Clinical Study to Evaluate Drug Interactions of Cannabidiol with Citalopram and Morphine in Healthy Adults

Abstract

Cannabidiol (CBD) is one of the most abundant bioactive cannabinoids. Research has demonstrated CBD’s ability to inhibit metabolic enzymes like cytochrome P450 (CYP) and UDP‐glucuronosyltransferase (UGT), potentially leading to drug interactions. However, clinical knowledge gaps remain, particularly with regard to drugs that are more commonly taken by consumers of unregulated CBD products. This study aimed to characterize the effects of daily CBD consumption, at doses typical of unregulated CBD products, on the pharmacokinetics of citalopram and morphine. These two commonly prescribed medications are metabolized by CYPs and UGTs, respectively. This open‐label, sequential study involved two cohorts of 20 healthy participants. Cohort one received a single dose of citalopram (20 mg) on days 1 and 13, with CBD (2.5 mg/kg twice daily) administered for 12 days. Cohort two received a single dose of morphine (15 mg) on days 1, 4, and 11, with CBD (2.5 mg/kg twice daily) given for 9 days. The geometric mean ratio (GMR, [90% confidence interval]) for citalopram with and without CBD for 12 days was 1.43 (1.34–1.52) for the area under the plasma concentration–time curve (AUC_0−inf) and 1.12 (1.06–1.17) for the maximum observed plasma concentration (C _max). The GMR for AUC_0−inf and C _max for morphine coadministered with CBD compared to morphine alone was 1.06 (0.96–1.16) and 1.19 (1.05–1.35), respectively. For morphine with CBD for 9 days compared to morphine alone, the GMR for AUC_0−inf and C _max was 1.12 (1.00–1.26) and 1.11 (0.94–1.30), respectively. While a significant pharmacokinetic interaction between CBD and citalopram was observed, interactions between CBD and morphine, as well as its metabolites, were limited.

Study Highlights.

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Cannabidiol and its metabolites are known to impact the metabolism of other drugs, including drugs that are substrates of UGT1A9, UGT2B7, CYP1A2, CYP2C8, CYP2C9, CYP2C19, and orally administered P‐gp substrates. The FDA‐approved cannabidiol product conducted studies with index CYP substrates and antiepilepsy drugs. Unregulated cannabidiol products are used by consumers at lower doses, and potential drug interactions at these lower dosages and with other commonly used drugs have limited data.

• WHAT QUESTION DID THIS STUDY ADDRESS?

Unregulated cannabidiol is often used for conditions such as pain, anxiety, insomnia, and depression. Do cannabidiol doses typical of unregulated cannabidiol products affect exposure of drugs such as citalopram or morphine, which are commonly used prescription medications for some of these indications?

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Citalopram exposure increased with cannabidiol, and increases were similar to those observed with known CYP2C19 inhibitors. No clinically relevant changes in morphine or metabolite exposures were observed when taken with cannabidiol.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

Cannabidiol increases citalopram exposure similar to that observed with the CYP2C19 inhibitor, cimetidine. Citalopram labeling includes language regarding a lower maximum dosage when used with CYP2C19 inhibitors. Consumers of unregulated cannabidiol products who are also on citalopram should be aware of this potential drug interaction and may need to adjust citalopram dosing accordingly.

The cannabis plant contains bioactive compounds known as cannabinoids, with delta‐9 tetrahydrocannabinol (THC) and cannabidiol (CBD) being the most abundant. The use of unregulated CBD has increased among consumers, raising various safety concerns. In a 2022 national drug survey of over 47,000 adults in the US, 20.6% reported using unregulated CBD in the previous 12 months. ¹ The variety of consumer CBD‐containing products has also increased, now including oils, capsules, supplements, syrups, teas, gummies, and creams. Studies have found that the actual CBD content in these consumer products does not always match the labeled content of CBD, with reports of approximately 75% of the CBD products studied being over‐ or underlabeled. ² , ³ , ⁴ This discrepancy with unapproved cannabidiol product packaging raises concerns as consumers may unknowingly be taking different doses than expected and may not be aware of the potential for drug–drug interactions (DDI) with other medications they may be taking.

Only one CBD product, Epidiolex®, is approved by the U.S. Food and Drug Administration (FDA). It is indicated for the treatment of seizures associated with Lennox–Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. Clinical studies have demonstrated DDIs when CBD is taken concurrently with medications such as valproate and clobazam. ⁵ The CBD product label primarily focused on drug interactions with medications relevant to epilepsy treatment and index cytochrome P450 (CYP) substrates and inhibitors. ⁵ Additional studies evaluated the potential for CBD to affect the pharmacokinetics of drugs that are substrates of drug‐metabolizing enzymes, CYP2B6 and CYP2C9, and UDP‐glucuronosyltransferase (UGT) UGT1A9 and UGT2B7. ⁵ , ⁶ However, these studies utilized typical probe (index) substrates for such interactions and are not necessarily medications commonly used by consumers of unregulated CBD products (e.g., midazolam, tolbutamide, mycophenolate mofetil, zidovudine).

In human liver microsomes (HLM), CBD inhibits major CYP enzymes, with half‐maximal inhibitory concentration (IC₅₀) values ranging from 1.0 to 8.0 μM. ⁷ , ⁸ , ⁹ CBD also inhibits UGT in HLM and recombinant enzymes, with IC₅₀ values ranging from 8–30 μM and 2–21 μM, respectively. ¹⁰ CBD was an in vitro inhibitor of citalopram metabolism in recombinant CYP3A4 and CYP2C19 enzymes with IC₅₀ values of 1.6 and 1.1 μM, respectively. ¹¹ In a small clinical trial with six patients on a stable citalopram dose, CBD (600 or 800 mg/day) significantly increased citalopram’s plasma concentration. ¹¹

A major pathway for morphine metabolism is via glucuronidation by UGT2B7 with some contribution by UGT1A1 and UGT1A8. ¹² , ¹³ CBD inhibited the formation of morphine‐3‐glucuronide and morphine‐6‐glucuronide in HLM and recombinant UGT2B7 enzymes with IC₅₀ values <10 μM. ¹⁴ Mechanistic modeling using the in vitro inhibition values predicted that oral cannabidiol (70–2000 mg) may increase the area under the plasma concentration–time curve (AUC) of morphine by 29–187%. ¹⁴ , ¹⁵ , ¹⁶

CBD’s ability to inhibit CYP and UGT enzymes in vitro suggests potential interactions with commonly prescribed medications, particularly those used for conditions that consumers often cite as reasons for using CBD. This knowledge gap underscores the need for high‐quality clinical studies to better characterize CBD’s safety profile in humans, particularly regarding potential DDIs with coadministered drugs. In this study, healthy subjects received either oral citalopram (20 subjects) or morphine (20 subjects) at baseline and then again after receiving CBD for 12 or 9 days, respectively, to characterize the effect of daily CBD use on the plasma concentration of citalopram and morphine which are inhibited in vitro by CBD. Citalopram was selected because it is a common prescription medication for depression and anxiety that is metabolized by CYP2C19 and CYP3A4. ¹¹ Morphine was selected as it is a common opioid analgesic that is metabolized by UGT2B7. ¹⁷

METHODS

Study design and sample collection

We conducted an open‐label, sequential study in healthy participants at a clinical pharmacology unit (Spaulding Clinical Research, West Bend, WI), evaluating the effects of daily CBD use at a dose within the range of what consumers are taking with unregulated cannabidiol products from June 2024 to September 2024 on drug interactions (NCT06192589). This study was approved by a local institutional review board (Advarra, Inc., Columbia, MD). All participants provided written informed consent.

Participants were recruited by standard approaches for healthy volunteer clinical pharmacology studies (i.e., online advertising and emails or texts to individuals in the site’s database). Key inclusion criteria were age 18–55 years (inclusive), nonsmoking, negative tests for drugs of abuse, and a weight of at least 50 kg (110 lbs). Participants were excluded if they had abnormal liver chemistry tests, consumed more than 14 units of alcoholic beverages in the preceding 6 months, or had a history of alcoholism or drug/substance abuse within 2 years of screening. Participants were also excluded if they used any medications within 14 days of study check‐in (Day −1) or tested positive for drugs of abuse and alcohol at screening or the study check‐in days.

In the citalopram cohort, 20 participants checked in on Day −1 for a 6 night in‐house stay (checkout on Day 6) and then returned on Day 12 for a second 6 night in‐house stay (checkout on Day 18). Participants were given 2.5 mg/kg twice daily for a total of 5 mg/kg/day of CBD from Day 6 to Day 17 for a total of 12 days of CBD dosing (Figure 1 ). During the in‐house stay, participants received 20 mg of oral citalopram on Day 1 (no CBD) and Day 13 (with CBD). Samples for pharmacokinetic analysis were collected on Day 1 and 13 at predose, 1, 2, 3, 4, 6, 8, 12, 24, 48, 72, 96, and 120 hours after dosing.

Figure 1.

Overall study design. (a) Overall study design of citalopram‐cannabidiol cohort, including cannabidiol dosing, citalopram (DDI drug) dosing, and laboratory collection. (b) Overall study design of morphine‐cannabidiol cohort, including cannabidiol dosing, morphine (DDI drug) dosing, and laboratory collection.

In the morphine cohort, 20 participants checked in on Day −1 for a 6 night in‐house stay (checkout on Day 6) and then returned on Day 10 for a 3 night in‐house stay (checkout on Day 13). Participants were given 2.5 mg/kg twice daily for a total of 5 mg/kg/day of CBD from Day 4 to Day 12 for a total of 9 days of CBD dosing. During the in‐house stay, participants received 15 mg of morphine on Day 1 (no CBD) and Day 4 (with single dose CBD) and Day 11 (after seven days of CBD dosing). Pharmacokinetic samples were collected on Day 1, 4, and 11 at predose, 15, 30, 45, 60, and 90 minutes and 2, 3, 4, 6, 12, 24, and 48 hours after dosing. Plasma concentrations of CBD, citalopram, morphine, and their metabolites were measured by validated liquid chromatography and tandem mass spectrometry (Methods S1–S3).

Pharmacokinetic and statistical analysis

Pharmacokinetic parameters (AUC extrapolated to infinity [AUC_0−inf], AUC from time 0 to the last quantifiable concentration [AUC_0−last], and maximum observed plasma concentration [C _max]) were calculated for citalopram, morphine, and metabolites (desmethylcitalopram, morphine‐3‐glucuronide, and morphine‐6‐glucuronide) using noncompartmental analysis. Comparisons were made between PK parameters for citalopram alone versus citalopram coadministered with CBD and for morphine (and metabolites) administered alone or coadministered with one dose or with 7 days of CBD. Linear mixed‐effects modeling was employed to compare log‐transformed pharmacokinetic parameters with treatment as a fixed effect and participant as a random effect on the intercept. The geometric mean ratio (GMR) and corresponding 90% confidence interval (CI) were calculated by exponentiation of the treatment effect and the 90% CI from the log‐transformed scale. Analyses were performed using R version 4.3.3 and PKNCA (for noncompartmental analysis), nlme (linear mixed‐effects modeling) packages among several others.

Bioanalytical assays

Two LC–MS/MS based assays were developed for this study. One for the quantitation of citalopram and the metabolite desmethylcitalopram over the linear ranges of 0.20–50.00 ng/mL and 0.16–40.00 ng/mL, respectively. The other for the quantitation of morphine, morphine‐3β‐glucuronide (M3G), and morphine‐6β‐glucuronide (M6G) over the following linear ranges of 0.78–100.00 ng/mL (morphine), 3.91–500.00 ng/mL (M3G), and 1.56–200.00 ng/mL (M6G). Both methods were validated, and samples were analyzed in accordance with the current Guidance for Bioanalytical Method Validation and Study Sample Analysis. ¹⁸ Validation parameters included specificity, selectivity, sensitivity, linearity, precision, and accuracy (intra‐ and inter‐batch), recovery, matrix effect, coadministration, injection carryover, various stability evaluations, along with additional evaluations. Importantly, specificity, coadministration, and all stability experiments were performed in the presence of 300.00 ng/mL CBD, 150.00 ng/mL 7‐hydroxy‐CBD (7‐OH‐CBD), and 8000.00 ng/mL 7‐carboxy‐CBD (7‐COOH‐CBD) to ensure the quantitation of all analytes and their respective metabolites was not impacted by CBD and its primary metabolites. A full reporting of extraction procedures and validation results can be found in the Supplemental Materials (Methods S2 and S3).

Genotyping

CYP2C19 variants known to be associated with citalopram metabolism were genotyped using the validated AccuType® CP, clopidogrel CYP2C19 genotype assay (16,924; Quest Diagnostics). Three UGT2B7 variants with the strongest evidence ¹⁹ , ²⁰ , ²¹ , ²² for influencing morphine pharmacokinetics or analgesic responses were genotyped using TaqMan assays and targeted amplicon next‐generation sequencing. Of these, only two variants were directly tested: rs7438135 and rs7668282. The variant rs7438135, a tag single‐nucleotide polymorphism (SNP), was used as a proxy for rs7439366 due to their high or complete linkage disequilibrium across different populations (see Methods S4).

RESULTS

Study participants

Of the 86 healthy volunteers eligible for screening, 40 participants were enrolled and randomized into two groups with 20 participants in the citalopram cohort and 20 in the morphine cohort. A total of 38 participants completed the study (Table 1 ).

Table 1.

Study participant demographics and baseline characteristics

Characteristic		Citalopram (N = 20)	Morphine (N = 20)
Median age (interquartile range) – year		37 (29–49)	38 (35–44)
Female Sex – no. (%)		7 (35%)	8 (40%)
Race – no. (%)	American Indian	0 (0%)	0 (0%)
	Asian	0 (0%)	1 (5%)
	Black or African American	9 (45%)	8 (40%)
	White	8 (40%)	10 (50%)
	More than One Racea	1 (5%)	1 (5%)
	Unknown or Not Reported	2 (10%)	0 (0%)
Hispanic or Latino Ethnicity – no. (%)		4 (20%)	2 (10%)
Median body weight (range) – kg		79.5 (59.6–102.1)	82.7 (58.9–102)
Median height (range) – m		1.74 (1.54–1.87)	1.76 (1.53–1.90)
Median body mass index (range) – kg/m2		26.6 (21.7–32.1)	26.7 (22.1–32.3)

^a For participants who reported more than one race: 2 White and Black or African American.

Drug–drug interaction between citalopram and cannabidiol

In comparison to citalopram alone, after 7 days of CBD dosing, the plasma concentration of citalopram increased (Figure 2 a ). AUC_0−inf increased from 1,033 (26% [percentage coefficient of variation]) to 1,475 (24%) ng × h/mL, AUC_0−last from 912 (22%) to 1,204 (20%) ng × h/mL, C _max increased from 23 (21%) to 26 (24%) ng/mL and t_1/2 increased from 39 (22%) to 49 (20%) hours (Table 2 ). T _max remained mostly unaffected (4 [2 to 6] to 4 [3 to 8] hours with citalopram alone and citalopram with 7 days of CBD dosing, respectively). This resulted in GMRs of 1.43 (1.34–1.52), 1.32 (1.25–1.39), and 1.12 (1.06–1.17) for citalopram after 7 days of CBD dosing in comparison to citalopram alone for AUC_0−inf, AUC_0−last and C _max respectively (Table 2 ). The population level increase in AUC_0−inf was observed individually in all subjects (Figure 2 b ).

Figure 2.

Effect of drug–drug interaction between citalopram and cannabidiol on citalopram and its metabolites’ plasma concentration and total plasma exposure in individual subjects. (a) Citalopram and desmethylcitalopram (citalopram metabolite) plasma concentration time courses for citalopram administration alone (20 mg) and after 7 days of CBD dosing (2.5 mg/kg/twice daily dosing). (b) Change in citalopram AUC_0−inf from citalopram administration alone (20 mg) to citalopram administration (20 mg) after 7 days of CBD dosing (2.5 mg/kg/twice daily dosing).

Table 2.

Effect of drug–drug interaction between citalopram and cannabidiol on citalopram and metabolite pharmacokinetics, as well as morphine and cannabidiol on morphine and metabolites pharmacokinetics

Parameter →	AUC0−inf		AUC0−last		C max
Analyte ↓	Drug with 1 dose of CBD vs. drug alone	Drug after 7 days of CBD dosing vs. drug alone	Drug with 1 dose of CBD vs. drug alone	Drug after 7 days of CBD dosing vs. drug alone	Drug with 1 dose of CBD vs. drug alone	Drug after 7 days of CBD dosing vs. drug alone
Citalopram	NS	1.43a (1.34–1.52)	NS	1.32a (1.25–1.39)	NS	1.12a (1.06–1.17)
Desmethylcitalopram	NS	1.26a (1.18–1.34)	NS	0.99 (0.94–1.03)	NS	0.88a (0.83–0.94)
Morphine	1.06 (0.96–1.16)	1.12 (1.00–1.26)	1.05 (0.97–1.14)	1.12 (1.00–1.25)	1.19a (1.05–1.35)	1.11 (0.94–1.30)
Morphine‐3‐glucuronide	1.01 (0.98–1.05)	0.99 (0.96–1.03)	1.02 (1.00–1.04)	0.98 (0.95–1.00)	1.12a (1.03–1.21)	0.98 (0.91–1.06)
Morphine‐6‐glucuronide	1.08 (0.99–1.18)	1.26a (1.17–1.36)	1.06 (1.00–1.12)	1.26a (1.19–1.35)	1.08 (1.00–1.17)	1.11a (1.01–1.21)

Each cell represents geometric mean ratio (GMR) 90% confidence interval (CI). For citalopram and its metabolites the number of subjects reported (N) in this table is 19 [one subject had detectable levels of citalopram and metabolites at predose at levels suggesting repeated administration. This participant was excluded from all analyses as a protocol violation as per I/E criteria]. For morphine and its metabolites, N is 20 for days 1 to 4 and 18 after 7 days of CBD dosing [two subjects returned to the site—one with a positive COVID test and one with a positive drug screening—and were early terminated from the study].

AUC_0−inf, area under the plasma concentration–time curve extrapolated to infinity (ng × h/mL); AUC_0−last, area under the curve from dosing to the time of the last measured concentration ≥ lowest level of quantification (ng × h/mL); C _max, maximum observed plasma concentration (ng/mL); NS, not studied; CBD, cannabidiol.

^a Denotes the 90% CI excludes 1.00.

In comparison to citalopram, no significant effect of CBD on the plasma concentration of its metabolite desmethylcitalopram was seen (Figure 2 a ). AUC_0−last remained similar with and without CBD (Table 2 ). While there was an increase in AUC_0−inf from 396 (23%) to 509 (31%) ng × h/mL and consequently a decrease in apparent clearance from 51 (23%) to 39 (31%) L/h, there was insufficient data collected for the half‐lives of desmethylcitalopram (72 [30%] and 115 [21%] hours, with and without CBD, respectively) to support AUC_0−inf calculation in most of the participants (Table 3 ). T _max increased from 24 (8 to 72) to 48 (12 to 72) hours. The lack of significant change in AUC_0−last and C _max was reflected in the GMRs as well, which are, respectively, 0.99 (0.94 to 1.03) and 0.88 (0.83 to 0.94) (Table 2 ). While AUC_0−inf geometric ratio shows a positive effect, 1.26 (1.18 to 1.34), it could potentially be inaccurate due to the short data collection window, as discussed before (Table 2 ). All individual subject time courses of citalopram and desmethylcitalopram plasma concentration with and without CBD dosing are presented in Figure S1 .

Table 3.

Pharmacokinetic parameters of citalopram and its metabolite, as well as morphine and its metabolites, for different dosing conditions (drug alone, drug with a single dose of cannabidiol, and drug after 7 days of cannabidiol dosing)

Analyte		Parameters
		AUC0−inf (ng*h/mL)	AUC0−last (ng*h/mL)	C max (ng/mL)	T max (h)	t 1/2 (h)	Cl/F (L/h)	V/F (L)
Citalopram	Drugs alone	1,033 (26%)	912 (22%)	23 (21%)	4 (2–6)	39 (22%)	19 (26%)	1,085 (22%)
	Drug w/1 dose of CBD	–	–	–	–	–	–	–
	Drug w/7 dose of CBD	1,475 (24%)	1,204 (20%)	26 (24%)	4 (3 to 8)	49 (20%)	14 (24%)	967 (20%)
Desmethylcitalopram	Drugs alone	396 (23%)	242 (17%)	2.7 (25%)	24 (8 to 72)	72 (30%)	51 (23%)	5,227 (30%)
	Drug w/1 dose of CBD	–	–	–	–	–	–	–
	Drug w/7 dose of CBD	509 (30%)	239 (15%)	2.4 (18%)	48 (12 to 72)	115 (21%)	39 (30%)	6,517 (21%)
Morphine	Drugs alone	44 (45%)	36 (50%)	8.3 (40%)	1 (0–3)	3.8 (40%)	344 (45%)	1895 (40%)
	Drug w/1 dose of CBD	47 (51%)	38 (52%)	9.9 (45%)	2 (1–4)	3.8 (46%)	321 (51%)	1743 (46%)
	Drug w/7 dose of CBD	50 (60%)	42 (59%)	9.3 (31%)	1 (0–3)	4.7 (42%)	297 (60%)	2026 (42%)
Morphine‐3‐glucuronide	Drugs alone	2,416 (18%)	2,211 (16%)	265 (21%)	2 (1–4)	16 (40%)	6.2 (18%)	140 (40%)
	Drug w/1 dose of CBD	2,450 (17%)	2,261 (16%)	296 (29%)	2 (1–4)	15 (37%)	6.1 (17%)	135 (37%)
	Drug w/7 dose of CBD	2,382 (14%)	2,129 (14%)	256 (25%)	2 (1–4)	18 (43%)	6.3 (14%)	159 (43%)
Morphine‐6‐glucuronide	Drugs alone	327 (30%)	295 (25%)	47 (24%)	2 (1–4)	8.0 (39%)	46 (30%)	532 (39%)
	Drug w/1 dose of CBD	355 (28%)	312 (24%)	51 (28%)	2 (1–4)	9.8 (66%)	42 (28%)	600 (66%)
	Drug w/7 dose of CBD	416 (27%)	373 (26%)	52 (28%)	2 (2–4)	12 (55%)	36 (27%)	628 (55%)

AUC_0−inf, area under the plasma concentration–time curve extrapolated to infinity (ng × h/mL); AUC_0−last, area under the curve from dosing to the time of the last measured concentration ≥ lowest level of quantification (ng × h/mL); C _max, maximum observed plasma concentration (ng/mL); T _max, time to reach C _max (h); t _1/2, half‐life (h); Cl/F, apparent clearance (L/h); V/F, apparent volume of distribution (L); CBD, cannabidiol. Each cell represents GM (CV%), except for T _max, where it represents the median (min to max).

Drug–drug interaction between morphine and cannabidiol

Neither a single dose nor 7 days of CBD dosing resulted in clinically meaningful changes in the pharmacokinetics of morphine (Figure 3 a ) with and without CBD (Table 2 ). AUC_0−last increased slightly from 36 (50%) to 38 (52%) with a single dose of CBD and to 42 (59%) ng × h/mL with 7 days of CBD dosing (Table 2 ). In a similar manner, AUC_0−inf increased between 44 (45%), 47 (51%), and 51 (60%) ng × h/mL, respectively, for morphine alone, with a single dose of CBD, and after 7 days of CBD dosing (Table 2 ). GMRs for AUC_0−inf were 1.06 (0.96–1.16) and 1.12 (1.00–1.26); GMRs of AUC_0−last were 1.05 (0.97–1.14), 1.12 (1.00–1.25). Lower bound of the confidence interval for comparisons between morphine alone versus morphine with 7 days of CBD dosing were above 1, mostly due to the study sample size and the increases of 12% were not considered to be clinically meaningful (Table 2 ). There was no clear trend in C _max, which was 8 (40%), 10 (45%), and 9 (31%) ng/mL across the group nor any differences in T _max (Table 3 ). GMRs for C _max were 1.19 (1.05–1.35) and 1.11 (0.94–1.30), respectively, with a single dose and after 7 days of CBD dosing in comparison to morphine alone (Table 2 ). Individual subject AUC_0−inf showed no trend of a consistent effect of cannabidiol on morphine kinetics (Figure 3 b ).

Figure 3.

Effect of drug–drug interaction between morphine and cannabidiol on morphine and its metabolites’ plasma concentration and total plasma exposure in individual subjects. (a) Plasma concentration time courses of morphine and its two predominant metabolites, morphine‐3‐glucuronide and morphine‐6‐glucuronide, for morphine administration alone (15 mg), morphine with a single dose of CBD (2.5 mg/kg), and morphine after 7 days of CBD dosing (2.5 mg/kg/twice daily). (b) Change in morphine, morphine‐3‐glucuronide (Morphine3G), and morphine‐6‐glucuronide (Morphine6G) AUC_0−inf from morphine administration alone (15 mg) to morphine administration after a single dose of cannabidiol (2.5 mg/kg) and to morphine administration (15 mg) after 7 days of CBD dosing (2.5 mg/kg/twice daily).

Morphine‐3‐glucuronide pharmacokinetics were less affected by CBD as evident by the plasma concentration time course (Figure 2 a ), pharmacokinetics parameters (Table 3 ), and GMRs of AUC_0−inf, AUC_0−last, and C _max with a single dose and after 7 days of CBD dosing versus morphine alone (Table 2 ). AUC_0−inf for individual subjects also did not exhibit a consistent pattern with changing cannabidiol concentration (Figure 3 b ).

Morphine‐6‐glucuronide was minimally affected by CBD, similar to morphine (Figure 2 a ). AUC_0−inf, AUC_0−last, and C _max all increased slightly with a single dose of CBD and slightly more after 7 days of CBD dosing (Table 3 ). This was consistent with the GMRs of AUC_0−inf with a single dose and after 7 days of CBD dosing vs. morphine alone being slightly above 1 and increasing with more cannabidiol, 1.08 (0.99–1.18) and 1.26 (1.17–1.36). A similar trend was observed for AUC_0−last with GMRs of 1.06 (1.00–1.12) and 1.26 (1.19–1.35) as well as C _max with GMRs of 1.08 (1.00–1.17) and 1.11 (1.01–1.21). There was no clear trend in AUC_0−inf of individual subjects for different cannabidiol levels (Figure 3 b ). All individual subject time courses of morphine, M3G, and M6G plasma concentration without CBD, with a single dose of CBD, and after 7 days of CBD dosing are presented in Figure S2 .

Genotyping

In the citalopram cohort, all 20 participants were classified as normal, intermediate, rapid, or ultra‐rapid CYP2C19 metabolizers based on genotyping results (Table S1 ). No individuals were identified as poor metabolizers. In the morphine cohort, genotyping was completed for all three UGT2B7 variants (Table S2 ). For rs7438135 and rs7439366, which are in complete linkage disequilibrium, participants with GG genotype showed a trend toward low plasma morphine levels, suggesting increased UGT2B7‐mediated glucuronidation. In contrast, each additional A allele was associated with increased morphine levels or trend, consistent with reduced glucuronidation activity (See Section S2). For rs7668282, no individual with the variant CC genotype was identified. Individuals with the TT genotype demonstrated lower morphine levels, suggesting enhanced UGT2B7 glucuronidation, while those with the CT genotype had higher morphine levels, consistent with decreased glucuronidation.

Safety

No serious adverse events occurred. Twelve participants (30%) experienced adverse events overall: 7 (35%) in the citalopram cohort and 5 (25%) in the morphine cohort. The most common adverse events in the citalopram cohort were nausea (21%), diarrhea (14%), and headache (14%). In the morphine cohort, no specific adverse event was experienced by multiple participants. Table S3 contains the incidence and number of adverse events by cohort.

DISCUSSION

In this open‐label, sequential drug–drug interaction study in healthy participants, CBD (2.5 mg/kg twice daily), at a dose similar to typical consumer use, increased the AUC_0−inf and AUC_0−last of citalopram by 43% and 32%, respectively, with a lower increase in C _max (12%) (Table 2 ). These results are similar to those reported by Anderson et al. where CBD (600 or 800 mg/day) elevated citalopram’s plasma levels in six patients. ¹¹ They are also similar to the increase in citalopram AUC (43%) by the multi‐CYP inhibitor cimetidine in citalopram’s product label. ²³ , ²⁴ Significant changes were not observed in morphine AUC_0−inf or AUC_0−last following single dose CBD or after 7 days of CBD dosing. This is in contrast to a static mechanistic in vitro to in vivo extrapolation model predicting that CBD (70–2000 mg) had the potential to increase morphine’s AUC by 29–187%. ¹⁴

The nonpsychoactive CBD is one of the major cannabinoids present in the cannabis sativa plant. Although CBD is not associated with the typical euphoric or “high effect” experienced with THC, another major cannabinoid of the cannabis sativa plant, its bioactive properties still raise safety concerns regarding the potential for DDIs and subsequent changes in coadministered drug levels in the blood. ²⁵ CBD consumer products have gained significant popularity and market presence in recent years, increasing in availability and usage. ²⁶ While most self‐dosing CBD users report consuming 0–100 mg/day, many consumers use higher doses. ²⁷ , ²⁸ , ²⁹ A 2023 survey of 5,635 CBD users found that 23% reported consuming over 200 mg daily. ³⁰ Two online surveys on CBD use reported 4.5% and 7.2% of subjects consuming over 200 mg/day, respectively. ²⁷ , ²⁸ An observational study conducted remotely in 1,160 self‐dosing CBD users reported doses as high as 390 mg/day in some individuals. ²⁹ These general CBD consumption patterns informed our study’s dosage selection of approximately 350 mg/day for adult participants. Given the noted increase in CBD usage and availability, a thorough understanding of its DDI potential, as well as the resulting clinical implications, is necessary to safeguard public health.

Clinical studies have previously explored the pharmacokinetic interactions of CBD with coadministered drugs. For instance, based on a clinical study with a CYP cocktail with brownies containing both THC and CBD, a physiologically based pharmacokinetic model was developed to predict the AUC ratio with probe substrates. ³¹ The predicted ratio was 2.72, 1.31, 1.82, and 3.00 for omeprazole (CYP2C19), losartan (CYP2C9), midazolam (CYP3A), and caffeine (CYP1A2), respectively, following a single oral dose of 640 mg CBD. In another clinical interaction study with a single 200 mg dose of caffeine, before and after 25 days of CBD dosing (250 mg q.d. to 750 mg b.i.d.), the AUC and C _max of caffeine increased by approximately 90% and 15%, respectively, in healthy subjects. ³²

A randomized trial examined the interaction of CBD in epilepsy patients on a stable dose of stiripentol or valproate therapy with oral CBD up to 20 mg/kg daily for 26 days. ³³ CBD increased both stiripentol’s C _max (17%) and AUC_tau (30%) with a small effect on valproate’s exposure with a decrease in its C _max (13%) and AUC_tau (17%). ³³ In a study in adult epilepsy patients, CBD (20 mg/kg/day) had no significant effect on clobazam AUC_tau at day 1 or 33, while significantly increasing the AUC_tau of norclobazam with a GMR of 2.6. ³⁴ Another study examined CBD’s effect on clobazam (5 mg, b.i.d.), stiripentol (750 mg b.i.d.), and valproate (500 mg b.i.d.) in healthy subjects. ³⁵ After 7 days of CBD dosing (750 mg b.i.d.), the AUC_tau ratio for clobazam, norclobazam, stiripentol, and valproate was 1.21, 3.38, 1.55, and 0.99, respectively.

Both everolimus and tacrolimus are substrates of CYP3A4 and P‐glycoprotein (P‐gp). In healthy subjects treated with a single dose of 5 mg everolimus before and after 12.5 mg/kg CBD twice daily, the C _max and AUC of everolimus increased by approximately 2.5‐fold. ³⁶ Similarly, the AUC_0−last of tacrolimus increased 2.55‐fold. ³⁷ Thus, CBD was a moderate inhibitor of CYP3A4 and P‐gp in these studies. Almost 80% of oxidative metabolism of clinical drugs is performed by the CYP enzyme family. ³⁸ Inhibition of these enzymes can therefore result in decreased drug metabolism and subsequent drug accumulation, as evidenced by the aforementioned studies. CBD also affects glucuronidation pathways, though to a lesser extent than CYP‐mediated metabolism. For instance, coadministration of CBD (7.5 mg/kg twice daily) with single dose zidovudine (300 mg), a UGT2B7 substrate, resulted in modest increases in zidovudine exposure C _max (7%) and AUC (19%). ⁵

The impact of these effects may be magnified in older adults, who commonly use unregulated CBD for conditions such as pain, anxiety, insomnia, and depression. ³⁹ , ⁴⁰ As such, citalopram, a selective serotonin reuptake inhibitor (SSRI) used to treat major depressive disorder (MDD) was selected as one of the study drugs to be coadministered with CBD. The other study drug, morphine, is an opioid used for pain management; however, its metabolism is largely facilitated by UGTs. The observed inhibitory properties of CBD on CYP enzymes may also have severe clinical implications when coadministered with drugs with a narrow therapeutic index. ⁴¹ For instance, case reports have documented the need to adjust warfarin dosing levels by as much as 30% when patients are concurrently taking CBD and other cannabinoids in order to avoid bleeding complications. ⁴² , ⁴³ Indeed, at toxic levels, citalopram has been associated with cardiotoxicity and seizures. ⁴¹

Furthermore, increased drug exposure secondary to CBD inhibition of CYP may contribute to an increased occurrence of adverse drug reactions (ADRs) and subsequent medication nonadherence, as most SSRI side effects are dose related. ⁴⁴ A systematic review of patients with MDD demonstrated that increased ADRs directly correlated with reduced medication adherence, with approximately 50% of patients failing to follow prescribed regimens. ⁴⁵ From data of over 50,000 patients with MDD, Kostev et al. reported somnolence as a specific antidepressant side effect associated with medication discontinuation. ⁴⁶ In addition, antidepressant‐induced sexual dysfunction is the leading cause of medication nonadherence, ⁴⁷ with anorgasmia being the most common dose‐dependent side effect of citalopram therapy. ⁴⁴ Disruptions in treatment are particularly problematic for a drug class such as SSRIs, where patients often require up to 6 weeks of treatment to reach full therapeutic effect. ⁴⁸ Any disruption in dosing could have significant impacts on patient health and clinical outcomes.

Although this was an open‐label sequential study, the use of objective pharmacokinetic parameters, coupled with laboratory blinding during bioanalytical analysis, mitigated any potential participant bias. A limitation of this study is that only healthy volunteers aged 18–55 were evaluated, and thus participants were not taking concomitant medications and had no comorbidities that may increase or alter DDIs. As such, the study may underestimate the potential for DDIs in the general population, especially given that CBD is frequently used by older adults, particularly for conditions such as pain, anxiety, insomnia, and arthritis—conditions often requiring multiple medications that could further amplify interaction risks. ³⁹

This clinical trial is part of FDA’s efforts to understand the safety of unregulated CBD products and inform discussions about safeguards and oversight to manage and minimize risks with unregulated CBD products. The study findings demonstrated that at doses typically used with unregulated CBD consumer products (2.5 mg/kg/day, b.i.d.), CBD significantly interacts with the SSRI citalopram. When coadministered with CBD, citalopram showed a 43% increase in AUC_0−inf and a 12% increase in C _max compared to administration alone, indicating meaningful pharmacokinetic interactions. Further study of whether these exposure changes in citalopram translate to clinically meaningful differences in patient outcomes is still needed. Pharmacokinetic interactions between CBD and morphine as well as its metabolites were relatively limited. As unregulated CBD products continue to gain popularity in consumer markets, healthcare providers should consider incorporating CBD use assessment into routine medical screening protocols. This screening is especially crucial for vulnerable populations, including patients with existing liver conditions or those taking medications metabolized by CYP liver enzymes, such as citalopram.

FUNDING

This work was funded by the U.S. Food and Drug Administration. The funder/sponsor (FDA) oversaw the design and overall conduct of the study, including overseeing the management, analysis, and interpretation of the data. The FDA also prepared, reviewed, and approved the manuscript for submission for publication.

CONFLICT OF INTEREST

All authors declared no competing interests for this work.

AUTHOR CONTRIBUTIONS

P.S., D.A.V., A.C., A.S., and J.F. wrote the manuscript; J.F., P.S., and R.R. designed the research; M.F., P.S., J.F., A.S., D.A.V., R.D., A.K., G.V., C.‐H.H., A.C., and P.L.H. performed the research. All authors analyzed the data. J.F. had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis.

DISCLAIMER

The opinions expressed in this manuscript are those of the authors and should not be interpreted as the position of the US Food and Drug Administration.

Supporting information

Data S1.