The 0.3% THC Rule

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The Difference Between THC and CBD

Learn more about how CBD and THC affect the endocannabinoid system, and explore the mechanisms of action for cannabinoids.

Endocannabinoid System (ECS)

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THC

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CBD

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The Phytocannabinoids Story

Out of more than 100 compounds in the cannabis plant, phytocannabinoids, such as THC, CBD, and cannabinol (CBN), were the first ones to be identified and isolated.^1,2

Then in 1988, while scientists were investigating how THC exerted its effects, the endocannabinoid system was discovered within the human body.³

This led to the exploration of how cannabinoids, including both the plant molecules and synthetic versions developed in laboratories that mimic their effects, might be used for therapeutic purposes.³

Differentiating Phytocannabinoids

CBD

Cannabidiol (CBD), the by-product of heating CBDA, is one of the major cannabinoids derived or synthesized from cannabis.^{2, 4}

CBD has very low affinity for cannabinoid receptor CB1 and so is lacking euphoric side effects.¹

It is under investigation because of its anticonvulsant properties, as well as other conditions.¹

A specific formulation of cannabidiol has been approved by the FDA as a drug for rare, severe forms of epilepsy.⁵

CBDV

Tetrahydrocannabivarin molecule, a lesser-known cannabinoid, is produced from tetrahydrocannabidivaric acid (THCVA).

Cannabidivarin (CBDV), a lesser-known cannabinoid, is produced from cannabidivarinic acid (CBDVA).⁶

Studies have been done in rodent models of epilepsy and autism spectrum disorder.^{1, 7}

It is under investigation for potential anticonvulsant properties.¹

CBDA

Cannabidiolic acid (CBDA) is how CBD naturally occurs in the plant.⁴

Testing of CBDA in rodent and rodent-like models illustrates that CBDA works on the serotonin receptor (specifically 5-HT1A) to prevent vomiting and suppress nausea and anxiety.⁸

THC

Tetrahydrocannabinol (THC) molecule, most commonly in its delta-9 form, is the by-product of heating THCA.1,2

Tetrahydrocannabinol (THC), most commonly in its delta-9 form, is the by-product of heating THCA.⁴

It is a major cannabinoid that may be derived from cannabis or synthesized.¹

It is primarily responsible for marijuana’s psychotropic properties.¹

Recreational and therapeutic uses: FDA-approved synthetic and analogue products, such as dronabinol, are indicated for nausea and vomiting related to chemotherapy and anorexia associated with AIDS.^{9, 10}

THCA

Tetrahydrocannabinolic acid A (how THC naturally occurs in the cannabis plant).¹¹

It has been investigated in a limited number of studies.¹¹

THCV

Tetrahydrocannabivarin, a lesser-known cannabinoid, is produced from tetrahydrocannabidivaric acid (THCVA).¹²

Studies have been conducted in rodent models of both Parkinson’s disease and insulin sensitivity (a model of diabetes).^{13, 14}

It is under investigation for potential use in type 2 diabetes.¹⁴

Not All Cannabinoid Products Are Created Equal

Products that sound similar may not be equivalent for various reasons, including potential differences in development, manufacturing, testing, and approval.

Medical
Marijuana

Medical Marijuana

The term “medical marijuana” refers to using the whole plant or its extracts to treat medical problems.¹⁵

The FDA does not recognize the whole marijuana plant as medicine.¹⁶

Research on extracts from the marijuana plant, called cannabinoids, has led to FDA-recognized medicines, proving this research is possible.¹⁶

Continued research may lead to more FDA-approved medications.¹⁶

The cannabis varieties used for medical or recreational marijuana are generally the same plants, grown in the same conditions, and subjected to the same cannabinoid extraction process.^{15, 17} It is the intent of use that separates these 2 terms legally.

Medical marijuana laws are in constant flux, but as of December 2021, 36 states, the District of Columbia, Guam, Puerto Rico, and the US Virgin Islands have comprehensive programs for access to medical marijuana.¹⁸

Medical marijuana is dispensed for use without any substantial research proving safety or efficacy.¹⁶ In contrast, the FDA requires carefully conducted research (randomized, placebo-controlled clinical trials) in hundreds to thousands of human patients to determine the benefits and risks of a possible medication.¹⁹

A systemic review by the National Academy of Sciences (2017) highlighted the lack of appropriate evidence for the use of medical marijuana to treat neurological conditions.²⁰

The American Association of Neurology (AAN) position statement noted that “it is not appropriate to extrapolate the results of trials of standardized preparations to other non-standardized, non-regulated medical marijuana products which may be commercially available…”²¹

Caution and monitoring are warranted when patients use medical marijuana. Repeated independent research has shown that these products may have inaccurate labels, and unknown constituents can be present in non–FDA-approved products (eg, pesticides, heavy metals, or THC).^{12, 22-25} Learn more about the state of cannabinoid testing.

Hemp-Derived
Products

Hemp-Derived Products

Hemp and marijuana are both types of cannabis.²⁶

Historically, hemp has been used to produce fibers and seeds for manufacturing, while marijuana has been used for recreational products.²⁶

Because marijuana is federally illegal, retailers became interested in growing hemp for CBD.²⁷ The 2018 Farm Bill descheduled CBD derived from hemp but only if there is less than 0.3% THC on a dry-weight basis.²⁸

The FDA notes that these products must not be used as supplements or foods, nor can they be used to treat a medical condition.²⁸

Changes in the 2014 Agriculture Act and the 2018 Agriculture Improvement Act, also known as the “Farm Bill,” expanded the federal definition of hemp, first specifying it for research (2014) and then for other non-consumed products (2018).^{27, 28}

The FDA maintains oversight of hemp-derived consumer products, including those used as a food or food ingredient, or as an ingredient in body products, cosmetics, dietary supplements, and therapeutic products.²⁸

The USDA maintains oversight of program implementation.²⁹ This includes developing regulations and guidance for the commercial production of industrial hemp in the United States, as well as, regulations for individual states or tribes. USDA will not begin reviewing plans until regulations go into effect at the end of 2019 for crop growth in 2020.

While the 2018 Agriculture Improvement Act stipulates that hemp-derived products can have no more than 0.3% THC by dry weight,²⁸ some purveyors are interpreting this to apply to finished product. This misinterpretation could lead to products being sold with high levels of THC – as much as 81 mg of THC in a single 30-mL bottle of hemp-derived CBD oil.³⁰

Hemp-derived products may pose a risk to the public with unintended high dose exposure to THC.³¹ Moreover, hemp plants are soil remediators that absorb toxic chemicals from the soil they are grown in.³²

When phytocannabinoids are extracted from these plants, toxic chemicals from the soil can also be in the extraction.³³ Rigorous growing, harvesting, extraction, manufacturing, and testing practices must be performed to ensure safe products for consumption.¹² Even products undergoing state testing may have inaccurate labels due either to lab quality issues or the post-testing degradation of cannabinoid content.^{34, 35}

FDA-Approved Cannabinoid Formulations

The U.S. Food and Drug Administration (FDA) is responsible for protecting public health by regulating products such as medical drugs, medical devices, tobacco products, food, and cosmetics.³⁶

When a product is “FDA-approved,” that means it has gone through a series of rigorous tests to assess safety and efficacy.¹⁶

With growing interest in the development of medicines from cannabis, the FDA is concerned that non–FDA-approved products can put the health and safety of consumers at risk.¹⁶

The FDA requires carefully conducted research studies (randomized, placebo-controlled clinical trials) in hundreds to thousands of patients to determine the benefits and risks of a possible medication before it can be marketed to the public or physicians.^{16, 19}

The FDA has approved 4 cannabinoid products: a plant-derived cannabidiol oral solution for the treatment of seizures associated with rare, severe forms of epilepsy; and 3 formulations of synthetic THC cannabinoid products, dronabinol and nabilone for the treatment of nausea and vomiting associated with cancer chemotherapy or loss of appetite and weight loss in people with AIDS.^{9, 10, 37, 38}

The FDA has not approved any marijuana or hemp products purchased at dispensaries, retail shops, or online for treating any medical conditions or as dietary supplements. It is also not legal to sell foods containing THC or CBD in interstate commerce.³⁹

As patient and consumer demand increases, so does the need for greater scientific understanding of cannabis and cannabinoids.¹⁶ Clinical trials to examine the medical validity and safety of these dispensary and retail products have not been conducted, thus they are not FDA-approved.

Testing of Schedule I products can seem daunting, but there are paths through the FDA and DEA to perform research on these restricted products.^{16, 40}

Without FDA approval and oversight, products are susceptible to error or corruption in production and marketing. Patients are left on their own to guess at the content and quality of non–FDA-approved cannabinoid products.^22-24

FDA has approved 3 synthetic cannabinoids and 1 plant-derived cannabinoid.

Three tetrahydrocannabinol (THC) and THC analogues (synthetics) - nabilone and 2 formulations of dronabinol - are indicated to treat anorexia associated with weight loss in adult patients with AIDS and nausea and vomiting associated with chemotherapy.^{9, 10, 37}

A plant-derived cannabidiol is indicated for the treatment of seizures associated with rare, severe forms of epilepsy.³⁸

See what really matters when considering cannabis-based treatments.

References

1. Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O. Cannabinoids and Epilepsy. Neurotherapeutics. Oct 2015;12(4):747-68. doi:10.1007/s13311-015-0375-5

2. ElSohly M, Gul W. Constituents of Cannabis sativa. In: Pertwee R, ed. Handbook of Cannabis. Oxford University Press; 2014:3-22:chap 1.

3. Szaflarski JP, Bebin EM. Cannabis, cannabidiol, and epilepsy--from receptors to clinical response. Epilepsy Behav. Dec 2014;41:277-82. doi:10.1016/j.yebeh.2014.08.135

4. Ujvary I, Hanus L. Human Metabolites of Cannabidiol: A Review on Their Formation, Biological Activity, and Relevance in Therapy. Cannabis Cannabinoid Res. 2016;1(1):90-101. doi:10.1089/can.2015.0012

5. US Food and Drug Administration. FDA Approves First Drug Comprised of an Active Ingredient Derived from Marijuana to Treat Rare, Severe Forms of Epilepsy. 2018. https://www.fda.gov/news-events/press-announcements/fda-approves-first-drug-comprised-active-ingredient-derived-marijuana-treat-rare-severe-forms

6. Thomas BF, ElSohly MA. Biosynthesis and Pharmacology of Phytocannabinoids and Related Chemical Constituents. The Analytical Chemistry of Cannabis. Elsevier; 2016:27-41:chap 2.

7. Zamberletti E, Gabaglio M, Woolley-Roberts M, Bingham S, Rubino T, Parolaro D. Cannabidivarin Treatment Ameliorates Autism-Like Behaviors and Restores Hippocampal Endocannabinoid System and Glia Alterations Induced by Prenatal Valproic Acid Exposure in Rats. Front Cell Neurosci. 2019;13:367. doi:10.3389/fncel.2019.00367

8. Pertwee RG, Rock EM, Guenther K, et al. Cannabidiolic acid methyl ester, a stable synthetic analogue of cannabidiolic acid, can produce 5-HT1A receptor-mediated suppression of nausea and anxiety in rats. British Journal of Pharmacology. 2018;175(1):100-112. doi:10.1111/bph.14073

9. Marinol® (dronabinol) capsules, for oral use [prescribing information]. North Chicago, IL: AbbVie Inc. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=d0efeeec-640d-43c3-8f0a-d31324a11c68

10. Syndros® (dronabinol) oral solution [prescribing information]. Chandler, AZ: Insys Therapeutics Inc. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a7801c70-995d-46a2-91ee-141ef427c6b5

11. Stone NL, Murphy AJ, England TJ, O'Sullivan SE. A systematic review of minor phytocannabinoids with promising neuroprotective potential. Br J Pharmacol. Oct 2020;177(19):4330-4352. doi:10.1111/bph.15185

12. Sarma ND, Waye A, ElSohly MA, et al. Cannabis Inflorescence for Medical Purposes: USP Considerations for Quality Attributes. J Nat Prod. Apr 24 2020;83(4):1334-1351. doi:10.1021/acs.jnatprod.9b01200

13. Espadas I, Keifman E, Palomo-Garo C, et al. Beneficial effects of the phytocannabinoid Delta(9)-THCV in L-DOPA-induced dyskinesia in Parkinson's disease. Neurobiol Dis. Jul 2020;141:104892. doi:10.1016/j.nbd.2020.104892

14. Abioye A, Ayodele O, Marinkovic A, Patidar R, Akinwekomi A, Sanyaolu A. Delta9-Tetrahydrocannabivarin (THCV): a commentary on potential therapeutic benefit for the management of obesity and diabetes. J Cannabis Res. Jan 31 2020;2(1):6. doi:10.1186/s42238-020-0016-7

15. Bostwick JM. Blurred boundaries: the therapeutics and politics of medical marijuana. Mayo Clin Proc. Feb 2012;87(2):172-86. doi:10.1016/j.mayocp.2011.10.003

16. US Food and Drug Administration. FDA and Cannabis: Research and Drug Approval Process. Updated Oct 10, 2020. Accessed Sept 2, 2021. https://www.fda.gov/news-events/public-health-focus/fda-and-cannabis-research-and-drug-approval-process

17. Cash MC, Cunnane K, Fan C, Romero-Sandoval EA. Mapping cannabis potency in medical and recreational programs in the United States. PloS one. 2020;15(3):e0230167-e0230167. doi:10.1371/journal.pone.0230167

18. National Conference of State Legislatures. State medical marijuana laws. 2021. Accessed Dec 6, 2021. https://www.ncsl.org/research/health/state-medical-marijuana-laws.aspx

19. US Food and Drug Administration. Inside Clinical Trials: Testing Medical Products in People. 2014. Accessed Feb 18, 2022. https://www.fda.gov/drugs/information-consumers-and-patients-drugs/inside-clinical-trials-testing-medical-products-people

20. National Academies of Sciences, Engineering, and Medicine. The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. The National Academies Press; 2017:486.

21. American Academy of Neurology. AAN POSITION: USE OF MEDICAL CANNABIS FOR NEUROLOGIC DISORDERS. Updated Sept 2020. Accessed Dec 2, 2021. https://www.aan.com/policy-and-guidelines/policy/position-statements/medical-cannabis/

22. Bonn-Miller MO, Loflin MJE, Thomas BF, Marcu JP, Hyke T, Vandrey R. Labeling Accuracy of Cannabidiol Extracts Sold Online. JAMA. Nov 7 2017;318(17):1708-1709. doi:10.1001/jama.2017.11909

23. Vandrey R, Raber JC, Raber ME, Douglass B, Miller C, Bonn-Miller MO. Cannabinoid Dose and Label Accuracy in Edible Medical Cannabis Products. JAMA. Jun 23-30 2015;313(24):2491-3. doi:10.1001/jama.2015.6613

24. US Food and Drug Administration. Warning Letters and Test Results for Cannabidiol-Related Products. FDA.gov. 2020. Accessed Feb 23, 2021. https://www.fda.gov/news-events/public-health-focus/warning-letters-and-test-results-cannabidiol-related-products

25. Clean Label Project. Hemp Study Infographic. 2019. Accessed Dec 2, 2021. https://cleanlabelproject.org/hemp-study-infographic/

26. Small E. Evolution and Classification of Cannabis sativa (Marijuana, Hemp) in Relation to Human Utilization. Bot Rev. Sept 1 2015;81(3):189-294. doi:10.1007/s12229-015-9157-3

27. VanDolah HJ, Bauer BA, Mauck KF. Clinicians' Guide to Cannabidiol and Hemp Oils. Mayo Clin Proc. Sep 2019;94(9):1840-1851. doi:10.1016/j.mayocp.2019.01.003

28. US Food and Drug Administration. Hemp Production and the 2018 Farm Bill. 2019. Accessed Dec 2, 2021. https://www.fda.gov/news-events/congressional-testimony/hemp-production-and-2018-farm-bill-07252019

29. Establishment of a Domestic Hemp Production Program, Department of Agriculture (USDA) 7 CFR §990 (2021). Accessed 3 Dec 2021. https://www.federalregister.gov/documents/2021/01/19/2021-00967/establishment-of-a-domestic-hemp-production-program

30. Cannabinoid Clinical. Creating Confusion: The THC 0.3% Threshold. 2020. Accessed Dec 6, 2021. https://www.cannabinoidclinical.com/covering-cannabinoids/q3%E2%80%93q4-2020/the-thc-0.3-percent-threshold

31. Yang Y, Lewis MM, Bello AM, Wasilewski E, Clarke HA, Kotra LP. Cannabis sativa (Hemp) Seeds, Delta(9)-Tetrahydrocannabinol, and Potential Overdose. Cannabis Cannabinoid Res. 2017;2(1):274-281. doi:10.1089/can.2017.0040

32. Rheay HT, Omondi EC, Brewer CE. Potential of hemp (Cannabis sativa L.) for paired phytoremediation and bioenergy production. GCB Bioenergy. 2020;13(4):525-536. doi:10.1111/gcbb.12782

33. McPartland JM, McKernan KJ. Contaminants of Concern in Cannabis: Microbes, Heavy Metals and Pesticides. In: Chandra S, Lata H, ElSohly MA, eds. Cannabis sativa L - Botany and Biotechnology. Springer International Publishing; 2017:457-474:chap 22.

34. Jikomes N, Zoorob M. The Cannabinoid Content of Legal Cannabis in Washington State Varies Systematically Across Testing Facilities and Popular Consumer Products. Scientific Reports. 2018/03/14 2018;8(1):4519. doi:10.1038/s41598-018-22755-2

35. Micalizzi G, Vento F, Alibrando F, Donnarumma D, Dugo P, Mondello L. Cannabis Sativa L.: a comprehensive review on the analytical methodologies for cannabinoids and terpenes characterization. J Chromatogr A. Jan 25 2021;1637:461864. doi:10.1016/j.chroma.2020.461864

36. US Food and Drug Administration. What We Do. FDA.gov. 2018. Accessed Dec 3, 2021. https://www.fda.gov/about-fda/what-we-do

37. Cesamet® (nabilone) capsules, for oral administration [prescribing information]. Costa Mesa, CA: Valeant Pharmaceuticals International. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=83c7ac15-ece9-47de-b83c-d575544fa449

38. Epidiolex® (cannabidiol) oral solution [prescribing information]. Palo Alto, CA: Jazz Pharmaceuticals, Inc. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=8bf27097-4870-43fb-94f0-f3d0871d1eec

39. Gottlieb S. Statement from FDA Commissioner Scott Gottlieb, M.D., on signing of the Agriculture Improvement Act and the agency’s regulation of products containing cannabis and cannabis-derived compounds. 2018. https://www.fda.gov/news-events/press-announcements/statement-fda-commissioner-scott-gottlieb-md-signing-agriculture-improvement-act-and-agencys

40. US Food and Drug Administration. Center for Drug Evaluation and Research. Cannabis and Cannabis-Derived Compounds: Quality Considerations for Clinical Research Guidance for Industry. 2020. https://www.fda.gov/media/140319/download

Title	Content
Agricultural Improvement Act of 2018
Bioaccessibility
Bioaccumulation
Botanical Drug Product
Broad Spectrum*
Cannabinoid Receptors
Cannabinoids
Cannabis
Cannabis Halo Effect
Cannabis sativa L.
CBD Oil/Hemp CBD Oil*
Dietary Supplement
Drug Enforcement Administration (DEA) Drug Scheduling
Endocannabinoid System & Receptors
Endocannabinoids
Entourage Effect*
FDA-Approved Formulations of Cannabinoids
FDA-Approved Medication
Full Spectrum*
Hemp
Hemp Oil/Hempseed Oil*
Isolate*
Marijuana
Medical Cannabis*
Nutraceutical*
Phytocannabinoids
Phytoremediation
Pyramid of Evidence
Real-World Evidence
Recreational Marijuana*
Synthetic Cannabinoids
Terpenes/Terpenoids
Trichomes

The 0.3% THC Rule

The Difference Between THC and CBD

Test your knowledge

The Phytocannabinoids Story

Differentiating Phytocannabinoids

CBD

CBDV

CBDA

THC

THCA

THCV

Not All Cannabinoid Products Are Created Equal

Medical Marijuana

Medical Marijuana

Hemp-Derived Products

Hemp-Derived Products

FDA-Approved Cannabinoid Formulations

FDA-Approved Cannabinoid Formulations

FDA has approved 3 synthetic cannabinoids and 1 plant-derived cannabinoid.

References

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Medical
Marijuana

Hemp-Derived
Products