957.
- Saroz Y, Kho DT, Glass M, Graham ES, Grimsey NL (2019-10-19). "Cannabinoid Receptor 2 (CB 2 ) Signals via G-alpha-s and Induces IL-6 and IL-10 Cytokine Secretion in Human Primary Leukocytes". ACS Pharmacology & Translational Science. 2 (6): 414–428. doi:10.1021/acsptsci.9b00049. ISSN 2575-9108. PMC 7088898. PMID 32259074.
- "Raised troponin and interleukin-6 levels are associated with a poor prognosis in COVID-19. 2 April 2020. Graham Cole (Imperial College Healthcare NHS Trust, London, UK)". Cardiac Rhythm News. Graham Cole, CRN. Retrieved 21 February 2021.
- Sardinha, Kelly, Zhou, Lehmann (2014). "Experimental cannabinoid 2 receptor-mediated immune modulation in sepsis". Mediators of Inflammation. 2014: 978678. doi:10.1155/2014/978678. PMC 3997158. PMID 24803745.
- Chakraborty, R. K.; Burns, B. (2021). "Systemic Inflammatory Response Syndrome". PMID 31613449. Cite journal requires
- Thapa, Cairns, Szczesniak, Toguri, Caldwell, Kelly (2018). "The Cannabinoids Δ8THC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation". Cannabis & Cannabinoid Research. 3 (1): 11–20. doi:10.1089/can.2017.0041. PMC 5812319. PMID 29450258.
- Toguri, Lehmann, Laprairie, Szczesniak, Zhou, Denovan-Wright, Kelly (March 2014). "Anti-inflammatory effects of cannabinoid CB(2) receptor activation in endotoxin-induced uveitis". British Journal of Pharmacology. 171 (6): 1448–61. doi:10.1111/bph.12545. PMC 3954484. PMID 24308861.
- Mukhopadhyay P, Rajesh M, Pan H, Patel V, Mukhopadhyay B, Bátkai S, Gao B, et al. (February 2010). "Cannabinoid-2 receptor limits inflammation, oxidative/nitrosative stress and cell death in nephropathy". Free Radical Biology and Medicine. 48 (3): 457–67. doi:10.1016/j.freeradbiomed.2009.11.022. PMC 2869084. PMID 19969072.
- Mechoulam R, Fride E, DiMarzo V (1998). "Endocannabinoids". Eur J Pharmacol. 359 (1): 1–18. doi:10.1016/s0014-2999(98)00649-9. PMID 9831287.
- Howlett AC, Barth F, Bonner TI, Cabral G, Casellas P, Devane WA, Felder CC, Herkenham M, Mackie K, Martin BR, Mechoulam R, Pertwee RG (2002). "International Union of Pharmacology. XXVII. Classification of cannabinoid receptors". Pharmacol Rev. 54 (2): 161–202. doi:10.1124/pr.54.2.161. PMID 12037135.
- Pacher P, Batkai S, Kunos G (Sep 2006). "International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. The Endocannabinoid System as an Emerging Target of Pharmacotherapy". Pharmacol Rev. 58 (3): 389–462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID 16968947.
- Batkai S, Osei-Hyiaman D, Pan H, El-Assal O, Rajesh M, Mukhopadhyay P, Hong F, Harvey-White J, Jafri A, Hasko G, Huffman JW, Gao B, Kunos G, Pacher P (Jun 2007). "Cannabinoid-2 receptor mediates protection against hepatic ischemia/reperfusion injury". FASEB J. 21 (8): 1788–1800. doi:10.1096/fj.06-7451com. PMC 2228252. PMID 17327359.
- Gallily R, Breuer A, Mechoulam R (2000-10-06). "2-Arachidonylglycerol, an endogenous cannabinoid, inhibits tumor necrosis factor-alpha production in murine macrophages, and in mice". Eur J Pharmacol. 406 (1): R5-7. doi:10.1016/s0014-2999(00)00653-1. PMID 11011050.
- Gaoni Y, Mechoulam R (1971-01-13). "The isolation and structure of delta-1-tetrahydrocannabinol and other neutral cannabinoids from hashish". J Am Chem Soc. 93 (1): 217–24. doi:10.1021/ja00730a036. PMID 5538858.
- García-Arencibia M, González S, de Lago E, Ramos JA, Mechoulam R, Fernández-Ruiz J (2007-02-23). "Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson's disease: importance of antioxidant and cannabinoid receptor-independent properties". Brain Res. 1134 (1): 162–70. doi:10.1016/j.brainres.2006.11.063. PMID 17196181.
- Sagredo O, González S, Aroyo I, Pazos M, Benito C, Lastres-Becker I, Romero J, Tolón R, Mechoulam R, Brouillet E, Romero J, Fernández-Ruiz J (2009-08-15). "Cannabinoid CB2 receptor agonists protect the striatum against malonate toxicity: Relevance for Huntington's disease". Glia. 57 (11): 1154–67. doi:10.1002/glia.20838. PMC 2706932. PMID 19115380.
- Ke P, Shao BZ, Xu ZQ, et al. (2016-09-09). "Activation of Cannabinoid Receptor 2 Ameliorates DSS-Induced Colitis through Inhibiting NLRP3 Inflammasome in Macrophages". PLOS ONE. 11 (9): e0155076. doi:10.1371/journal.pone.0155076. PMC 5017608. PMID 27611972.
- Storr MA, Keenan CM, Zhang H, Patel KD, Makriyannis A, Sharkey KA (Nov 2009). "Activation of the cannabinoid 2 receptor (CB(2)) protects against experimental colitis". Inflammable Bowel Disease. 15 (11): 1678–1685. doi:10.1002/ibd.20960. PMC 5531765. PMID 19408320.
- Pacher P, Batkai S, Kunos G (Sep 2006). "The endocannabinoid system as an emerging target of pharmacotherapy". Pharmacol. Rev. 58 (3): 389–462. doi:10.1124/pr.58.3.2. PMC 2241751. PMID 16968947.
- Bátkai S, Járai Z, Wagner JA, Goparaju SK, Varga K, Liu J, Wang L, Mirshahi F, Khanolkar AD, Makriyannis A, Urbaschek R, Garcia N Jr, Sanyal AJ, Kunos G (July 2001). "Endocannabinoids acting at vascular CB1 receptors mediate the vasodilated state in advanced liver cirrhosis". Nat Med. 7 (7): 827–32. doi:10.1038/89953. PMID 11433348.
- Engeli S, Böhnke J, Feldpausch M, Gorzelniak K, Janke J, Bátkai S, Pacher P, Harvey-White J, Luft FC, Sharma AM, Jordan J (October 2005). "Activation of the Peripheral Endocannabinoid System in Human Obesity". Diabetes. 54 (10): 2838–2843. doi:10.2337/diabetes.54.10.2838. PMC 2228268. PMID 16186383.
- Osei-Hyiaman D, DePetrillo M, Pacher P, Liu J, Radaeva S, Batkai S, Harvey-White J, Mackie K, Offertaler L, Wang L (May 2005). "Endocannabinoid activation at hepatic CB1 receptors stimulates fatty acid synthesis and contributes to diet-induced obesity". J Clin Invest. 115 (5): 1298–305. doi:10.1172/JCI23057. PMC 1087161. PMID 15864349.
- Kunikowska G, Jenner P (2001-12-13). "6-Hydroxydopamine-lesioning of the nigrostriatal pathway in rats alters basal ganglia mRNA for copper, zinc- and manganese-superoxide dismutase, but not glutathione peroxidase". Brain Res. 922 (1): 51–64. doi:10.1016/s0006-8993(01)03149-3. PMID 11730701.
- Gui H, Liu X, Liu LR, Su DF, Dai SM (Jun 2015). "Activation of cannabinoid receptor 2 attenuates synovitis and joint distruction in collagen-induced arthritis". Immunobiology. 220 (6): 817–22. doi:10.1016/j.imbio.2014.12.012. PMID 25601571.
- Earlenbaugh, Emily (August 20, 2020). "Synthetic Cannabinoid Drug For Covid-19 Approved For Phase-1 Clinical Trials". Forbes.
- "Tetra Bio-Pharma, Targeted Pharmaceutical & the George Mason University Partner on ARDS-003 to Prevent & Treat COVID-19" (Press release). Ottawa, Ontario: Tetra Bio-Pharma. October 22, 2020.
- "Lance Liotta". GMU College of Science.
- "SEDAR TBP Annual Report 17 Feb 2021". SEDAR. SEDAR Tetra Bio-Pharma. Retrieved 20 February 2021.
- Narayanan, Aarthi; Liotta, Lance. "GMU Grant Announcement: Narayanan and Liotta testing therapeutic efficacy of potential COVID-19 treatments". EurekAlert! operated by the nonprofit American Association for the Advancement of Science (AAAS). George Mason University. Retrieved 24 February 2021.
- Cachapero, Joanne. "Cannabis and Coronavirus: Sales Surge as the Industry Carries On". MG Retailer. Retrieved 28 February 2021.
Canadian cannabis pharmaceutical company Tetra Bio-Pharma recently contracted with Dalton Pharma Services to produce batches of its HU-308 and ARDS-003, which could help to treat severe cytokine reactions.
- Nov 2018, Tetra Bio-Pharma Enters into Non-Binding Proposal to Acquire Panag Pharma Inc.
- Jan 2019, Tetra Bio-Pharma Enters into Definitive Agreement to Acquire Panag Pharma Inc.
- Apr 2019, Tetra Bio-Pharma Shareholders Approve the Acquisition of Panag Pharma
- May 2019, Tetra Bio-Pharma Closes the Acquisition of Panag Pharma
- USPTO, Compositions and methods for treatment of ocular inflammation and/or pain (Lynch & Kelly Jan 2017). In certain embodiments, the non-psychotropic phytocannabinoid is beta-caryophyllene or cannabidiol [CBD] and the synthetic cannabinoid is HU-433, HU-308, or a modified CBD such as CBD-DMH.
- Justia, Compositions and methods for treatment of ocular inflammation and/or pain (Lynch & Kelly May 2015)
- Lynch, Mary; Kelly, Melanie. "Patent 9549906 Composition & Methods for Treatment of Ocular Inflammation &/or Pain Jan 2017". U.S. Patent & Trademark Office. USPTO, Panag Pharma. Retrieved 20 February 2021.
- 21 CFR — Schedules of controlled substances §1308.11 Schedule I.
- Florida Statutes - Chapter 893 - Drug abuse prevention and control