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Cannabis is a complex plant with as many as 113 different phytocannabinoids including cannabidiol (CBD) and ∆9-tetrahydrocannabinol (∆9-THC) which are the most investigated. However, there is growing interest in the lesser known phytocannabinoids whose effects have not yet been fully investigated. In this article, we will focus on ∆8 tetrahydrocannabinol (∆8-THC), ∆9-THC’s “younger sibling”.

The cannabis plant contains more than 500 known compounds including phytocannabinoids, terpenes and flavonoids. 1 As opposed to endocannabinoids which are synthesized in the human body, phytocannabinoids are produced in the glandular trichome of female flowers and are in part responsible for the effects one may feel when consuming the plant. 2  There are as many as 113 different phytocannabinoids including cannabidiol (CBD) and ∆9-tetrahydrocannabinol (∆9-THC) which are the most used and studied and will not be discussed. A non-exhaustive list of the lesser-known phytocannabinoids include D8 tetrahydrocannabinol (∆8-THC), cannabigerol (CBG), cannabinol (CBN), cannabinodiol (CBND), cannabichromene (CBC), cannabielsoin (CBE), cannabivarin (CBV) or cannabitriol (CBT) whose effects have not yet been fully investigated.

Understanding how each may interact with the endocannabinoid system and corresponding receptors (e.g., cannabinoid receptor 1 and 2 (CB1R and CB2R)) may shine new light onto novel therapeutic targets for different diseases as well as reveal potential negative outcomes.  In this article, we will focus on ∆8-THC.

∆8-THC (C21H30O2) is chemically similar as ∆9-THC but the location of the carbon-carbon interaction (double bond, circled in black in the two molecules) differs in each; it is located on the 8th carbon for ∆8-THC and on the 9th carbon for ∆9-THC, hence the different names. 3,4

In the United States, ∆8-THC-based products have started to get commercialized in the form of flowers, edibles, creams or tinctures due of the signature of the Agriculture Improvement Act or Farm Bill in 2018, which removed hemp and cannabis derivates with less than 0.3% of ∆9-THC from the definition of marijuana in the Controlled Substance Act (CSA). 5  This allowed legalization for cultivation and selling of industrial hemp at the federal level, but it also created a loophole allowing ∆8-THC to obtain legal status. However, the rise of current products on the market have alarmed chemists who express high concerns regarding the purity of ∆8-THC based products and the validity of the description on the labels as there is no quality control required.  6 Along those lines, 20  US states have banned its use including Arizona, Colorado and New York (as of March 2022). 7 But how is ∆8-THC made, what are some of the known pharmacological effects of ∆8-THC and how does it compare to its “younger sibling” ∆9-THC?

∆8-THC occurs naturally in very small concentrations, but it can be converted synthetically by refluxing (heating) CBD in an organic solvent leading to a high percentage of ∆8-THC as well as lower doses of ∆9-THC and ∆10-tetrahydrocannabinol (∆10-THC). 8

Previous studies have shown that ∆8-THC is less psychotropic than ∆9-THC with similar pharmacokinetics (movement of drug to the body) and pharmacodynamics (body’s biological response to the drug) profiles. 9 As with ∆9-THC, ∆8-THC acts as a partial agonist to both CB1R and CB2R.  10,11 A 1995 study done in the laboratory of Dr. Mechoulam demonstrated that ∆8-THC administration prevented nausea and vomiting on eight pediatric cancer patients with no side effects, suggesting it may have antiemetic properties. 12 A few year later, Avraham et al. found that small doses of ∆8-THC in mice increased food consumption, decreased dopamine and serotonin levels in the hypothalamus and hippocampus, brain regions associated with appetite and learning, respectively. 13 These findings suggest that it may be used an alternative agent for the treatment of anorexia nervosa, an eating disorder characterized by abnormally low body weight. Using an experimental mouse model of corneal injury, Thapa et al. showed that topical ∆8-THC administration had antinociceptive (blocking pain) and anti-inflammatory effects primarily via activation of CB1R, suggesting this could be an important disease area to explore further. 14

More recently, an exploratory study assessing a broad range of issues regarding ∆8-THC and comparing it to ∆9-THC was published. 15 Results from 521 participants showed that most ∆8-THC consumers experienced relaxation, euphoria, and pain relief while generally favoring it to ∆9-THC and other pharmaceutical drugs. On average, they reported that their experiences were less intense and shorter in duration compared to ∆9-THC. Despite positive responses, these findings should be interpreted cautiously due to the lack of controlled studies.

Currently, there are no trials available on clinicaltrials.gov (one trial comparing ∆8-THC to ondansetron in the prevention of acute nausea from chemotherapy started in 2006 but was terminated a couple years later). 16

Despite its potential antiemetic, anxiolytic, appetite-stimulating, and analgesic activities, limited research and double-blind placebo-controlled studies are available to investigate ∆8-THC’s therapeutic effects and caution should be taken when ingesting these products. 17 On September 14th 2021, the US Food and Drug Administration (FDA) and Center for Disease Control (CDC) issued a warning statement about ∆8-THC-based products due to the recent increase in adverse event reports (e.g., vomiting, hallucinations, loss of consciousness…) and the use of potentially harmful chemicals to create the final product. 18 There is a need for double-blind, placebo-controlled trials to further investigate whether it can be used as a therapeutic agent for disease areas and determine its safety profile.

 References

  1. Goncalves J, Rosado T, Soares S, et al. Cannabis and Its Secondary Metabolites: Their Use as Therapeutic Drugs, Toxicological Aspects, and Analytical Determination. Medicines (Basel) 2019;6(1). DOI: 10.3390/medicines6010031. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473697/)
  2. Grof CPL. Cannabis, from plant to pill. Br J Clin Pharmacol 2018;84(11):2463-2467. DOI: 10.1111/bcp.13618. (https://pubmed.ncbi.nlm.nih.gov/29701252/)
  3. Delta-8 tetrahydrocannabinol, assessed September 1st 2021. (https://pubchem.ncbi.nlm.nih.gov/compound/delta8-Tetrahydrocannabinol).
  4. Delta-9 tetrahydrocannabinol, assessed September 1st 2021. (https://pubchem.ncbi.nlm.nih.gov/compound/delta9-Tetrahydrocannabinol).
  5. H.R.5485 – Hemp Farming Act of 2018, assessed on September 1st 2021. (https://www.congress.gov/bill/115th-congress/house-bill/5485).
  6. Erickson BE. Delta-8-THC craze concerns chemists, assessed September 14th 2021. (https://cen.acs.org/biological-chemistry/natural-products/Delta-8-THC-craze-concerns/99/i31).
  7. Delta-8 is currently banned or restricted in 18 states and is under review in 4 more, assessed on September 2nd 2021. (https://mogreenway.com/2021/07/14/delta-8-legality-map/).
  8. Mechoulam R. US 7,399,872 B2, 15 July 2008. (https://patentimages.storage.googleapis.com/43/43/9f/9910319ce43eb8/US7399872.pdf).
  9. Hollister LE, Gillespie HK. Delta-8- and delta-9-tetrahydrocannabinol comparison in man by oral and intravenous administration. Clin Pharmacol Ther 1973;14(3):353-7. DOI: 10.1002/cpt1973143353. (https://pubmed.ncbi.nlm.nih.gov/4698563/)
  10. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI. Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature 1990;346(6284):561-4. DOI: 10.1038/346561a0. (https://www.nature.com/articles/346561a0)
  11. Gerard CM, Mollereau C, Vassart G, Parmentier M. Molecular cloning of a human cannabinoid receptor which is also expressed in testis. Biochem J 1991;279 ( Pt 1):129-34. DOI: 10.1042/bj2790129. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1151556/)
  12. Abrahamov A, Abrahamov A, Mechoulam R. An efficient new cannabinoid antiemetic in pediatric oncology. Life Sci 1995;56(23-24):2097-102. DOI: 10.1016/0024-3205(95)00194-b. (https://pubmed.ncbi.nlm.nih.gov/7776837/)
  13. Avraham Y, Ben-Shushan D, Breuer A, et al. Very low doses of delta 8-THC increase food consumption and alter neurotransmitter levels following weight loss. Pharmacol Biochem Behav 2004;77(4):675-84. DOI: 10.1016/j.pbb.2004.01.015. (https://pubmed.ncbi.nlm.nih.gov/15099912/)
  14. Thapa D, Cairns EA, Szczesniak AM, Toguri JT, Caldwell MD, Kelly MEM. The Cannabinoids Delta(8)THC, CBD, and HU-308 Act via Distinct Receptors to Reduce Corneal Pain and Inflammation. Cannabis Cannabinoid Res 2018;3(1):11-20. DOI: 10.1089/can.2017.0041. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5812319/)
  15. Kruger JS, Kruger DJ. Delta-8-THC: Delta-9-THC’s nicer younger sibling? J Cannabis Res 2022;4(1):4. DOI: 10.1186/s42238-021-00115-8. (https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-021-00115-8)
  16. Comparison of Delta-8-THC to Ondansetron in the Prevention of Acute Nausea From Moderately Emetogenic Chemotherapy, assessed on September 14th 2021. (https://www.clinicaltrials.gov/ct2/show/record/NCT00285051?term=Delta+8+-THC&draw=3&rank=1).
  17. National Cancer Institute, Delta-8-Tetrahydrocannabinol (Code C61312), assessed on September 14th 2021. (https://ncit.nci.nih.gov/ncitbrowser/ConceptReport.jsp?dictionary=NCI_Thesaurus&ns=NCI_Thesaurus&code=C61312).
  18. 5 Things to Know about Delta-8 Tetrahydrocannabinol – Delta-8 THC, Assessed September 14th 2021. (https://www.fda.gov/consumers/consumer-updates/5-things-know-about-delta-8-tetrahydrocannabinol-delta-8-thc).

 

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Author Yoel H. Sitbon

Yoel is a Medical Writer in the Medical Content division at Csequence. His scientific expertise is in Neuroscience (neural mechanisms behind drug addiction) and Molecular & Cellular Pharmacology (molecular mechanisms behind mutations induced cardiovascular diseases). Yoel has over five years of scientific writing experience as evidenced by 8 peer-reviewed publications in scientific journals. He is an effective oral communicator having presented his PhD thesis work at many biomedical conferences nationally. He also has strong mentorship and leadership experience. Yoel has a B.S in Neuroscience at the University of California, Los Angeles and a Ph.D. in Molecular & Cellular Pharmacology at the University of Miami, Miller School of Medicine.

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