current status of regulatory requirements for hemp … · introduction the hemp-derived cbd market...

CURRENT STATUS OF REGULATORY REQUIREMENTS FOR HEMP AND CANNABIS IN

THE UNITED STATESRichard Sams, PhDScientific DirectorKCA Laboratories

Nicholasville, Kentucky

Overview of Presentation

■ Introduction

■ Definitions

■ History of Cannabis

■ Legal and Regulatory Issues

■ The Endocannabinoid System

■ Laboratory Testing

■ Questions

10/10/2019 KCA Laboratories 2

INTRODUCTIONHemp and Cannabis


Introduction

■More than 1,000 cannabis-related bills are moving through state legislatures and Congress for 2020 sessions.


Introduction■ Preparations

of Cannabis plants have been used for medicinal, religious, and recreational purposes for thousands of years.

■ They affect appetite, pain, mood, motor control, memory, cognition, and perception.

■ Cannabis plants have also been the source of fiber for making rope and textiles as well as seeds and oils.

■ By the mid-1930s cannabis was regulated as a drug in every state, including 35 states that adopted the Uniform State Narcotic Drug Act.

■ The first national regulation was the Marihuana Tax Act of 1937.

■ All Cannabis (specifically Cannabis sativa L.) was prohibited in the US with the Controlled Substances Act of 1970.


Introduction■ Marijuana and its psychoactive

component ∆9-tetrahydrocannabinol (THC) have been classified as a DEA Schedule I controlled substances with no accepted medical use in the US since 1970.

■ California approved use of marijuana for medical purposes in 1996 in conflict with federal law.

■ Thirty-three states and the District of Columbia allow medicinal use.

■ The export of marijuana to other states remains illegal since the U.S. Drug Enforcement Administration considers it a Schedule I drug.

■ Various states (beginning with Colorado in 2012) allow recreational use of marijuana under a tightly regulated system.

■ Eleven states and the District of Columbia permit recreational use of marijuana in conflict with federal law.

■ The 2018 Farm Bill exempts hemp from the DEA classification and allows sale and use of cannabidiol (CBD).

■ Hemp and CBD production are expanding rapidly throughout the US.


Introduction


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By Lokal_Profil, CC BY-SA 2.5, https://commons.wikimedia.org/w/index.php?curid=2370050

Introduction■ The hemp-derived CBD market

is predicted to become a $5.7 billion market by 2019 and a $22 billion market by 2022.

■ Regulations for standards of safety and integrity for cannabis products are evolving and are common to the pharmaceutical, food, beverage, and tobacco industries.


Introduction■ Marijuana is a common name for

the cannabis plant, Cannabis sativa L.

■ Cannabis is a dioicous plant; male and female flowers are found on different plants.

■ Cannabis has been domesticated from the “wild type” and cultivated for thousands of years.

■ Numerous cultivars have been developed to enhance and optimize production of fiber or cannabinoids.

■ Cannabis contains 483 different substances including 113 phytocannabinoids, 140 terpenoids plus fatty acids, hydrocarbons, steroids, flavonoids, vitamins, etc.


DEFINITIONS


Definitions

■ Cannabis– Cannabis sativa L– Hemp

■ Cannabinoids– Psychoactive– Non-psychoactive– Synthetic

■ Endocannabinoid System■ Full-spectrum and broad-spectrum■ Entourage effect


HISTORY OF CANNABIS


Origins of Cannabis


■ The genus Cannabis(Family Cannabaceae) is probably indigenous to wet habitats of Asia.

■ It is one of the oldest cultivated plants in East Asia, grown for grain and fiber as well as for recreational, medical, and ritual purposes.

■ Analysis of residues from a brazier from an ancient archeological site revealed residues of CBN, CBL, and CBD.

History of Cannabis


■ Cannabis was probably domesticated in Asia where it was bred for a variety of purposes.

■ The long coexistence between humans and Cannabis led to domestication of the plant, which resulted in various uses as a source of textile fibers as well as psychoactive substances.

■ Today, the species belonging to the genus Cannabis is represented by myriads of cultivated varieties, often with unknown taxonomic foundations.

■ Linnaeus described a single species of hemp, Cannabis sativa in Species Plantarum (1753). This plant was a domesticated plant used for hemp production in Europe.

■ Lamarck (1785) proposed two species of Cannabis: C. sativa, the species largely cultivated in Europe, and Cannabis indica, a wild species growing in India and neighboring countries.

■ Smart argues that there is one species (C. sativa) and recognizes indica as a subspecies of C. sativa.

History of Cannabis in the US


■ Hemp has been grown for fiber in the US since colonial times.

■ Hemp for fiber production requires retting in order to isolate the fiber.

■ Retting in northern states involved soaking the stems in ponds and streams for several weeks.

■ In Kentucky, the “dew” method was used because it was thought that hemp would poison the water.

■ The dew method involves cutting the hemp and allowing it to lie in the field where moisture from dew aided retting.



■ The fiber produced by the dew method was considered inferior to the northern fiber.

■ Disputes between northern states and Kentucky resulted in disputes in Congress involving Henry Clay and others.

■ Fibers were critical for production of ropes for use in sailing vessels in the US and Europe.



■ The use of Cannabis for its psychomotor effects was relatively uncommon in the US until early 20th century.

■ Use of various strains (primarily C. sativa indica) during the early part of the 20th century by immigrants and ethnic minorities resulted in efforts to curtail its use.

■ The Marihuana Tax Act of 1937 was one of several efforts.

■ Inclusion of all varieties of Cannabis as a DEA Schedule I substance made all uses illegal with sale and possession punishable with fines and imprisonment.

■ Cultivation of Cannabis for use for its psychomotor effects has continued.

■ Amateur plant breeders have developed multiple named varieties (cultivars) with different amounts of THC and other cannabinoids as well as terpenes.

■ These breeders created undocumented hybrid strains with unsupportable claims for a distinction between indica and sativa.

History of Cannabis in Kentucky


■ Industrial hemp was a major agricultural crop on central Kentucky farms from the late eighteenth and nineteenth centuries.

■ Almost all hemp was grown for its fiber.

■ Hemp is a very labor-intensive crop both at harvest and during processing.

■ Historically, hemp production involved use of slaves, indentured servants, and extended family members.

■ Hemp production became impractical after 1937 with the passage of the Marihuana Tax Act.

– Intended to curb use of marijuana for recreational use.

■ Production of hemp seed resumed during WWII. The seed was used for fiber production in northern states.

History of Cannabis in Kentucky


■ All Cannabis became illegal to produce or possess following the passage of the Controlled Substance Act 1978.

■ Under the CSA, all forms of Cannabis were classified as Schedule 1 controlled substances and remain in that classification today.

■ The Agricultural Act of 2014 provided for legal pilot research programs with hemp to be administered by either state departments of agriculture or universities

■ In Kentucky, the General Assembly passed Senate Bill 50 in 2013 in anticipation of the 2014 Farm Bill.

■ This bill authorized the Kentucky Department of Agriculture (KDA) to administer the statewide pilot research program in spring 2014.

■ The pilot research program in Kentucky continues under the management of the KDA.

CANNABISDescription and History


Cannabis■ Cannabis is an annual plant of

the species Cannabis sativa L.

■ It is photoperiod-sensitive (i.e., it flowers according to day length/photoperiod not physiological maturity).

■ It is mostly dioecious - male and female flowers occur on separate plants

■ There are several monoecious commercial varieties (male and female flowers parts on the same plant).


Cannabis■ Different plant parts are

harvested for specific purposes.

■ Contemporary hemp may be produced for one or sometimes dual purposes.

■ Depending on the harvestable component of interest, (i.e. fiber, grain, or cannabinoids) male plants and/or pollen might be vitally necessary or completely unwanted.


Cannabis■ Different plant parts are

harvested for specific purposes.■ Contemporary hemp may be

produced for one or sometimes dual purposes.

■ Depending on the harvestable component of interest, (i.e. fiber, grain, or cannabinoids) male plants and/or pollen might be vitally necessary or completely unwanted.

■ Unfertilized (non-pollinated) female flowers tend to produce more cannabinoids than when they are pollinated and allowed to produce seed.


Cannabis■ Cannabis produces numerous

cannabinoids primarily in trichomes (see figure) on the female plant.

■ The cannabinoids include psychoactive ∆9-THC and non-psychoactive cannabidiol (CBD) among others.


Cannabis■ Trichomes also produce

terpenes that vary in composition and amount from one cultivar to another.

■ Terpenes are the volatile substances that give cultivars their characteristic aroma and taste.


Marijuana ■ Cannabis containing ∆9-

THC at a concentration greater than 0.3% by dry weight is termed marijuana.

■ Marijuana is a DEA Schedule I substance throughout the US.

■ Cultivars producing high amounts of ∆9-THC have been developed and are cultivated in those states that have legalized medical or recreational marijuana.


Hemp

■ Hemp is grown primarily for its fiber.

■ By definition hemp must contain less than 0.3% THC by dry weight.

■ If THC is greater than 0.3%, the material is marijuana and illegal.


Full-Spectrum Products

■ Extract that contains all of the cannabinoids in the original plant material.

■ Extract includes terpenes and terpenoids.

■ Needs CofA to interpret cannabinoid contents due to differences between source materials.


Broad-Spectrum Products

■ Extract that contains fewer cannabinoids than in the original plant material.

■ Extract includes terpenes and terpenoids.

■ THC absent from broad-spectrum products.

■ Need CofA to interpret contents.


CANNABINOIDSChemistry and Pharmacology


Cannabinoids

Psychogenic

■ Typified by ∆9-THC■ Act at cannabinoid

receptors CB1 and CB2

■ Produce psychogenic effects at CB1 receptor

■ Produce the “high” associated with marijuana use

Non-Psychogenic

■ Typified by cannabidiol (CBD)

■ Produce no psychogenic effects

■ May reduce or modify psychogenic effects of ∆9-THC when administered with it

■ Not an agonist at the CB1receptor


Psychogenic Cannabinoids■ THC acts at CB1 and CB2receptors.■ Highly lipophilic substance

with MW 314.■ Low water solubility. No

readily ionizable groups.■ Obtained by decarboxylation

of THCA.■ Poor oral availability due to

poor absorption AND high first-pass effect.

■ Primary metabolite (see structure on right) is also psychogenic.

■ Better systemic availability by inhalation (smoking).

OH

OH

H


Synthetic PsychogenicCannabinoids■ Various analogues

synthesized to investigate binding of ∆9-THC to CB receptors.


Synthetic Psychogenic Cannabinoids

Synthetic

■ JW Hoffman synthesized various analogues in 1996 to investigate binding of ∆9-THC to CB1 and CB2receptors.

■ Never intended for human use.

■ Many available online as “research chemicals”.

■ Some have been detected in marijuana as well as hemp and CBD products.


Non-psychogenic Cannabinoids■ CBD is structurally similar to THC (see

figure)

■ CBD does not act at CB1 and CB2receptors although it may modify interactions between psychogenic cannabinoids and these receptors.

■ Highly lipophilic substance with MW 314.

■ Low water solubility. No readily ionizable groups.

■ CBD is produced by decarboxylation of CBDA during heating.

■ CBD has poor and variable oral availability due to low solubility in water that reduces the rate and extent of absorption AND high first-pass effect for those molecules that are absorbed.

■ Fats in meals enhance absorption and reduce first-pass effect.


Cannabidiol■ CBD is sold in a variety of

formulations for human and animal use and promoted for a number of indications.

■ Evidence for efficacy except in the case of seizures in infants and children is scarce.

■ Side effects of CBD include nausea, fatigue and irritability.

■ CBD can inhibit metabolism of certain substances and medications by the same mechanism that grapefruit juice does.

■ The FDA does not regulate the safety and purity CBD.

■ Therefore, a user cannot know with certainty that the product they purchase has active ingredients at the dose listed on the label.

■ In addition, the product may contain other (unknown) substances including residual solvents, heavy metals, pesticides, and molds and bacteria.

■ The effective therapeutic dose range of CBD for any particular medical condition is unknown.


ENDOCANNABINOID SYSTEM

Chemistry and Pharmacology


Endocannabinoid System■ The endocannabinoid system is an

endogenous cannabinoid system found in invertebrates, fish, reptiles, birds, and mammals.

■ ∆9-THC was originally thought to interact with lipophilic membranes via a non-receptor mechanism.

– Early studies indicated lack of stereospecificity because (+)∆9-THC showed activity;

– Later shown that (+)∆9-THC was contaminated with (-)∆9-THC;

■ Receptor binding then postulated by Mechoulam and others to account for pharmacologic effects of (+)∆9-THC.

■ Howlett et al. discovered the endogenous cannabinoid receptor in the brain in 1990.

– Designated it the CB1receptor.

– Activation of CB1 accounts for most of the behavioral effects of THC.

■ Endogenous receptor agonist subsequently isolated from pig brains by Mechoulam et al.

– Named the endogenous ligand anandamide.

– Other endogenous ligands including 2-arachidonoylglycerol (2-AG) identified.

■ Munro et al. identified a second cannabinoid receptor in 1993;

– Designated it the CB2receptor.– CB2 is expressed primarily by

immune cells, including microglia in the brain, and is thought to mediate THC’s immunosuppressive effects.


Endocannabinoid System■ Anandamide is degraded

to arachidonic acid and ethanolamine by FAAH.

■ 2-AG is degraded to arachidonic acid and glycerol by MAGL.

■ Endocannabinoid tone is maintained at a low concentration by biosynthesis, re-uptake, and degradation.

■ Stress initiates endocannabinoid signaling by anandamide and 2-AG.


Endocannabinoid System■ Endocannabinoid signaling

regulates numerous aspects of mammalian neurophysiology, including pain perception, feeding, emotional state, learning and memory, and reward behaviors.

■ Re-uptake of anandamide followed by degradation by FAAH terminate its action.

■ CBD is an FAAH inhibitor.

■ Re-uptake inhibitors and inhibitors of FAAH are being evaluated as therapeutic substances.


LEGAL AND REGULATORY


Regulatory Climate

■ The flood of CBD products onto the market despite the ingredient’s legal impediments has been unprecedented in the history of dietary supplements. The Hemp Farming Act, passed as part of the 2018 Farm Bill, removed the DEA hurdle for cannabidiol from hemp. However, for FDA, the IND exclusion clause still prohibits the inclusion of CBD in dietary supplement, foods, and beverages.

■ This has not stemmed the tide of CBD product launches, whether those are dietary supplements, beverages, or food. Quality standards appear to be all over the place, as are the claims being made. While FDA has reined in some of the more egregious players, the Agency has remained largely passive.


Regulatory Climate■ FDA recently completed its evaluation of

three GRAS notices for hemp seed-derived food ingredients. The agency reported that it has no questions about the submitter’s conclusion that the hemp ingredients are GRAS under their intended conditions of use. The ingredients are identified as hulled hemp seed (GRN765), hemp seed protein powder (GRN771), and hemp seed oil (GRN778).


CBD Regulation in US■ Cole Memo was rescinded

in January 2018– DOJ policy statement

regarding enforcement of federal marijuana laws in states where marijuana is legal under state law.

■ FDA approved Epidiolex in mid-2018

– Prescription only drug made from a CBD isolate for treatment of epilepsy

■ 2018 Farm Bill signed in December 2018

■ 2018 Farm Bill– Legalized hemp at

the federal level– Made it an

agricultural commodity

– Removed hemp and certain derivatives including CBD from DEA Schedule I when produced in compliance with a state program

– Defined hemp (THC < 0.3%)


Regulation of Cannabis in Kentucky■ “Even though the 2018 Farm Bill removes hemp from the

controlled substance list, no person can grow, handle, or process hemp plants, viable seed, leaf or floral materials without a hemp license issued by the Kentucky Department of Agriculture.”

■ “Penalties for persons who cultivate, handle, process, or market living industrial hemp plants or viable seeds, leaf materials, or floral materials derived from industrial hemp without a license are the same as those penalties that are applicable to persons who violate KRS Chapter 218A, relating to marijuana.”


Regulation of Cannabis in Kentucky


LABORATORY ANALYSIS


Why Analyze Cannabis and Hemp?■ In the absence of federal oversight, states have produced a

patchwork of regulations, where rules governing cannabis testing differ substantially across state lines - a challenge for everyone in the industry.

■ Some states mandate specific cannabis testing regimens, such as potency testing and foreign material contamination screening. Others also require laboratories to achieve official accreditation – such as the ISO/IEC 17025 standard for testing laboratories – in order to comply with their regulations.

■ Requirements may be standardized by Congressional action.


Why Analyze Cannabis and Hemp?■ Medical cannabis market in the US was essentially unregulated with

respect to quality control when California passed proposition 215 in 1996.

■ Testing for active ingredients, pesticide residues, microbiological contamination, heavy metals, and other potentially harmful chemical constituents was not available until the first laboratories appeared in 2009.

■ Medical cannabis patients, caregivers, producers, and attending physicians had very little analytical data available when making decisions on dosage and even less information about potential adulterants and contaminants.


Why Analyze Cannabis and Hemp?■ Legalization of recreational cannabis in Colorado and Washington

then Oregon and Alaska, as well as new legislation legalizing medical cannabis in states like Hawaii, New York, Ohio, and Illinois, has led to laws requiring quality control testing.

■ Testing typically includes potency, heavy metals, residual solvents, microbial and fungal contamination, and pesticides (including insecticides, fungicides, and herbicides).

■ Terpenes and terpenoids are included in test methods because they contribute to the aroma and taste and are believed to contribute to the effects of cannabis. If the product label lists terpenes, then terpenoids must be determined by testing.


Why Analyze Cannabis and Hemp?■ Trade groups like the American Herbal Pharmacopeia, the American

Herbal Products Association, the American Chemical Society, Association of Official Analytical Chemists, American Society for Testing Materials, and others have issued recommendations for best practices, tolerances for contaminants, and guidance with respect to acceptable analytical methods.

■ Limited information regarding the test results of the cannabis products has been reported.

■ SC Laboratories tested nearly 300,000 unique samples of cannabis, cannabis extracts, and cannabis-infused products from the California market for a range of potential contaminants including pesticides, plant growth regulators, microbiological contaminants, and residual solvents.


Why Analyze Cannabis and Hemp?■ Based on this analysis, SC Labs reported that pesticide use was rampant with

findings as high as 80%.

■ No pesticides or plant growth regulators are approved for use on cannabis. Health effects are unknown when consumed via inhalation. Consequently, pesticides are prohibited in most states.

■ Microbiological and residual solvent contamination is less of an issue with a smaller portion of the cannabis supply failing to meet required or recommended safety levels.


Analytical Testing of Cannabis


Potency Determination of Cannabinoids in Cannabis and Hemp

■ Quantitative determination of cannabinoids in plant materials and finished products to support label claims and to conform to regulatory requirements:

– Total THC <0.3% in hemp on a dry weight basis■ Total THC is the sum

of THC and THCA– 10-12 cannabinoids

typically determined by instrumental methods of analysis


Potency Determination of Cannabinoids in Cannabis■ Methods

– Liquid Chromatography■ Diode array detector

(HPLC-DAD or HPLC-PDA)

■ Mass spectral detector (LC-MS)

– Gas Chromatography■ Flame ionization

detector (GC-FID)■ Mass spectral

detector (GC-MS)


JAMA. 2017;318(17):1708-1709. doi:10.1001/jama.2017.11909

Labeling Accuracy of Cannabidiol Extracts Sold Online

Terpenes■ Terpenes account for the vast

array of smells and flavors in cannabis flowers and extracts, and provide the notable aromas of cannabis varieties.

■ Some of the medical and physiological benefits found in cannabis have been attributed to terpenes.

■ Genetic and environmental factors, as well as drying and curing processes, determine the types and levels of terpenes present in usable cannabis.

■ Terpenes are oxidized and denatured to form terpenoids during the process of drying and curing.

■ Terpenes and terpenoids determined by headspace GC-MS.


Terpenes in Cannabisalpha-BisabololBorneol*CampheneCamphor*3-Carenebeta-CaryophylleneCaryophyllene Oxidealpha-CedreneCedrolEndo-Fenchyl alcohol EucalyptolFenchone*GeraniolGeranyl acetateGuaiolHexahydrothymol (Menthol)alpha-HumuleneIsoborneolIsopulegolLimonene Linaloolp-Mentha-1,5-diene (alpha-Phellandrene)beta-Myrcene

Nerolcis-Nerolidoltrans-NerolidolOcimene isomer IOcimene isomer IIalpha-Pinenebeta-Pinene PulegoneSabineneSabinene Hydratealpha-Terpinenegamma-TerpineneA-TerpineolB/Y-TerpineolTerpinoleneValencene


Residual Solvents

■ Solvents used in extractions may persist in products.

■ Headspace GC-MS is typically used to detect residual solvents.


Heavy Metals

■ Cannabis plants are potential bioaccumulatorsof heavy metals. In the production of these products, a large amount of plant material is processed to extract concentrates and oils, thereby increasing the risk of heavy metal contamination.

■ Heavy metals are typically determined by ICP-MS.

■ All cannabis products undergo testing for cadmium, lead, arsenic, and mercury.


Heavy Metals


Pesticides■ Under the current US

regulatory system, pesticides must be registered with the EPA.

■ The EPA sets tolerances for pesticide residues that may remain on crops sold within the US and requires that all pesticide products be labeled to indicate approved usage.

■ Marijuana is not considered a crop and does not fall into any category for which the EPA (or the FDA or USDA) have oversight.

■ The only guidance that states currently have is FIFRA, which states that it is unlawful to use a pesticide in a manner that is inconsistent with its label.

■ Therefore, since no pesticides are labeled for usage on Cannabis, any application of a registered pesticide is in violation of FIFRA.

■ States have approved specific pesticides for use in marijuana and hemp production.


Pesticides■ Very wide range of

polarities of prohibited pesticides.

■ Each state has chosen to regulate pesticides differently and with different residue limits.

■ LC-MS and GC-MS analysis are typically required to achieve qualitative and quantitative requirements.


Kentucky Regulations

■ Kentucky has announced that certain pesticides are authorized for use for industrial hemp production in 2019.


Oregon Experience


Distributions of concentrations of PBO and bifenthrin forflowers versus concentrates. The OHA limit of 100 ppb is shownwith a black hashed line. Note: The Y-axis is log scaled.

Proportion of samples that tested positive for anydetectable level of pesticide residue. (B) Proportion of samples having greater than 100 ppb of one or more pesticides covered by the current OHA rules. (C) Proportion of samples having greater than 100 ppb of any pesticide defined by statute.

Colorado Experience

■ Employee of a medicinal grow facility in Idaho Springs complained to the state in 2012 about a lack of protective clothing for use when spraying plants.

■ Tests at the facility found Floramite and Avid

– miticides not labeled for use on fruits and vegetables let alone cannabis, in the growers product.

■ Colorado state regulators began to conduct testing two years after recreational

marijuana was approved.■ Nearly half of the marijuana

tested positive for unapproved pesticides.

■ In 2015 Governor Hickenlooper issued an executive order executive banning all “off-label” use of pesticides.

■ All use was “off label” because EPA could not authorize use on marijuana due to its DEA Schedule.

■ Recently allowed pesticide use on marijuana.


■ Certificate of Analysis1. Name of laboratory

performing analysis of the commercial product; preferably 3rd party analysis.

2. Certificate of Analysis identifies the purpose of the report.

3. Name of company that provides software and LIMS for reporting results.

4. Name of producer of the product.

5. Identification # of product and date of testing.

6. Description of product.7. QR code that may contain

additional information. 8. Photograph of product

tested.


■ Certificate of Analysis9. Total potential THC from

THCA and THC in product.

10. Total potential CBD from CBDA and CBD in product.

11. Statement that the photo is one of the product submitted for testing.

12. Header for the analytical report.

13. Results for THCA and THC in the product.

14. Results for other cannabinoids in the product. Note bar graph on right hand side.


■ Certificate of Analysis15. Total cannabinoid

content of product.16. Definition of unit for this

product (1 ounce bottle).17. Description of methods

used to determine the cannabinoids in the product. Includes calculation used to convert THCA and CBDA to THC and CBD, respectively.

18. Signature and contact information for the individual responsible for the Certificate of Analysis.


Broad Spectrum CofA

■ Note that this particular product contains no detectable THCA or ∆9-THC.

■ Note that the product contains mostly CBD but it also contains CBDV, CBC, and CBDA.


Summary■ The long-standing regulation of Cannabis in

all forms in the US as a DEA Schedule I substance resulted in a dearth of reliable research with regard to its potential therapeutic uses.

■ The decision by individual states to permit medical and/or recreational marijuana creates complexity due to differing licensing and testing requirements.

■ The needs for standardized testing and laboratory standards are obvious.


current status of regulatory requirements for hemp … · introduction the hemp-derived cbd market...

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