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Volume 6, Issue 1
January – December 2023

* Abstract
* Introduction
* CANNabinoid Drug Interaction Review (CANN-DIRTM)
* Medication Reconciliation Platform
* Languages
* Demographics
* Cannabinoid (PRECIPITANT) Medications
* Database (OBJECT) Medications
* Results
* Conclusion
* Acknowledgments
* Conflict of Interest Statement
* Funding Sources
* Author Contributions
* References

Article Navigation
Product Reviews| January 12 2023

CANNABINOID DRUG INTERACTION REVIEW (CANN-DIR™)

Topic Article Package: Topic Article Package: Antibody-Drug Conjugates
Subject Area: General Medicine , Pharmacology , Public Health
Paul T. Kocis;
Paul T. Kocis *
aDepartment of Pharmacy, Penn State Milton S. Hershey Medical Center, Hershey,
Pennsylvania, USA
bDepartment of Pharmacology, College of Medicine, Penn State University,
Hershey, Pennsylvania, USA
puk4@psu.edu
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Samuel Wadrose;
Samuel Wadrose
cDepartment of Computer Science, School of Science, Engineering, and Technology,
Penn State University, Harrisburg, Pennsylvania, USA
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Ryan Lee Wakefield;
Ryan Lee Wakefield
cDepartment of Computer Science, School of Science, Engineering, and Technology,
Penn State University, Harrisburg, Pennsylvania, USA
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Aqib Ahmed;
Aqib Ahmed
cDepartment of Computer Science, School of Science, Engineering, and Technology,
Penn State University, Harrisburg, Pennsylvania, USA
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Renata Calle;
Renata Calle
cDepartment of Computer Science, School of Science, Engineering, and Technology,
Penn State University, Harrisburg, Pennsylvania, USA
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Rohan Gajjar;
Rohan Gajjar
cDepartment of Computer Science, School of Science, Engineering, and Technology,
Penn State University, Harrisburg, Pennsylvania, USA
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Kent E. Vrana
0000-0003-4902-7733
Kent E. Vrana
bDepartment of Pharmacology, College of Medicine, Penn State University,
Hershey, Pennsylvania, USA
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puk4@psu.edu
Med Cannabis Cannabinoids (2023) 6 (1): 1–7.
https://doi.org/10.1159/000528528
Article history
Received:
September 10 2022
Accepted:
November 28 2022
Published Online:
January 12 2023
PubMed:
36814686

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Citation

Paul T. Kocis, Samuel Wadrose, Ryan Lee Wakefield, Aqib Ahmed, Renata Calle,
Rohan Gajjar, Kent E. Vrana; CANNabinoid Drug Interaction Review (CANN-DIR™).
Med Cannabis Cannabinoids 20 December 2023; 6 (1): 1–7.
https://doi.org/10.1159/000528528

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ABSTRACT

Non-prescription cannabidiol (CBD) and medical marijuana (cannabis) currently do
not have US Food and Drug Administration (FDA)-approved prescribing information
nor a dedicated resource to evaluate potential cannabinoid drug-drug
interactions with other medications. The CANNabinoid Drug Interaction Review
(CANN-DIR™) is a free web-based platform that has been developed to screen for
potential drug-drug interactions from the perspective of how a cannabinoid
delta-9-tetrahydrocannabinol (THC), CBD, or a combination of THC/CBD may affect
the metabolism of another prescribed medication. CANN-DIR™ is based on
FDA-approved prescribing information for the prescription cannabinoids
(dronabinol, nabilone, nabiximols, and prescription CBD) and other FDA-approved
prescribing information for medications sharing similar metabolic enzymes (e.g.,
the FDA “Drug Development and Drug Interactions: Table of Substrates, Inhibitors
and Inducers”). The Summary of Product Characteristics (SmPC) was the source of
drug-drug interaction information for the combined ∆9-THC &amp; CBD product
nabiximols (Sativex®). CANN-DIR™ provides an expeditious review of cannabinoid
drug-drug interaction information, and also a platform from which the patient
and health care provider can print out the search results to either initiate a
conversation, or for the health care provider to provide a written information
sheet to supplement their verbal discussion. Additionally, to more effectively
reach a global audience, the end user of CANN-DIR™ has the ability to currently
navigate and print results in any of the following ten languages: Chinese,
English, French, German, Nepali, Polish, Russian, Spanish, Swedish, and
Vietnamese.

Journal Section:
Product Review
Keywords:
Cannabinoid, Cannabidol, Delta-9-THC; ∆9-THC, Tetrahydrocannabinol, CANN-DIR,
Drug-drug interaction, Review, URL, Medication reconciliation

INTRODUCTION

As prescription cannabidiol (CBD) and non-prescription CBD oil, recreational and
medical marijuana (cannabis), and other prescription cannabinoids (dronabinol,
nabilone, nabiximols) are increasingly being used, there is the risk of
unintended drug-drug interactions (DDIs) [1]. These potential DDIs should not be
simply limited to the dizziness, somnolence, or confusion when co-administered
with other sedating medications but from the perspective of how various
cannabinoids may affect the metabolism of other prescription medications
co-administered by the patient. Specifically, the co-administration of any
cannabinoid with a prescription medication has the potential to interfere with
the metabolism of the prescription medication and therefore alter blood levels.
Recognizing the opportunity to increase patient safety by reducing unintended
DDIs, we have developed the CANNabinoid Drug Interaction Review (CANN-DIRTM) as
a free digital resource to highlight potential DDIs.

CANNABINOID DRUG INTERACTION REVIEW (CANN-DIRTM)

CANN-DIRTM is a digital evolution of the authors’ prior work entitled
“Delta-9-tetrahydrocannabinol and Cannabidiol Drug-Drug Interactions. Medical
Cannabis and Cannabinoids” [2]. CANN-DIRTM was developed to screen for potential
DDIs from the perspective of how a cannabinoid delta-9-tetrahydrocannabinol
(THC), CBD, or a combination of THC/CBD may affect the metabolism of another
concomitantly prescribed medication. CANN-DIRTM is freely accessible at the
following URL https://CANN-DIR.psu.edu or its QR code (Fig. 1).

Fig. 1.
View largeDownload slide

CANN-DIRTM QR Code.

Fig. 1.
View largeDownload slide

CANN-DIRTM QR Code.

Close modal

MEDICATION RECONCILIATION PLATFORM

Medication reconciliation is the formal process of developing the most accurate
list of medications a patient is taking to further evaluate their
pharmacodynamic and pharmacokinetic interactions [3]. The January 2020 Joint
Commission (TJC) National Patient Safety Goals® continues to focus on the
medication reconciliation performance element (NPSG.03.06.01) in both the
ambulatory health care [4] and the hospital [5] programs as a means of enhancing
patient safety. Potential DDIs are not just limited to prescription medications
but can also occur with other concomitantly taken herbal medications, over the
counter medications, supplements, and now the increasingly available
cannabinoids. It is important to develop a comprehensive and accurate medication
list along with the medication’s corresponding, dose, frequency, route of
administration, and medical indication to further reduce adverse events that can
be attributed to DDIs, especially during transitions of care [6].

CANN-DIRTM provides a platform from which written medication information can be
provided. A patient/caregiver can search how the cannabinoid of interest may
affect other concomitantly prescribed medications, print this information, and
provide to their health care provider for further discussion. Likewise, the
health care provider can perform this same process and provide a written
document to supplement their patient consultation in any of the ten languages
currently supported. It is anticipated that supplementing verbal instructions
with this written information will help improve patient outcomes and improve
patient safety [7].

LANGUAGES

This latest iteration of CANN-DIRTM was translated from English into additional
nine languages: Chinese, French, German, Nepali, Polish, Russian, Spanish,
Swedish, and Vietnamese. These languages were selected because they are the most
commonly spoken at our Penn State Health clinics and hospitals along with the
languages of countries from which CANN-DIRTM was viewed. We plan to include
additional languages in future iterations.

DEMOGRAPHICS

Before a search begins, CANN-DIRTM has a de-identified one-time demographics
page that allows the user to self-identify as either being a “Health Care
Professional,” “Patient/Caregiver,” or the opportunity to “Prefer Not to
Identify.” This provides the authors an opportunity to tailor future iterations
to a more specific audience and to assess knowledge base and gaps [8]. At the
time of this publication, CANN-DIRTM has been viewed in 36 countries. We also
created the CANN-DIR@psu.edu email address with which the end user can
communicate with our team.

CANNABINOID (PRECIPITANT) MEDICATIONS

CANN-DIRTM is based on three broad categories of cannabinoids:
delta-9-tetrahydrocannabinol (THC), CBD, or a combination of THC/CBD as
illustrated in Figure 2 [2]. The US Food and Drug Administration (FDA) approved
prescribing information served as the initial reference to DDI information for
dronabinol (Marinol® [9], Syndros® [10]); delta-9-tetrahydrocannabinol (THC);
nabilone (Cesamet®) [11]; and CBD (Epidiolex®) [12]. The Summary of Product
Characteristics (SmPC) was the source of DDI information for the combined ∆9-THC
and CBD product nabiximols (Sativex®) [13].

Fig. 2.
View largeDownload slide

∆9-THC and CBD cannabinoid (prescription, OTC, and medical cannabis)
formulations. This figure taken with permission from the author’s prior work
titled: ‘Delta-9-Tetrahydrocannabinol and Cannabidiol Drug-Drug Interactions’
[2]. OTC, over the counter.

Fig. 2.
View largeDownload slide

Close modal

CANN-DIRTM provides an opportunity to choose “THC,” “CBD,” or “THC/CBD” as the
cannabinoid (PRECIPITANT) medication of interest (Fig. 3). The “THC” category
comprised the delta-9-tetrahydrocannabinol therapeutic class composed of
dronabinol (Marinol®, Syndros®) and nabilone (Cesamet®) prescription
medications. The “CBD” category comprised non-prescription CBD oil and the
prescription CBD (Epidiolex®). Lastly, the “THC/CBD” category comprised THC/CBD
mixtures such as recreational cannabis use, medical marijuana extracts, or
nabiximols (Sativex®) a medication that is available in other countries, but
currently an investigational product in the USA.

Fig. 3.
View largeDownload slide

Screens depicting cannabinoid selection for THC, CBD, or the combination of
THC/CBD.

Fig. 3.
View largeDownload slide

Screens depicting cannabinoid selection for THC, CBD, or the combination of
THC/CBD.

Close modal

DATABASE (OBJECT) MEDICATIONS

In order to assure a comprehensive list of medications, whether there is a
potential DDI identified at this time or not, the drug database contained within
CANN-DIRTM comprised medications listed in the US FDA document “Drug Development
and Drug Interactions: Table of Substrates, Inhibitors and Inducers” [14]. This
list of medications was further supplemented using FDA-approved prescribing
information based on the Agency for Healthcare Research and Quality (AHRQ) list
of the top 225 most commonly prescribed medications in the USA in 2018 [15]. In
addition, the drug database contained within CANN-DIRTM contains commonly
prescribed oral oncology, oral HIV, oral antiepileptic medications, as well as
the recent Emergency Use Authorized (EUA) oral medications (ritonavir-boosted
nirmatrelvir and molnupiravir) to treat COVID-19.

RESULTS

CANN-DIRTM lists the OBJECT medications in alphabetical order by generic name
along with its corresponding brand name. Either the generic or brand name can be
used to search for potential DDIs. CANN-DIRTM permits the end user to save the
other OBJECT medications of interest so that they can be evaluated with a THC,
CBD, or THC/CBD cannabinoid of interest without having to input the medications
repeatedly.

The drug interaction results screen lists the cannabinoid (PRECIPITANT)
medication that has no DDI or either inhibits, induces, or competes as a
substrate for a specific enzyme/receptor for the OBJECT medications of interest.
The results also include a URL directing to detailed information on the
cannabinoid or other medication of interest. The results screen can also be
printed from a downloaded PDF as illustrated in Figure 4.

Fig. 4.
View largeDownload slide

Printed CANN-DIRTM drug interaction results screen.

Fig. 4.
View largeDownload slide

Printed CANN-DIRTM drug interaction results screen.

Close modal

CONCLUSION

CANN-DIRTM is the only known DDI web-based platform specific to the cannabinoid
class of medications. This online tool provides a free publicly accessible
mechanism by which a health care provider, caregiver, or patient can determine
if there is a potential DDI between a cannabinoid medication and other
prescription medications. If such a potential DDI is identified, it does not
necessarily mean that it is a contraindicated combination nor a clinically
significant interaction but an opportunity to evaluate the combination or adjust
the dose of either the cannabinoid or concomitantly prescribed medication.
CANN-DIRTM provides a readily accessible DDI resource for the patient and health
care provider that can be navigated in several different languages. This
platform also provides the patient and health care provider an opportunity to
print out their results to either initiate a conversation or provide written
documentation supplementing a consultation.

CANN-DIRTM is intended to be an adjunct in decision-making since individual
patient characteristics (e.g., gender, age, genomic profile, ethnicity, hepatic
function, renal function, and disease state) for the medically complex patient
should also be taken into account. In the time since CANN-DIRTM was deployed
(March 2022), it has already undergone planned updates to keep the medication
database current, along with software code enhancements. At this time, we have
completed a v2.0.3 update and have a planned v3 update for the Spring of 2023.

LIMITATIONS

By design, this web-based URL platform does not evaluate DDIs from the
perspective of how a medication (e.g., warfarin) affects the cannabinoid, nor
does it make explicit predictions of the outcome of potential DDIs. Currently,
CANN-DIRTM provides DDI results written for the health care provider; however,
future iterations will have a more patient-focused results section when the
“Patient/Caregiver” button is selected.

ACKNOWLEDGMENTS

The authors would like to thank Josh Leppo, Nan Chen, Dr. Hyuntae Na, James
Robertson, Joshua Lease, Shanne Kenny, and Brad Winters. In addition, the
authors would like to thank the members of the Penn State College of Medicine
Medical Marijuana Academic Clinical Research Center (ACRC) for discussions and
support and the Penn State Center of Medical Innovation (CMI) by whom this
project was made possible.

CONFLICT OF INTEREST STATEMENT

K.E.V. and the Penn State College of Medicine are the recipients of research
support from PA Options for Wellness (a state-approved medical marijuana
clinical registrant). The funding source had no involvement in the writing or
analysis of work presented, nor the decision of what to present.

FUNDING SOURCES

K.E.V. and the Penn State College of Medicine are the recipients of research
support from PA Options for Wellness, a Pennsylvania-approved medical marijuana
clinical registrant. The Penn State College of Medicine is a
Pennsylvania-approved Medical Marijuana Academic Clinical Research Center. The
authors also acknowledge Penn State College of Medicine’s Center for Medical
Innovation for undergraduate student Capstone project funding.

AUTHOR CONTRIBUTIONS

Paul T. Kocis and Kent E. Vrana substantially contributed to the conception and
design of the work; drafted the work and revised it critically for important
intellectual content; was involved in the final approval of the version to be
published; and agreed to be accountable for all aspects of the work in ensuring
that questions related to the accuracy or integrity of any part of the work are
appropriately investigated and resolved.

Samuel Wadrose, Ryan Lee Wakefield, Aqib Ahmed, Renata Calle, and Rohan Gajjar
substantially contributed to the design of the work; revised the work critically
for important intellectual content; was involved in the final approval of the
version to be published; and agreed to be accountable for all aspects of the
work in ensuring that questions related to the accuracy or integrity of any part
of the work are appropriately investigated and resolved.

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