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Abstract

Introduction:

Over the past decade, use of cannabidiol (CBD) to manage common symptoms such as anxiety, sleep disturbance, and pain has expanded rapidly. However, few clinical trials have investigated CBD's safety or efficacy. Furthermore, whether effects vary by characteristics of the product or individual characteristics is largely unknown.

Materials and Methods:

The safety and health effects of 13 orally ingested, commercially available CBD products were evaluated using an open-label, randomized, waitlist controlled design. Participants (n = 2816; 94% female) residing in the United States and reporting symptoms of anxiety, sleep disturbance, or chronic pain were randomized to receive a 4-week supply of a CBD product or no product (waitlist control). CBD products varied by dose, form (e.g., capsules), and spectrum (isolate, broad, or full). Participants completed online surveys assessing well-being, anxiety, sleep disturbance, and pain using validated outcome measures weekly for 4 weeks. Linear mixed models were used to assess the effect of taking any product relative to waitlist control and the interaction effects of participant prior (prestudy) CBD use. Effects of CBD spectrum were investigated using post hoc analyses.

Results:

Well-being, anxiety, sleep disturbance, and pain significantly improved among those assigned to take a CBD product relative to waitlist control. Among those assigned to a CBD product, the percentage of individuals with a given condition who experienced an improvement which could be considered clinically meaningful or important was 46.6% for anxiety; 47.9% for sleep disturbance, and 35.2% for pain. No significant differences in effect were found as a function of spectrum or prior CBD use for any outcome. Approximately 9.5% of participants reported one or more side effects, the most common of which were gas/flatulence (1.6%), headache (1.4%), diarrhea (1.2%), and bloating (1.2%). No severe side effects were reported.

Discussion:

Our results suggest that the commercially available CBD products included in this study are safe and may serve as potentially effective complementary therapies for management of anxiety, sleep disturbance, and pain. These effects appear independent of the prior CBD use and product spectrum.

Clinical Trial Registration number: NCT05003882.

Introduction

In 2018, the Agricultural Improvement Act (HR 2 [115 th]) removed hemp (defined as cannabis plants containing <0.3% delta-9-tetrahydrocannabinol [D-9-THC]) from Schedule I of the Controlled Substances Act,¹ making hemp-derived cannabidiol (CBD) the first federally legal cannabinoid product Americans could access without a prescription. Use of CBD products in the United States climbed rapidly; as of 2019, 14% of Americans reported that they currently use CBD, and approximately one in three Americans reported having tried CBD at least once.² The majority (62%) of CBD users report that they use these products to manage a medical condition,³ the most common of which include chronic pain, anxiety, and insomnia or other sleep disorders.^4,5

Despite the legalization and widespread use of hemp products, research on the purity, safety, and effectiveness of commercially available products has been scarce.⁶ The lack of research and regulatory oversight has raised critical public safety concerns, as well as confusion among consumers and health care practitioners, as to which products, if any, are safe, and which, if any, are effective for the management of specific health conditions of interest.^7–9

Preclinical research indicates that CBD possesses anxiolytic, analgesic, and anti-inflammatory properties.¹⁰ Retrospective and prospective observational studies have found that the clinical administration of CBD may improve sleep, anxiety, pain, and depression symptoms, as well as overall well-being.^11–13 Furthermore, small studies investigating the acute effects of CBD have found support for the hypothesis that CBD may improve symptoms of anxiety and insomnia. In an experimental study of 10 healthy volunteers, a single dose of 400 mg CBD decreased acute subjective ratings of anxiety relative to placebo.¹⁴ Another randomized study conducted with 24 individuals with social phobia found that pretreatment with 600 mg of CBD significantly reduced anxiety during simulated public speaking compared to placebo.¹⁵ In a study of 15 individuals with insomnia, those who received 160 mg CBD slept significantly more than those who received placebo.¹⁶ In a study of 33 individuals with Parkinson's Disease, 300 mg of CBD per day led to a transient improvement in sleep quality relative to placebo.¹⁷

Finally, at least two studies have investigated the acute effects of CBD on pain. A trial of 100 patients who presented to the emergency department for nontraumatic low back pain found no significant difference in the pain scores of those randomized to receive standard analgesic medication plus CBD compared to standard analgesic medication plus placebo.¹⁸ Single doses of CBD (200, 400, or 800 mg) also did not significantly reduce experimentally-induced acute pain in a study of 17 healthy noncannabis-using volunteers, relative to placebo.¹⁹ However, the sample sizes of these two trials were small, and no studies to our knowledge have investigated the efficacy of CBD for reducing pain in real-world settings outside the emergency department.

Despite the (limited^20,21) evidence from clinical trials suggesting therapeutic effects of CBD on anxiety and insomnia, it is unknown whether the doses of CBD that are typically found within commercially available products are sufficient to produce these effects. Notably, the vast majority of interventional trials on CBD test doses over 150 mg CBD, whereas recommended doses for commercially available products typically range from 5 to 100 mg CBD per serving. Preclinical and clinical studies on CBD have suggested a bell shaped dose–response curve in which an intermediate dose of CBD exhibits a greater therapeutic effect than low or high dose.^22,23 More clinical studies are needed to evaluate the therapeutic benefits of CBD for the management of anxiety symptoms, sleep difficulty, and pain symptoms, particularly at lower CBD dosages that reflect those found within commercially available products.²⁴

There is also limited understanding as to the development of tolerance to the therapeutic effects of CBD. Continuous use may attenuate the effects of the cannabinoid, although few clinical studies have evaluated the potential for CBD treatment tolerance.²⁵ In addition, few studies have explored the effect of CBD “spectrum.”^7,26 In the CBD industry, spectrum refers to the presence of other hemp constituents (particularly THC) found within the CBD product. CBD products can be broadly classified into the following spectrums: (isolate [containing >99% CBD]; broad [containing other hemp constituents (e.g., minor cannabinoids) but no detectable D-9-THC]; and full [containing other hemp constituents, as well as up to 0.3% D-9-THC]).

While some preclinical research suggests that cannabinoids and other components of the hemp plant (e.g., terpenes, flavonoids) could work synergistically, stimulating a different effect compared with CBD or THC alone,^27,28 no clinical study to date has directly compared the health effects of commercial hemp/CBD products that vary in THC content.

Objective

The primary aim of the Radicle Science Advancing CBD Education and Science (ACES) study was to explore the safety and effectiveness of orally ingested, commercially available CBD products on health-related outcomes. Effects on self-reported well-being, anxiety, sleep disturbance, and pain were evaluated using an open-label randomized controlled trial (RCT). As secondary aims we also sought to explore whether effects varied according to spectrum or prior CBD use.

Methods

Study design and participants

Between August 2 and 5, 2021, we recruited participants using a third-party consumer network. Recruitment emails were sent through the network's database of over 8 million consumers from across the United States. Participants were eligible if they were 21 years old or older (in accordance with all state-imposed age limits for purchasing of CBD products), resided in the United States, and reported that they were experiencing symptoms of anxiety, sleep disturbance, and/or chronic pain.

Individuals were excluded if they were pregnant or breastfeeding, currently using CBD, or taking medications with which CBD could interfere. Eligible individuals were advised to consult with their health care provider before participating if they had a diagnosed medical condition, were on any prescription medication or supplements, or had any upcoming medical procedures planned. Electronic informed consent was obtained through a secure online portal from eligible individuals. Participants indicating their consent could electronically sign and date the informed consent form. Consenting participants were then provided a copy of the electronic consent for their records.

We screened 13,473 individuals for eligibility. Of those screened, 3500 individuals were determined to be eligible. Due to over-recruitment, only the first 2816 eligible individuals who completed the study screener were presented with the informed consent form and were assigned to a study group (2601 to a product group and 215 to waitlist control; Fig. 1). Participants who were assigned to a product group received a 28-day supply of product (according to each product's suggested daily servings) in the mail along with instructions for study participation within the product insert. Study products took the form of capsules, tablets, tinctures, soft gels, gummies, and an oral spray. The CBD product spectrum (“Broad,” “Full,” and “Isolate”) and suggested usage and dosage of CBD per serving varied by product (see Table 1 for the full list of products included in the study).

FIG. 1.

CONSORT diagram.

Table 1.

Characteristics of Products in the Radicle Advancing Cannabidiol Education and Science Study

	Form	CBD (mg per serving)	CBG (mg per serving)	CBN (mg per serving)	THC (mg per serving)	Mode of absorption
Altwell broad spectrum hemp extract gummies	Soft gel	25	0.74	0	0	Ingestion
Trokie fast melt tablets	Tablet	15	0	0	0	Oromucosal
Healer whole plant hemp drops	Tincture	1	0.85	0.04	0	Sublingual
Columbia care CBD softgels	Soft gel	30	0.698	0	0	Ingestion
Puraura premium tincture lemon flavor	Tincture	100	0	0	0	Ingestion
Lord Jones full spectrum hemp-derived CBD tincture	Tincture	20	0.43	0.09	0	Ingestion
MD Farma clinical CBD softgels	Soft gel	25	0	0	0	Ingestion
Charlotte's web hemp extract	Tincture	50	0.56	0.1	0	Ingestion
Prospect farms balance tincture	Tincture	35	0.91	0	0	Sublingual
Rae wellness CBD capsules	Capsule	20	0.36	0.36	0.31	Ingestion
Peels CBD oil tincture	Tincture	34	0	0	0	Sublingual
Versea broad spectrum hemp enriched oral spray	Oral spray	40	0.6	0.46	0	Sublingual
Maven 2500 mg total hemp extract tincture	Tincture	10	1.42	0.12	1.84	Ingestion

CBD, cannabidiol; CBG, cannabigerol; CBN, cannabinol; THC, tetrahydrocannabinol.

All products were provided by the respective brand and analyzed at an independent laboratory to ensure active ingredient identification, safety, and potency. All products were packaged, labeled for commerce, and are currently being sold and used by consumers in the United States. To reflect real world usage, participants were instructed to use the study product based on product label instructions, health care provider advice, and/or personal preference.

At baseline (1 week before receipt of product) and weeks 1, 2, 3, and 4, participants were asked to complete an online survey, sent through email or text, which asked them to report their well-being, anxiety, sleep disturbance, and pain symptoms using patient reported outcome measures (see below for details). They were also asked to report their product usage and any side effects that they may have experienced.

The study was registered using ClinicalTrials.gov Advarra Institutional Review Board (IRB) approved the study [Identification number: Pro00054811]. All participants provided written consent to participate.

Randomization

Participants were randomly assigned using a computer program (Excel) to either (1) receive one of the 13 different CBD products immediately or (2) the waitlist control group. Participants assigned to the waitlist were asked to abstain from using CBD products throughout the study period. Before randomization, participants were stratified by health condition(s) endorsed at baseline (anxiety, difficulty sleeping, and pain, alone or in combination [making up eight possible groupings]) to ensure balance across these conditions in all study groups. We did not mask group assignment; product labels and packaging were not altered for the purposes of the study.

Note that, while the primary objective of the study was to evaluate the effect of taking any CBD product against waitlist control, we also aimed to estimate the health effects of each individual product relative to waitlist control. Individual product effects are not reported in this article as these data are proprietary to our partnering brands, although participants were randomized into individual product groups to maintain an equal number of participants in each product group and waitlist control for individual product comparisons.

Outcomes

All outcomes were collected using patient reported outcome measures. These included the following:

World Health Organization Five Well-being Index

World Health Organization Five Well-being Index (WHO-5) is a 5-item assessment of psychological well-being. Participants are asked to respond to items (e.g., “I have felt cheerful and in good spirits”) using a 6-point Likert scale (0 “none of the time” to 5 “all of the time”). Cumulative scale scores range from 0 to 25, with higher scores signifying greater well-being.²⁹ The recall period for the original index was 2 weeks; for this study, the measure was adapted to assess well-being over the past 7 days. We evaluated the portion of participants who experienced clinically meaningful improvement (CMI) in well-being, defined as an increase of 10 or more in the WHO-5 Well-Being Index score.²⁹

Patient-Reported Outcomes Measurement Information System™ Sleep Disturbance SF 8B

Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance SF 8B is an 8-item assessment of sleep disturbance during the past 7 days. The items assess characteristics of sleep, frequency of sleep disturbances, and sleep quality using a 5-point Likert scale. Cumulative scale scores range from 8 to 40, with higher scores signifying lower sleep quality.³⁰ Raw cumulative scores are then mapped onto T-scores metric with a mean of 50 points and standard deviation of 10 points centered on the mean of a nationally representative sample. We evaluated the portion of participants who experienced a minimally clinically important difference (MCID) in sleep disturbance, defined as a decrease of 6.5 or more in the PROMIS Sleep Disturbance SF 8b T-score.³¹

Generalized Anxiety Disorder-7 scale

Generalized Anxiety Disorder (GAD)-7 scale is a 7-item assessment of the severity of symptoms associated with GAD. Participants indicate the frequency with which they have experienced various problems (e.g., “Feeling nervous, anxious, or on edge”) using a 4-point Likert scale (0 “Not at all” to 3 “Nearly every day”). Cumulative scale scores range from 0 to 21, with higher scores signifying greater anxiety severity.³² The original index assesses frequency in the past 2 weeks; for this study, the measure was adapted to assess frequency in the past 7 days. We evaluated the portion of participants who experienced a MCID in their anxiety, defined as a decrease of four or more in their GAD-7 score.³³

Pain intensity, Interference and General activity-3 Scale

Pain intensity, Interference and General activity (PEG)-3 Scale is a 3-item assessment of pain intensity and interference. On a scale of 0 to 10, the items evaluate the average pain intensity [P], interference with enjoyment of life [E], and interference with general activity [G] in the past week. Cumulative scores range from 0 to 10 (scores are averaged across the three items), with higher scores signifying greater pain intensity and pain interference.³⁴ We evaluated the portion of participants who experienced CMI in their pain, defined as a reduction of 30% or more in their PEG score.³⁵

Side effects

Side Effects Participants were prompted to report side effects in each study survey. Participants were also encouraged to contact the research team directly if at any point they experienced side effects. We determined the severity of spontaneously reported side effects based on reported utilization of medical services in response to the side effects according to the following grading schema based on the Common Terminology Criteria for Adverse Events (CTCAE; v5.0 USDHHS)³⁶: mild: no intervention (medication or medical advice) needed; moderate: a medication was taken due to the side effect; severe: the side effect was significant enough that the participant sought medical care from a health care provider, outpatient clinic, or emergency department/room; and life threatening: the participant was hospitalized due to the side effect.

Demographics and other sample characteristics

Participants self-reported their age, sex assigned at birth, ethnicity, race, highest level of education completed, employment status, and previous CBD usage at baseline (experienced users [“I'm an experienced user”], inexperienced users [“I've never tried it”], and familiar users [“I've tried CBD a few times”]). Participants also reported their weight in pounds and height in feet and inches, which were used to calculate body mass index.

Consumption behaviors

Participants randomized to receive a commercially available CBD product received weekly surveys assessing consumption on the previous week (“In the past 7 days, on the days you took your study CBD product, how many total servings did you typically take throughout the day?”). Average CBD dose was calculated by multiplying the number of reported servings by the dose of CBD per serving. In the final study survey (Day 28), participants were also asked to report other cannabinoid consumption during the study period (“During the last 28 days, how frequently did you consume any CBD product?” [Waitlist Control Group], “During the last 28 days, how frequently were you consuming any other CBD product that was not the specific CBD product provided to you by the study?” [Product Group], and “During the last 28 days, how frequently did you consume any THC/cannabis product?” [all participants]) using a 4-point Likert scale (0 “Not at all” to 3 “Daily or nearly daily”).

Data analysis

Baseline characteristics, including demographics, health-related outcomes, and previous cannabis usage, were compared between participants who received a CBD product and those with no product (i.e., waitlist control condition) using chi-square or Fisher's exact tests for discrete variables and Mann–Whitney U tests for continuous variables. These same tests were used to compare baseline characteristics across different spectrums of CBD.

The amount of missing data on individual health-related outcomes at any given time point was limited; all four outcomes had fewer than 1.3% missing data across timepoints. Health-related outcomes were analyzed using longitudinal mixed-effects regression models that implicitly account for incomplete longitudinal data. The longitudinal models included an unstructured covariance model for the within-subject repeated measures, fixed effects for assignment to any product (Product Group) relative to the waitlist control, categorical indicators for time postbaseline (week 1, 2, 3, and 4), and the interaction between any product and time. Product effects were estimated as the average of product effects minus the waitlist control effects.

The models further allowed for interaction effects between prior CBD use and any CBD use and time (with effects added individually). Additional mixed effects models with similar longitudinal structure were used to examine the effects of CBD spectrum, on the outcomes of interest, and then post hoc analyses (unadjusted and Bonferroni-adjusted p-values) were conducted comparing the effects of each CBD spectrum to one another. Analyses were performed using Stata SE software version 16. All participants assigned to a study group were included in the analyses.

Results

Sample characteristics

The median age was 40 years (interquartile range = 15); more than half of participants (54%) were between 33 and 44 years, and just above one quarter (29%) were between 45 and 59 years of age. Ninety-four percent of participants were assigned female at birth. Approximately 90% of participants were non-Hispanic, where White participants comprised 83% of the sample. Thirty-six percent had a college degree, and more than half were employed (57%). Close to half of the sample were obese (47%), and about a quarter (25%) were overweight.

A majority (82%) reported that they experienced sleep disturbance at baseline; of these, 18% experienced severe disturbance, 56% experienced moderate disturbance, and 26% experienced mild disturbance (based on established thresholds of the PROMIS-8a Sleep Disturbance Index).³⁰ A majority of participants (74%) reported symptoms of anxiety at baseline; of these, 27% experienced severe anxiety, 36% experienced moderate anxiety, and 37% experienced mild anxiety (based on established thresholds of the GAD-7 scale).³² More than half (58%) reported experiencing longer term pain; of these, 40% experienced severe pain, 49% experienced moderate pain, and 12% experienced mild pain (based on established thresholds of the PEG scale).³⁴

Participants reported taking an average of 17.2 mg of CBD per day. Upon completion of the study, 18.2% of all participants reported having used any THC/cannabis product during the last 28 days and 6.7% of all participants reported using a CBD product (among the Product Group, a CBD product other than the study product assigned) in the past 28 days.

Baseline demographics and behaviors of the study sample are shown across study arms in Table 2. No significant differences were observed at baseline except for age, where Product Group participants had higher median age relative to the control group. In addition, there was no evidence of significant baseline differences when the sample was stratified by CBD spectrum (“broad”: 21%, “full”: 42.8%, and “isolate”: 28.6%; Supplementary Table S1). Out of the 2816 participants enrolled in the study, 52% retained at 4-weeks follow-up, 5 withdrew because of side effects, 6 withdrew because of unrelated illness/medical concerns, and 13 withdrew the study for other reasons (Fig. 1). Compared with those who did not retain, retained participants were more likely to be randomized to the Product Group, be assigned male at birth, be non-Hispanic, endorse anxiety symptoms at baseline, and have a college degree.

Table 2.

Baseline Demographic, Health, and Behavioral Characteristics of Participants in Radicle Advancing Cannabidiol Education and Science Study, Total and by Study Arm

	All product arms (n = 2601)	Waitlist control (n = 215)	Total (n = 2816)	p ^a
	n (%)	n (%)	n (%)	p ^a
Demographics
Age [median (IQR)]	41 (15)	39 (11)	40 (15)	0.020
Age categories
21–29	235 (9.0)	18 (8.4)	253 (9.0)	0.03
30–44	1417 (54.5)	139 (64.7)	1556 (54.5)
45–59	752 (28.9)	47 (21.9)	799 (28.9)
60 and older	197 (7.6)	11 (5.1)	208 (7.7)
Sex at birth
Female	2437 (93.7)	203 (94.4)	2640 (93.8)	0.673
Male	164 (6.3)	12 (5.6)	176 (6.3)
Ethnicity
Hispanic	267 (10.3)	23 (10.7)	290 (10.4)	0.865
Non-Hispanic	2318 (89.7)	192 (89.3)	2510 (89.6)
Race
Black/African American	186 (7.3)	18 (8.4)	204 (7.4)	0.873
Asian/AN/HPI/other	114 (4.5)	10 (4.7)	124 (4.5)
White	2126 (83.1)	174 (80.9)	2300 (82.9)
Multiple	134 (5.2)	13 (6.1)	147 (5.3)
BMI categories
Obese	1202 (46.4)	107 (49.8)	1309 (46.7)	0.334
Overweight	654 (25.3)	53 (24.7)	707 (25.2)
Healthy	700 (27.0)	55 (25.6)	755 (26.9)
Underweight	33 (1.3)	0 (0)	33 (1.2)
Employment status
Employed	1443 (56.4)	124 (58.5)	1567 (56.5)	0.904
Unemployed, seeking employment	173 (6.8)	15 (7.1)	188 (6.8)
Unemployed, not seeking employment	315 (12.3)	22 (10.4)	337 (12.2)
Homemaker	514 (20.1)	43 (20.3)	557 (20.1)
Retired	116 (4.5)	8 (3.8)	124 (4.5)
Education
Less than high school	47 (1.8)	1 (0.5)	48 (1.7)	0.453
High school diploma/equivalent	526 (20.3)	46 (21.6)	572 (20.4)
Some college, no degree	655 (25.3)	57 (26.8)	712 (25.4)
College degree (associate or bachelor's degree)	936 (36.2)	71 (33.3)	1007 (36.0)
Graduate degree	221 (8.6)	16 (7.5)	237 (8.5)
Trade school	201 (7.8)	22 (10.3)	223 (8.0)
Baseline health
Symptom endorsement^b
Anxiety	1928 (74.1)	163 (75.7)	2091 (74.3)	0.586
Sleep disturbance	2132 (82.0)	173 (80.5)	2305 (81.9)	0.583
Pain	1504 (57.8)	125 (58.1)	1629 (57.9)	0.928
Anxiety severity^c
Severe	488 (26.9)	42 (26.9)	530 (26.9)	0.995
Moderate	654 (36.1)	58 (37.2)	712 (36.2)
Mild	670 (37.0)	56 (35.9)	726 (37.0)
Sleep disturbance severity^d
Severe	343 (17.4)	34 (21.0)	377 (17.4)	0.535
Moderate	1113 (56.4)	88 (54.0)	1201 (56.2)
Mild	517 (26.2)	41 (25.1)	558 (26.1)
Pain severity^e
Severe	596 (39.6)	48 (38.4)	644 (39.5)	0.734
Moderate	732 (48.7)	64 (51.2)	796 (48.9)
Mild	176 (11.7)	13 (6.9)	189 (11.6)
Behaviors
Prior CBD use
Inexperienced user	670 (34.8)	62 (38.0)	732 (35.0)	0.639
Familiar user	1224 (63.5)	99 (60.7)	1323 (63.3)
Experienced user	34 (1.8)	2 (1.2)	36 (1.7)
THC use in past month
None	2192 (84.3)	180 (83.7)	2372 (84.2)	0.627
1–15 days	320 (12.3)	25 (11.6)	345 (12.3)
16–30 days	89 (3.4)	10 (4.7)	99 (3.5)

p-Values estimated using chi-square or Fisher's exact tests for discrete variables and Mann–Whitney U test for continuous variables.

Note that participants could endorse multiple symptoms, thus the reported proportions will exceed 100%.

Among those who endorse anxiety symptoms (n = 1928); anxiety severity classification is based on predetermined thresholds of the GAD-7 scale (5–9: mild anxiety; 10–14: moderate anxiety; 15–21: severe anxiety).

Among those who endorse sleep disturbance (n = 2132); sleep disturbance severity classification is based on predetermined thresholds of the T-scores for the PROMIS Sleep Disturbance 8b scale (Less than 55: None to slight; 55.0—59.9: Mild; 60.0—69.9: Moderate; 70 and over: Severe).

Among those who endorse longer-term pain (n = 1504); pain severity classification is based on predetermined thresholds of the PEG scale (less than 4: mild pain; greater than 4 and less than 7: moderate pain; greater than 7: severe pain).

AN, Alaskan Native; GAD-7, Generalized Anxiety Disorder-7; BMI, body mass index; HPI, Hawaiian or Pacific Islander; IQR, interquartile range; PEG, Pain intensity, Interference and General activity-3 Scale.

Overall effects of CBD product assignment and CBD spectrum

In this section, we report the estimated mean differences (MDs) in score, along with their 95% confidence intervals (CIs), for each outcome of interest. Full results can also be found in Tables 3 and 4.

Table 3.

Effect of Cannabidiol (Mean Differences from Baseline, Relative to Control), Overall and by Cannabidiol Spectrum

	WHO-5 well-being			GAD-7 anxiety			PROMIS sleep disturbance 8b			PEG-3 pain
	Estimate	SE	95% CI	Estimate	SE	95% CI	Estimate	SE	95% CI	Estimate	SE	95% CI
CBD	4.95	0.38	(4.21 to 5.70)	−4.71	0.39	(−5.48 to −3.94)	−7.38	0.55	(−8.46, −6.30)	−1.67	0.19	(−2.04, −1.31)
CBD spectrum
Broad	5.12	0.43	(4.26 to 5.95)	−4.94	0.45	(−5.82 to −4.06)	−7.63	0.62	(−8.85, −6.40)	−1.62	0.21	(−2.04, −1.20)
Full	4.92	0.40	(4.14 to 5.70)	−4.78	0.41	(−5.58, −3.97)	−7.41	0.58	(−8.53, −6.28)	−1.68	0.20	(−2.07, −1.30)
Isolate	4.89	0.42	(4.07 to 5.71)	−4.44	0.43	(−5.29, −3.60)	−7.14	0.60	(−8.32, −5.96)	−1.69	0.20	(−2.09, −1.29)

CI, confidence interval; SE, standard error; WHO-5, World Health Organization Five Well-being Index.

Table 4.

Effect of Cannabidiol (Mean Differences from Baseline, Relative to Control) by Week Across the Outcomes of Interest

	WHO-5 well-being			GAD-7 anxiety			PROMIS sleep disturbance 8b			PEG-3 pain
	Estimate	SE	95% CI	Estimate	SE	95% CI	Estimate	SE	95% CI	Estimate	SE	95% CI
CBD
Week 1	4.07	0.43	3.22 to 4.91	−4.07	0.42	−7.85 to −5.58	−6.71	0.58	−7.85 to −5.58	−1.50	0.20	−1.89 to −1.11
Week 2	4.74	0.44	3.87 to 5.61	−4.45	0.44	−8.39 to −6.00	−7.20	0.61	−8.39 to −6.00	−1.62	0.21	−2.03 to −1.21
Week 3	5.17	0.46	4.27 to 6.07	−4.97	0.44	−8.83 to −6.39	−7.61	0.62	−8.83 to −6.39	−1.60	0.22	−2.04 to −1.17
Week 4	5.83	0.47	4.91 to 6.75	−5.38	0.46	−9.32 to −6.71	−8.01	0.67	−9.32 to −6.71	−1.96	0.24	−2.42 to −1.50

World Health Organization Five Well-being Index

Using a CBD product (MD: 4.95; 95% CI: 4.21 to 5.70) and Broad (MD: 5.12; 95% CI: 4.26 to 5.95), Full (MD: 4.92; 95% CI: 4.14 to 5.70), and Isolate (MD: 4.89; 95% CI: 4.07 to 5.71) CBD spectrums led to significant increases in WHO-5 scale scores, indicating improvement in well-being relative to control. Significant improvements relative to control were observed at each study week, compared to baseline scores. Approximately 20.3% (n = 528) of those assigned to a CBD product experienced a CMI in their well-being score, compared to 3.3% (n = 7) in control. There was no evidence of interaction effects between group assignment (product vs. control), time, and prior CBD use.

Generalized Anxiety Disorder-7

Using a CBD product (MD: −4.71; 95% CI: −5.48 to −3.94) and Broad (MD: −5.82, −4.06; 95% CI: −5.82 to −4.06), Full (MD: −4.78; 95% CI: −5.58 to −3.97), and Isolate (MD: −4.44; 95% CI: −5.29 to −3.60) CBD spectrums led to significant declines in GAD-7 scale scores, indicating improvement in anxiety symptoms relative to control. Significant improvements relative to control were observed at each study week, compared to baseline scores. Among those with anxiety, 46.6% (n = 899) of those assigned to a CBD product experienced a MCID in their anxiety score, compared to 19.6% (n = 32) in control. There was no evidence of interaction effects between group assignment (product vs. control), time, and prior CBD use.

PROMIS Sleep Disturbance 8b

Using a CBD product (MD: −7.37; 95% CI: −8.46 to −6.30) and Broad (MD: −7.63; 95% CI: −8.85 to −6.40), Full (MD: −7.41; 95% CI: −8.53 to −6.28), and Isolate (MD: −7.14; 95% CI: −8.32 to −5.96) CBD spectrums led to significant declines in PROMIS Sleep Disturbance 8b scale scores, indicating improvement in sleep quality relative to control. Significant improvements relative to control were observed at each study week, compared to baseline scores. Among those with sleep disturbance, 47.9% (n = 1022) of those assigned to a CBD product experienced a MCID in their sleep disturbance score, compared to 14.4% (n = 25) in the control. There was no evidence of significant interaction effects between group assignment (product vs. control), time, and prior CBD use.

Pain intensity, Interference and General activity-3 Scale

Using a CBD product (MD: −1.67; 95% CI: [−2.04 to −1.31] and Broad (MD: −1.62; 95% CI: −2.04 to −1.20), Full (MD: −1.68; 95% CI: −2.07 to −1.30), and Isolate (MD: −1.69; 95% CI: −2.09 to −1.29) CBD spectrums led to significant declines in PEG-3 scale scores, indicating a reduction in pain intensity and interference relative to control. Significant improvements relative to control were observed at each study week, compared to baseline scores. Among those with pain, 35.2% (n = 530) of those assigned to a CBD product experienced a CMI in their pain score, compared to 9.6% (n = 12) in the control. There was no evidence of significant interaction effects between group assignment (any product vs. control), time, and prior CBD use.

No significant effect of CBD spectrum was observed for any outcome assessed.

Safety

Approximately 9.5% (n = 248) of participants assigned to receive a CBD product spontaneously reported any side effect from taking their product throughout the study period. The proportion of participants reporting any side effects by product ranged from 5.9% to 13.9%. Side effects included the following: gas/flatulence (n = 42; 1.6%), headaches (n = 36; 1.4%), diarrhea (n = 32; 1.2%), bloating (n = 32; 1.2%), mental fog/forgetfulness (n = 30; 1.1%), heartburn/chest pain (n = 29; 1.1%), nausea (n = 28; 1.1%), cramps (n = 25; 0.1%), trouble falling or staying asleep (n = 24; 0.1%), anxiety (n = 24; 0.1%), irritability or depressed mood (n = 22; <0.1%), increased appetite (n = 20; <0.1%), fatigue (n = 20; <0.1%), reduced appetite (n = 18; <0.1%), jittery feelings/twitching (n = 15; <0.1%), itchiness (n = 14; <0.1%), muscle aches (n = 12; <0.1%), skin rash (n = 9; <0.1%), sore throat (n = 2; <0.1%), dry mouth (n = 2; <0.1%), mouth numbness (n = 1; <0.1%), elevated heart rate (n = 1; <0.1%), lower back pain (n = 1; <0.1%), lost of taste (n = 1; <0.1%), and indigestion (n = 1; <0.1%). All side effects were either mild or moderate; no participant reported using outpatient or emergency medical services to treat a side effect.

Discussion

In this open-label trial evaluating commercially available CBD products, we observed that well-being, anxiety, sleep quality, and pain significantly improved among those assigned to take a CBD product, relative to waitlist control. Among those who reported anxiety or sleep disturbance at baseline, roughly half of those assigned to a CBD product experienced a change which they could consider clinically important, and about one-third of pain sufferers in the product group experienced a CMI in their pain. Moreover, all products in the study exhibited a favorable safety profile; no severe side effects were reported.

Few studies to date have investigated the safety or effectiveness of CBD for the management of symptoms for which CBD is most commonly used, including anxiety, sleep difficulties, or pain.^7,20,21 The present study represents the largest prospective clinical trial on the health effects of CBD to date. This study is also among the first to evaluate the safety and effectiveness of CBD dose ranges and formulations commonly found within commercially available CBD products. Our results demonstrate that the relatively lower doses of CBD found within commercially available products may be sufficient to produce significant improvements in symptoms of anxiety, sleep disturbance, and pain.

It is noteworthy that nearly half of CBD product group participants reporting anxiety and sleep disturbance symptoms at baseline experienced a MCID in their respective outcome scores. This portion mirrors the cutoff to determine minimum thresholds for effective therapeutic doses, known as Effective Dose 50 (ED50), referring to the dose which produces a desired effect in 50% of the population.³⁷ This study was not designed to determine therapeutic doses, and participants could take as much, or as little, of their study product as they saw fit. Thus, we make no conclusions about the optimal CBD dose to induce the desired therapeutic effect. Nonetheless, it is notable that use of the CBD products in this sample, when taken in a real world setting, could reach this threshold for the alleviation of anxiety and sleep disturbance symptoms.

Although this study was not specifically designed to assess tolerance (diminished response) to CBD over time, we found no differences in effect size between experienced, familiar, and naive CBD users for any outcome. This suggests that experienced users may derive a similar benefit of CBD as naive users. However, the categories for prior CBD use were broad, subjective, and did not specify the recency of prior CBD use. Future research should explore the potential for CBD tolerance using more in-depth assessment of prior CBD use, as well as longer term follow-up.

Our study was also not specifically designed to determine the effect of CBD spectrum on health-related outcomes, as the commercially available products included in this study varied on a range of factors other than spectrum (e.g., CBD dose, product form, mode of absorption). As such, the lack of observable difference in effect between Isolate, Full, and Broad spectrum products in this study is not conclusive. Future RCTs and meta-analyses will be helpful for determining whether specific spectrums are more effective and whether effects differ as a function of other product characteristics.

Our findings regarding the safety of CBD products in this sample are consistent with previous clinical research. CBD has been used with apparent safety when taken daily over a similar period—often at doses substantially higher than those in this sample (which was 17.2 mg per day, on average). For example, prior clinical research has found no serious adverse events or indications of toxicity for orally ingested doses of 700 mg of CBD daily for up to 6 weeks³⁸ or for 1200 mg daily for up to 4 weeks.³⁹

Our study has several limitations. As this was an open-label trial, we cannot ascertain the extent to which participant expectancy/placebo effects may have influenced the observed effects. For many drugs, placebo responses can account for a substantial portion of the therapeutic effect.⁴⁰ Previous research suggests that the impact of CBD on anxiety and stress could be driven in large part by the placebo response.⁴¹ Future double-blind placebo-controlled studies are needed to determine the therapeutic effects of CBD for anxiety, sleep, and pain.

Our sample was also fairly homogenous (94% of participants were female and 83% were White) due to the specific demographics of people who engaged with our online recruitment partner. This homogeneity could limit the generalizability of our findings to the broader population of CBD users in the United States; according to a 2017 survey by the Brightfield Group, 55% of American CBD users were female, and 66% were White.⁴² Future research evaluating the effects of CBD should work to include a more diverse population which reflects both current and potential users.

In addition, our study had a limited follow-up time of only 4 weeks. We thus cannot conclude whether continued use of these CBD products would result in heightened effects through an increase in blood plasma levels of CBD. However, in a 6-week clinical trial of 14 Huntington's disease patients involving repeated oral administration of 700 mg of CBD per day, plasma levels of CBD remained constant throughout the trial.³⁸ These results suggest that, had our participants continued to take these CBD products, we may not expect increased effects through an elevation in blood plasma levels of the cannabinoid. Also as a result of the limited follow-up period, we could not assess whether longer term use of CBD could result in diminished effects, whether through the “wearing off” of placebo effects or drug tolerance.

Finally, as this was a “real world” study, we did not engage in the intensive monitoring that is characteristic of traditional clinical trials. While we requested that participants refrain from using other cannabinoid products, at the conclusion of the study, about one in five participants reported using another cannabinoid product during the study period. Nonetheless, our findings may also be more reflective of the real world effectiveness of these products as the actions of our participants better represent the true behaviors of potential users.

Conclusion

CBD use, already commonplace in the United States, will likely continue to increase in the coming years. According to a recent report by Statistica and The Brightfield Group, consumer spend on CBD in the United States is expected to rise from $4.6 billion in 2020 to an estimated $16 billion in 2026, exceeding a threefold increase in just 5 years.⁴³ In light of this potential growth, it is critical to provide information surrounding the safety and effectiveness of these products to guide the decisions of consumers, health care providers, and regulators. Our results suggest that the commercially available CBD products included in this study are safe and may serve as potentially effective complementary therapies for management of anxiety, sleep disturbance, and pain.

Footnotes

Authors' Contributions

Drs. J.L.S. and K.T.L. had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: K.T.L., E.K.P., J.C., P.T., M.B., C.S.C., D.L., E.R., K.W.-T., J.W., R.V. Acquisition, analysis, or interpretation of data: J.L.S., P.R., O.C., J.W. Drafting of the article: J.L.S., K.T.L., P.R., R.V. Critical revision of the article for important intellectual content: All authors. Statistical analysis: P.R., O.C., J.W. Administrative, technical, or material support: J.C., P.T. Supervision: K.T.L.

Author Disclosure Statement

Dr. R.V. has received payment for consulting or advisory board services to Canopy Health Innovations, MyMD Pharmaceuticals, Mira1a Therapeutics, Syqe Medical Ltd., Radicle Science, Inc., and WedMD. No other authors have conflicts of interest to declare. All coauthors have seen and agree with the contents of the article, and there is no financial interest to report. We certify that the submission is original work and is not under review at any other publication.

Funding Information

This research was supported by Radicle Science's brand partners for the Radicle ACES study, including: ALTWELL, Charlotte's Web, Columbia Care, Healer, Lord Jones, Maven Hemp, MD FARMA, Peels, Prospect Farms, PURAURA Naturals from Enhanced Botanicals, Rae Wellness, Trokie, and Verséa Wellness. The supporters had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the article; and decision to submit the article for publication.

Supplementary Material

Abbreviations Used

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Supplementary Material

Please find the following supplemental material available below.

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The Safety and Effectiveness of Commercially Available Cannabidiol Products for Health and Well-Being: A Randomized,Multi-Arm,Open-Label Waitlist-Controlled Trial

Abstract

Introduction:

Materials and Methods:

Results:

Discussion:

Introduction

Objective

Methods

Study design and participants

Randomization

Outcomes

World Health Organization Five Well-being Index

Patient-Reported Outcomes Measurement Information System™ Sleep Disturbance SF 8B

Generalized Anxiety Disorder-7 scale

Pain intensity, Interference and General activity-3 Scale

Side effects

Demographics and other sample characteristics

Consumption behaviors

Data analysis

Results

Sample characteristics

Overall effects of CBD product assignment and CBD spectrum

World Health Organization Five Well-being Index

Generalized Anxiety Disorder-7

PROMIS Sleep Disturbance 8b

Pain intensity, Interference and General activity-3 Scale

Safety

Discussion

Conclusion

Footnotes

Authors' Contributions

Author Disclosure Statement

Funding Information

Supplementary Material

Abbreviations Used

References

Supplementary Material