Safety and Sourcing of Topical Cannabinoids: Many Questions, Few Answers

Abstract

Background:
Topical cannabinoid products are increasingly being recommended and used for a variety of dermatologic conditions. Despite this, safety and efficacy data of topical preparations are lacking, and the differences between topical and oral formulations are not well characterized.

Objective:
We reviewed the literature to gather published data on topical cannabinoid products and the differences between topical and oral formulations.

Methods:
The PubMed/MEDLINE literature database was searched using the terms "cannabinoids," "cannabidiol," "CBD," "topical cannabidiol," "transdermal cannabidiol," "hemp" and "skin." Results were manually screened to identify published data on topical formulations of cannabinoids or cannabidiol use, adverse effects, sourcing, and solubility.

Results:
Topical formulations of cannabinoids might be more nuanced than oral formulations, due not only to dosing differences, but also to potential differences in transcutaneous absorption. Safety and efficacy might need to be evaluated on a product-by-product basis until universal standards for topical preparations are better established. CONCLUSION: Topical cannabinoid products might be an important addition to the dermatologic armamentarium, with the potential to dose cannabinoids directly to the skin while minimizing systemic exposure. However, before this can be done reliably, important formulation parameters must be established and verified.

Full text

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JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY August 2021 • Volume 14 • Number 8
REVIEW
IIn the past several years, there has been
a noteworthy surge in the availability and
demand of topical cannabidiol (CBD) products
for medical uses, including for pain, pruritus,
and general skincare.1–4 However, while there
is increasing acceptance of cannabinoids in
both medical and consumer cultures, many
questions have been raised regarding their
safety, bioavailability, and sourcing. We sought
to examine the literature for what is known
regarding topical CBD formulations.
Since orally consumed CBD is subject to  rst-
pass metabolism and transdermal CBD has low
aqueous solubility,  nding ways to increase the
therapeutic e cacy of CBD are imperative.5,6
Transdermal delivery systems are designed to
overcome the skin barrier in order to increase
the systemic bioavailability of therapeutics,
unlike topical formulations that are not meant
to enter systemic circulation.7,8 If the drug has
poor solubility and di usivity through the
skin, it may accumulate within the layers of
the skin, rendering it ine cient systemically.8
Therefore, the e ciency of penetration
enhancers in improving the bioavailability of
highly lipophilic CBD has been a recent point of
investigation.
In nude mice, occluded application of
ethanolized liposomes greatly increased drug
accumulation in the skin and the underlying
muscle. Steady-state levels were reached at
about 24 hours and lasted at least until 72
hours, while also preventing carrageenan-
induced in ammation and edema in the same
animal model.6 Comparatively, in human skin,
the solubility of CBD is 5.72μmol/mL and
the addition of 30.8% ethanol increased the
solubility nearly three-fold to 16.2μmol/mL,
establishing ethanol as an important additive
ingredient to enhance transdermal CBD
bioavailability. CBD’s increased hydrophobicity
also allowed for increased retention time
relative to Δ-9-tetrahydrocannabinol
(THC).9 In a later experiment using guinea
pigs, transdermal CBD was found to have
high accumulation in the skin, but plasma
concentration was increased 3.7-fold using
an ethanol-derived permeation enhancer
(Transcutol HP; Gattefossé, Saint-Priest,
France).10 Together, these studies con rm that
transdermal CBD with enhancing agents serves
as a promising delivery route for CBD, but
also underscore that simply standardizing the
amount of CBD in a topical product might not
ABSTRACT
BACKGROUND: Topical cannabinoid products are
increasingly being recommended and used for a
variety of dermatologic conditions. Despite this,
safety and e cacy data of topical preparations are
lacking, and the di erences between topical and oral
formulations are not well characterized. OBJECTIVE:
We reviewed the literature to gather published data
on topical cannabinoid products and the di erences
between topical and oral formulations. METHODS:
The PubMed/MEDLINE literature database was
searched using the terms “cannabinoids,” “cannabidiol,”
“CBD,” “topical cannabidiol,” “transdermal cannabidiol,”
“hemp” and “skin.” Results were manually screened
to identify published data on topical formulations
of cannabinoids or cannabidiol use, adverse
e ects, sourcing, and solubility. RESULTS: Topical
formulations of cannabinoids might be more
nuanced than oral formulations, due not only to
dosing di erences, but also to potential di erences
in transcutaneous absorption. Safety and e cacy
might need to be evaluated on a product-by-
product basis until universal standards for topical
preparations are better established. CONCLUSION:
Topical cannabinoid products might be an important
addition to the dermatologic armamentarium, with
the potential to dose cannabinoids directly to the
skin while minimizing systemic exposure. However,
before this can be done reliably, important formulation
parameters must be established and veri ed.
KEY WORDS: Topical cannabidiol, cannabinoids, CBD,
medical marijuana, cannabis
Safety and Sourcing of Topical
Cannabinoids: Many Questions,
Few Answers
by PAYAL M. PATEL, MD and PETER A. LIO, MD
Dr. Patel is with the Department of Dermatology at the University of Illinois at Chicago in Chicago, Illinois. Dr. Lio is with
Northwestern University Feinberg School of Medicine, and Medical Dermatology Associates of Chicago in Chicago, Illinois.
J Clin Aesthet Dermatol. 2021;14(8):49–51.
FUNDING: No funding was provided for this article.
DISCLOSURES: Dr. Lio reports research grants/funding from the National Eczema Association, Regeneron/Sano Genzyme,
and AbbVie; is on the speaker's bureau for Regeneron/Sano Genzyme, P zer, and L'Oreal; and reports consulting/advisory
board work for UCB, Dermavant, Regeneron/Sano Genzyme, Dermira, P zer, LEO Pharmaceuticals, AbbVie, Kiniksa, Eli
Lilly, Micreos (stock options), La Roche Posay/L'Oreal, Pierre-Fabre, Johnson & Johnson, Unilever, Menlo Therapeutics,
Theraplex, IntraDerm, Exeltis, AOBiome, Realm Therapeutics, Franklin Bioscience/Altus Labs (stock options), Verrica,
TopMD, Arbonne, Amyris, Bodewell, and Burt's Bees. In addition, Dr. Lio has a patent pending for a Theraplex product, with
royalties paid, and is a board member and Scienti c Advisory Committee member of the National Eczema Association Dr.
Patel reports no con ic ts of interest relevant to the content of this article.
CORRESPONDENCE: Peter A. Lio, MD; Email: peterlio@gmail.com

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JCAD JOURNAL OF CLINICAL AND AESTHETIC DERMATOLOGY August 2021 • Volume 14 • Number 8
REVIEW
be a valid indicator of the  nal bioavailability
across products and vehicles.
Another common obstacle to CBD use is the
lack of regulation of commercially available
CBD products and the need for analytical
testing to evaluate the sourcing of the active
compound. For CBD products, a method
incorporating gas chromatography-mass
spectrometry has been validated for the
qualitative analysis of cannabinoids in food
and topicals, among others.11 For quantitative
analysis of CBD products, however, a high-
performance liquid chromatography-diode
array detection method might be suitable,
but extensive validation is still required.12 CBD
products undergoing routine analysis with
analytical studies could allow companies to
manufacture puri ed compounds and remove
impurities, such as those found in conventional
plant-based samples.11
Of particular importance for patients using
topical CBD products is possible contamination
with THC due to the laws and mandated drug
testing by individual organizations. As they
remain unregulated and widely available, it
might be di cult to de nitively answer this
question across commercial CBD products. It
was found that oral consumption of low-
content THC hemp oil (0.046mg of THC per
5-mL dose) did not result in positive biological
assessments. No THC was detected in oral
 uid, blood, or urine samples at any time point
following consumption of low-content THC
oil, with the exception of trace amounts of
11-nor-Δ9-tetrahydrocannabinol-9-carboxylic
acid (M=0.0001mg/L) in urine at four hours
postconsumption.13 Additionally, while drug
tests are primarily designed to detect the
metabolites of smoked cannabinoids, some
molecules cross-react with the test, generating
false positives.14 Fortunately, CBD has low cross-
reactivity (<0.1%) in at least some varieties
of THC assays.14 However, no studies have
con rmed the aforementioned  ndings using
transdermal CBD preparations (with or without
THC), and drug testing kits use di erent THC
assays based on regional standards, rendering
this a complex, unknown problem.
Without rigorous safety studies for
transdermal CBD, data on adverse e ects must
be inferred through studies evaluating oral
CBD treatment for epilepsy. CBD doses up to
300mg daily can be used safely for up to six
months.15 However, some commonly reported
adverse e ects of oral CBD oil (Epidiolex;
Greenwich Biosciences, Carlsbad, California)
include somnolence, low appetite, diarrhea,
and elevated liver function test results.16
CBD metabolism by cytochrome P450 might
also result in drug-drug interactions, but
these adverse e ects might be minimized
through the transdermal route due to delayed
accumulation of drug levels.17 Moreover, since
CBD oil preparations are not standardized, there
are varying amounts of CBD/THC concentrations
in commercial products.18
Cannabinoids do not appear to be highly
allergenic or common contact allergens thus far
and might actually be helpful in attenuating
allergic contact dermatitis.19 However, the
 nal products may contain contact allergens
or irritants in the excipient and potentially
aggravate dermatitis in patients using
transdermal CBD preparations, reinforcing the
need for appropriate labeling of these products.
When educating patients on how to  nd
a quality CBD/hemp oil product, products
imported from Europe have been recommended
over those originating in the United States due
to stricter regulations.20 VanDolah et al21 have
developed helpful guidelines that are worth
enumerating (Table 1).
Despite the increased legalization of
cannabis derivatives across multiple regions
of the United States,21 CBD/hemp oils remain
Schedule 1 substances federally. Following
changes implemented under the 2018
Farm Bill, the United States Food and Drug
Administration (FDA) has clari ed some rules
on cannabis derivatives and removed hemp
from controls under the Controlled Substances
Act.22 Although the FDA has stated that this can
streamline the process to study CBD (that falls
under the de nition of hemp), it recognizes
that the regulatory framework for CBD still
needs updating. There are no standardization
processes to ensure that commercially
available CBD/hemp oil products are
appropriately sourced or prepared. However,
the FDA recommends that drug development
follows the following general principles:
characterization of CBD via a chemical
 ngerprint, routine testing for residual
pesticides applicable to substances originating
from botanical raw materials, microbial
enumeration testing, elemental impurities
testing, and principles on the assessment
of extractables/leachables associated with
pharmaceutical packaging or delivery.23 Selling
CBD and hemp oils is legal if the THC content
is below the 0.3% threshold in a majority of
the United States. For solutions or solids, the
THC percentage should be calculated with the
amount of water removed from excipients (for
more detail, see work from the Center for Drug
Evaluation and Research23). The FDA routinely
tests CBD products and warns organizations
when data show irregularities in the labeling
of the packages or concerns of additives,
such as nitrosamines. Some of their concerns
include false marketing and unproven medical
claims, such as those touting CBD to be a viable
treatment for coronavirus disease 2019.24
Moreover, regardless of these regulations,
certain positions and private organizations have
separate standards that mandate drug testing,
so these questions will continue to be relevant,
even in the event of federal legalization. If the
source is certi ed to be free of THC or contain
very low amounts of THC (de ned as 0.046mg
of THC per 5-mL dose), then topical application
is unlikely to be detected in biological
assessments. However, without regulations,
patients and practitioners alike must exercise
their use with caution due to di erences in
regional/local laws and the paucity of data
regarding the e cacy and safety of other
additive compounds
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