The effects of a brand-specific, hemp-derived cannabidiol product on physiological, biochemical, and psychometric outcomes in healthy adults: a double-blind, randomized clinical trial

Figures & data

Figure 1. Study design: Visit schedule.

Each box represents the schedule of events for each of the 5 study visits.

Table 1. Exclusion criteria.

Exclusion Criteria

Have a known sensitivity or allergy to any of the investigational products or their ingredients.

Female participants who are lactating, pregnant or planning to become pregnant, or male participants of reproductive potential in a heterosexual relationship planning a pregnancy as confirmed at the baseline visit.

Documented medical history of immune disorder, hepatitis B or hepatitis C, or reported immune disorder diagnosis.

Active psychiatric disorder requiring hospitalization within the 12 months prior to screening or currently on medication(s) to treat any psychiatric disorder(s).

Any cognitive impairment that would preclude study participation or compliance with study procedures (e.g. Alzheimer’s, dementia).

History of malignancy or those with any first-degree relatives with a history of cancer (e.g. familial cancer disorders) within 5 years.

History of clinically significant cardiovascular, respiratory, renal, cerebrovascular, metabolic, pulmonary, gastrointestinal, neurological, hematological, autoimmune, lymphatic, psychiatric, chronic pain and sleep disorders, hepatobiliary (with the exception of Gilbert’s syndrome or asymptomatic gallstones) or endocrine disorders, or other clinically significant medical condition that may preclude safe study participation.

Participants with controlled or uncontrolled hypertension including stage 1 hypertension (systolic blood pressure ≥129 mmHg and diastolic blood pressure ≥89 mmHg).

Participants who are on medications as prescribed for any of the aforementioned exclusionary criteria. Participants on stable dose of thyroid medication (no dosage changes within last 3 months) are acceptable.

Consumption of prescription or non-prescription: angiotensin converting enzyme inhibitors, angiotensin receptor blockers, barbiturates, cocaine, ethanol, selective serotonin reuptake inhibitor, protease inhibitors, warfarin, sildenafil, theophylline, tricyclic antidepressants.

Receipt or use of an investigational product in another research study within 30 days or 5 half lives (whichever is longer) prior to baseline (Visit 2) or currently participating in another study.

History of alcohol or substance abuse in the 12 months prior to baseline visit (Visit 2).

Current or recent use (within one month prior to Visit 2) of cannabis (e.g. marijuana) or cannabis related products (e.g. CBD) in any ingestible or inhalable forms.

Positive urine drug test for THC or drugs of abuse (Amphetamine, cocaine, marijuana, methamphetamine, and opiates) at baseline (Visit 2).

Safety blood tests at screening more than 2 times the upper limit of normal (ULN) for liver or kidney function tests.

Evidence of clinically significant anemia (as judged by the Investigator) on screening hematological testing.

Fasting blood glucose of ≥160 mg/dL (after a repeat that confirms the original result) at screening.

Table 2. Immune system, safety endpoint, and Foundational Pain Index biomarkers.

Immune System Markers	Comprehensive Metabolic Panel	Foundational Pain Index Urinary Biomarkers
Absolute Monocytes Absolute Eosinophils Absolute Neutrophils Absolute Basophils Absolute Lymphocytes Hemoglobin (HGB) Hematocrit (HCT) Mean Corpuscular Volume (MCV) Mean Corpuscular Hemoglobin (MCH) Mean Corpuscular Hemoglobin Concentration (MCHC) Platelets White Blood Cell Count (WBC) Red Blood Cell Count (RBC) Red Blood Cell Distribution Width (RDW) Mean Platelet Volume (MPV)	Blood Urea Nitrogen (BUN) Albumin Calcium Potassium Alkaline Phosphate (ALK) Aspartate Aminotransferase (AST) BUN/Creatinine Ratio Chloride Creatinine Fasting Blood Glucose Potassium Sodium Total Bilirubin Total Protein	Quinolinate Kyrurenate methylmalonic acid xanthurenate homocysteine 3-HPMA Vanilmandelate 5-HIAA Hydroxymethylglutarate Pyroglutamate Ethylmaolnate

Figure 2. Consort diagram.

This diagram depicts the progress of participants through screening, enrollment, randomization into parallel groups, and follow-up.

Table 3. Baseline participant descriptive data.

	Total (N = 54)	Female (n = 27)	Male (n = 27)
Age (years)	25 ± 7	24 ± 8	24 ± 5
BMI (kg/m^2)	24.82 ± 3.25	23.7 ± 3.4	26.1 ± 2.7
Non-Hispanic White (%)	85.2	70.4	81.5

Data are presented as mean ± SD.

Table 4. Changes in blood biomarkers by group and sex.

Measure	Sex	CBD				Placebo					p-value
		V2	V3	V4	V5	V2	V3	V4	V5	Time	Group	Interaction
ACE (µKat/L)	Overall	0.54 ± 0.27	0.56 ± 0.34(0.07)	0.58 ± 0.32(0.15)	0.58 ± 0.31(0.14)	0.60 ± 0.31	0.56 ± 0.22(0.13)	0.58 ± 0.27(0.06)	0.61 ± 0.24(0.03)	0.232	0.205	0.615
	Male	0.65 ± 0.26	0.68 ± 0.39(0.12)	0.68 ± 0.32(0.12)	0.68 ± 0.31(0.24)	0.65 ± 0.39	0.56 ± 0.26(0.23)	0.63 ± 0.34(0.05)	0.66 ± 0.29(0.03)	0.405	0.287	0.378
	Female	0.44 ± 0.26	0.44 ± 0.26(0.00)	0.46 ± 0.31(0.08)	0.48 ± 0.29(0.15)	0.56 ± 0.19	0.56 ± 0.17(0.00)	0.51 ± 0.17(0.26)	0.56 ± 0.19(0.00)	0.109	0.160	0.339
TNF-a(pg/mL)	Overall	14.1 ± 34.7	8.2 ± 9.9(0.17)	12.8 ± 25.5(0.04)	12.5 ± 23.4(0.05)	10.1 ± 13.1	7.1 ± 5.8(0.23)	7.6 ± 5.8(0.19)	7.6 ± 7.5(0.19)	0.301	0.277	0.461
	Male	9.4 ± 13.5	9.9 ± 13.3(0.04)	10.1 ± 12.5(0.05)	10.3 ± 13.2(0.07)	6.4 ± 2.7	6.0 ± 2.2(0.15)	6.6 ± 2.1(0.07)	6.4 ± 2.2(0.00)	0.423	0.025*	0.423
	Female	19.1 ± 48.8	6.4 ± 3.5(0.26)	15.8 ± 35.0(0.07)	15.0 ± 31.6(0.08)	15.3 ± 19.6	8.6 ± 8.8(0.34)	8.9 ± 8.8(0.33)	9.3 ± 11.6(0.31)	0.402	0.601	0.480
IL-6(pg/mL)	Overall	80 ± 161	58 ± 76(0.14)	87 ± 162(0.04)	82 ± 158(0.01)	55 ± 77	49 ± 59(0.08)	50 ± 62(0.06)	45 ± 61(0.13)	0.381	0.340	0.298
	Male	54 ± 71	57 ± 76(0.04)	59 ± 76(0.07)	57 ± 72(0.04)	36 ± 63	35 ± 60(0.01)	38 ± 65(0.03)	29 ± 60(0.11)	0.240	0.044*	0.525
	Female	113 ± 231	60 ± 81(0.23)	120 ± 230(0.03)	113 ± 225(0.00)	75 ± 90	65 ± 58(0.11)	62 ± 60(0.14)	63 ± 60(0.13)	0.354	0.684	0.302
IL-10(pg/mL)	Overall	14.3 ± 24.4	12.5 ± 18.3(0.07)	15.1 ± 24.3(0.03)	15.0 ± 23.8(0.03)	10.0 ± 11.5	9.2 ± 10.8(0.07)	9.2 ± 11.5(0.07)	9.3 ± 11.0(0.06)	0.476	0.240	0.490
	Male	13.8 ± 21.1	14.5 ± 21.6(0.03)	14.3 ± 20.8(0.02)	14.5 ± 20.2(0.03)	8.6 ± 14.1	7.9 ± 13.2(0.05)	8.3 ± 14.1(0.02)	8.1 ± 13.3(0.04)	0.978	0.013*	0.616
	Female	14.8 ± 29.0	10.0 ± 14.1(0.17)	16.0 ± 29.1(0.04)	15.6 ± 28.6(0.03)	11.3 ± 9.0	10.5 ± 8.2(0.09)	10.0 ± 9.0(0.14)	10.5 ± 8.7(0.09)	0.411	0.682	0.340

Data are presented as mean ± SD(d). All effect sizes (d) are compared to Visit 2 (V2).

*Denotes p < 0.05.

ACE = angiotensin converting enzyme, µKat/L = microkatals per liter, pg/mL = picogram per milliliter.

Table 5. Changes in immune system biomarkers by group and sex.

Measure	Sex	CBD				Placebo					p-value
		V2	V3	V4	V5	V2	V3	V4	V5	Time	Group	Interaction
WBC (10^3/μL)	Overall	5.67 ± 1.50	5.80 ± 1.53(0.09)	5.85 ± 1.65(0.12)	5.65 ± 1.59(0.01)	5.13 ± 1.20	5.38 ± 1.00(0.21)	5.42 ± 1.37(0.24)	5.30 ± 1.13(0.14)	0.587	0.984	0.965
	Male	5.38 ± 1.43	5.42 ± 1.50(0.03)	5.34 ± 1.22(0.03)	4.97 ± 0.87(0.29)	4.76 ± 0.92	5.08 ± 0.93(0.35)	5.03 ± 1.27(0.29)	4.85 ± 0.91(0.10)	0.066#	0.384	0.757
	Female	5.95 ± 1.56	6.16 ± 1.53(0.13)	6.33 ± 1.88(0.24)	6.28 ± 1.86(0.21)	5.56 ± 1.39	5.74 ± 1.01(0.13)	5.89 ± 1.40(0.24)	5.85 ± 1.16(0.21)	0.852	0.654	0.999
RBC (10^6/μL)	Overall	4.76 ± 0.35	4.69 ± 0.41(0.20)	4.74 ± 0.42(0.06)	4.74 ± 0.41(0.06)	4.88 ± 0.32	4.83 ± 0.39(0.16)	4.90 ± 0.31(0.06)	4.87 ± 0.31(0.03)	0.197	0.467	0.876
	Male	4.99 ± 0.24	4.99 ± 0.3(0.00)	5.06 ± 0.27(0.29)	4.99 ± 0.32(0.00)	5.05 ± 0.31	5.03 ± 0.33(0.06)	5.02 ± 0.31(0.10)	5.00 ± 0.31(0.16)	0.499	0.512	0.471
	Female	4.56 ± 0.32	4.42 ± 0.30(0.44)	4.44 ± 0.30(0.38)	4.50 ± 0.34(0.19)	4.67 ± 0.20	4.59 ± 0.31(0.4)	4.76 ± 0.25(0.45)	4.70 ± 0.23(0.15)	0.141	0.079#	0.342
HGB (g/dL)	Overall	14.2 ± 1.1	14.3 ± 1.4(0.09)	14.3 ± 1.4(0.09)	14.2 ± 1.2(0.00)	14.1 ± 1.5	14.0 ± 1.5(0.07)	14.2 ± 1.4(0.07)	14.1 ± 1.5(0.00)	0.141	0.755	0.942
	Male	15.1 ± 0.5	15.2 ± 0.7(0.20)	15.3 ± 0.8(0.40)	15.1 ± 0.7(0.00)	15.2 ± 0.7	15.0 ± 0.7(0.29)	15.0 ± 0.7(0.29)	15.0 ± 0.8(0.29)	0.489	0.149	0.640
	Female	13.4 ± 0.7	13.1 ± 1.0(0.43)	13.3 ± 1.0(0.14)	13.3 ± 1.0(0.14)	12.9 ± 1.2	12.7 ± 1.2(0.17)	13.1 ± 1.5(0.17)	12.9 ± 1.4(0.00)	0.068#	0.674	0.656
HCT (%)	Overall	43.0 ± 2.9	42.5 ± 3.8(0.17)	43.2 ± 3.9(0.07)	42.9 ± 3.7(0.03)	42.8 ± 3.4	41.4 ± 5.0(0.41)	43.1 ± 3.3(0.09)	42.9 ± 3.4(0.03)	0.019*	0.780	0.432
	Male	45.5 ± 1.2	45.5 ± 2.2(0.00)	46.5 ± 2.3(0.83)	45.7 ± 2.3(0.17)	45.2 ± 2.2	43.2 ± 5.8(1.05)	45.1 ± 2.1(0.18)	45.0 ± 1.9(0.23)	0.169	0.103	0.584
	Female	40.7 ± 1.9	39.7 ± 2.6(0.53)	40.2 ± 2.1(0.26)	40.3 ± 2.6(0.21)	39.9 ± 2.2	39.4 ± 3.1(0.23)	40.7 ± 3.0(0.36)	40.4 ± 3.2(0.23)	0.063#	0.457	0.612
MCV (fL)	Overall	90.4 ± 4.4	90.6 ± 4.3(0.05)	91.3 ± 5.1(0.20)	90.7 ± 4.6(0.07)	87.6 ± 4.6	87.7 ± 4.5(0.02)	88 ± 4.9(0.09)	88.2 ± 5.4(0.13)	0.287	0.752	0.472
	Male	91.4 ± 4.1	91.4 ± 4.5(0.12)	91.9 ± 4.5(0.12)	91.7 ± 4.0(0.07)	89.6 ± 3.1	89.3 ± 3.0(0.10)	90.1 ± 3.5(0.16)	90.1 ± 3.7(0.16)	0.211	0.716	0.782
	Female	89.5 ± 4.6	89.8 ± 4.1(0.07)	90.7 ± 5.8(0.26)	89.8 ± 5.1(0.07)	85.3 ± 5.0	85.8 ± 5.4(0.16)	85.6 ± 5.4(0.04)	86.0 ± 6.5(0.04)	0.835	0.873	0.386
MCH (pg)	Overall	29.9 ± 2.0	30.1 ± 2.0(0.10)	30.2 ± 1.8(0.15)	30.0 ± 2.2(0.05)	29.0 ± 2.2	28.9 ± 2.1(0.05)	28.9 ± 2.3(0.05)	28.9 ± 2.4(0.05)	0.643	0.076#	0.674
	Male	30.3 ± 2.0	30.7 ± 2.0(0.20)	30.4 ± 1.8(0.05)	30.4 ± 1.9(0.05)	30.1 ± 1.0	29.9 ± 1.0(0.02)	30.0 ± 1.0(0.10)	30.0 ± 1.0(0.10)	0.476	0.160	0.325
	Female	29.6 ± 2.0	29.6 ± 1.9(0.00)	30.0 ± 2.0(0.20)	29.6 ± 2.4(0.00)	27.7 ± 2.6	27.6 ± 2.5(0.04)	27.6 ± 2.8(0.04)	27.5 ± 3.0(0.08)	0.510	0.336	0.632
MCHC(g/dL)	Overall	33.1 ± 0.9	33.4 ± 1.2(0.33)	33.0 ± 0.9(0.11)	33.0 ± 1.10(0.11)	33.1 ± 1.2	32.9 ± 1.2(0.17)	32.8 ± 1.3(0.25)	32.7 ± 1.4(0.33)	0.176	0.072#	0.745
	Male	33.2 ± 1.1	33.5 ± 0.9(0.27)	33.0 ± 0.6(0.18)	33.1 ± 1.0(0.09)	33.6 ± 0.8	33.5 ± 0.8(0.13)	33.3 ± 0.7(0.38)	33.3 ± 1.1(0.38)	0.092#	0.967	0.799
	Female	33.0 ± 0.8	33.3 ± 1.5(0.38)	33.1 ± 1.2(0.13)	32.9 ± 1.1(0.13)	32.4 ± 1.4	32.1 ± 1.1(0.21)	32.1 ± 1.6(0.21)	31.9 ± 1.5(0.36)	0.653	0.057#	0.876
RDW (%)	Overall	12.6 ± 0.7	12.5 ± 0.7(0.14)	12.4 ± 0.5(0.29)	12.4 ± 0.5(0.29)	12.8 ± 0.9	12.8 ± 0.9(0.00)	12.8 ± 0.9(0.00)	12.8 ± 0.9(0.00)	0.905	0.100	0.728
	Male	12.7 ± 0.7	12.4 ± 0.6(0.43)	12.4 ± 0.5(0.43)	12.3 ± 0.5(0.57)	12.5 ± 0.4	12.5 ± 0.4(0.00)	12.4 ± 0.4(0.25)	12.4 ± 0.4(0.25)	0.021*	0.147	0.899
	Female	12.6 ± 0.8	12.5 ± 0.8(0.13)	12.5 ± 0.5(0.13)	12.6 ± 0.5(0.00)	13.1 ± 1.3	13.1 ± 1.3(0.00)	13.2 ± 1.2(0.08)	13.3 + 1.1(0.15)	0.619	0.215	0.643
Platelets (10^3/μL)	Overall	248 ± 51	251 ± 52(0.06)	251 ± 64(0.06)	254 ± 58(0.12)	247 ± 69	241 ± 55(0.10)	245 ± 59(0.12)	235 ± 53(0.21)	0.718	0.087#	0.221
	Male	226 ± 38	233 ± 30(0.18)	222 ± 35(0.11)	236 ± 40(0.26)	218 ± 42	212 ± 32(0.14)	214 ± 39(0.10)	211 ± 34(0.17)	0.458	0.067#	0.149
	Female	270 ± 55	269 ± 64(0.02)	279 ± 74(0.16)	272 ± 69(0.04)	287 ± 80	279 ± 57(0.16)	285 ± 57(0.27)	266 ± 59(0.07)	0.161	0.407	0.454
MPV (fL)	Overall	10.9 ± 1.1	10.9 ± 1.0(0.00)	10.9 ± 1.0(0.00)	11.0 ± 1.0(0.09)	11.3 ± 1.1	11.2 ± 1.1(0.09)	11.3 ± 1.1(0.00)	11.3 ± 1.2(0.00)	0.317	0.742	0.998
	Male	11.0 ± 1.2	10.8 ± 1.1(0.17)	11.0 ± 1.1(0.00)	10.8 ± 1.1(0.17)	11.3 ± 1.3	11.3 ± 1.2(0.00)	11.3 ± 1.3(0.00)	11.4 ± 1.4(0.08)	0.752	0.198	0.305
	Female	10.9 ± 0.9	10.9 ± 0.9(0.00)	10.9 ± 0.8(0.00)	11.2 ± 0.9(0.33)	11.3 ± 0.9	11.1 ± 0.8(0.22)	11.2 ± 1.0(0.11)	11.2 ± 1.1(0.11)	0.316	0.533	0.678
Neutrophils (10^3/μL)	Overall	2.91 ± 1.1	2.89 ± 0.9(0.02)	3.07 ± 1.28(0.15)	2.72 ± 1.06(0.17)	2.69 ± 0.88	2.67 ± 0.72(0.02)	2.76 ± 0.79(0.08)	2.67 ± 0.8(0.02)	0.288	0.882	0.670
	Male	2.63 ± 0.99	2.75 ± 0.80(0.12)	2.66 ± 0.83(0.03)	2.49 ± 0.88(0.14)	2.52 ± 0.71	2.48 ± 0.64(0.06)	2.54 + 0.81(0.03)	2.46 ± 0.64(0.08)	0.358	0.707	0.529
	Female	3.18 ± 1.17	3.01 ± 1.00(0.15)	3.45 ± 1.51(0.23)	2.94 ± 1.19(0.21)	2.91 ± 1.05	2.9 ± 0.78(0.01)	3.01 ± 0.74(0.10)	2.92 ± 0.92(0.01)	0.365	0.853	0.644
Lymphocytes (10^3/μL)	Overall	2.00 ± 0.63	2.18 ± 0.76(0.29)	2.03 ± 0.57(0.05)	2.09 ± 0.93(0.14)	1.74 ± 0.5	1.95 ± 0.51(0.42)	1.91 ± 0.60(0.34)	1.85 ± 0.57(0.22)	0.448	0.856	0.711
	Male	1.91 ± 0.45	1.88 ± 0.56(0.24)	1.91 ± 0.43(0.00)	1.82 ± 0.44(0.20)	1.61 ± 0.36	1.81 ± 0.39(0.61)	1.75 ± 0.45(0.15)	1.67 ± 0.33(0.36)	0.299	0.442	0.729
	Female	2.07 ± 0.77	2.46 ± 0.83(0.51)	2.14 ± 0.66(0.09)	2.35 ± 1.18(0.36)	1.90 ± 0.61	2.10 ± 0.61(0.33)	2.10 ± 0.73(0.33)	2.06 ± 0.73(0.26)	0.607	0.607	0.584
Monocytes (10^3/μL)	Overall	0.51 ± 0.18	0.69 ± 1.00(0.18)	0.50 ± 0.13(0.06)	0.47 ± 0.11(0.22)	0.50 ± 0.12	0.49 ± 0.09(0.08)	0.48 ± 0.11(0.16)	0.48 ± 0.09(0.16)	0.354	0.458	0.432
	Male	0.54 ± 0.20	0.52 ± 0.17(0.10)	0.53 ± 0.13(0.05)	0.45 ± 0.09(0.45)	0.48 ± 0.14	0.49 ± 0.08(0.07)	0.48 ± 0.13(0.00)	0.47 ± 0.10(0.07)	0.047*	0.616	0.178
	Female	0.48 ± 0.16	0.85 ± 1.39(2.31)	0.47 ± 0.13(0.06)	0.48 ± 0.14(0.00)	0.51 ± 0.08	0.50 ± 0.11(0.13)	0.49 ± 0.1(0.25)	0.49 ± 0.07(0.25)	0.466	0.429	0.522
Eosinophils (10^3/μL)	Overall	0.20 ± 0.16	0.20 ± 0.14(0.00)	0.20 ± 0.12(0.00)	0.33 ± 0.72(0.81)	0.18 ± 0.14	0.21 ± 0.22(0.21)	0.21 ± 0.19(0.21)	0.22 ± 0.21(0.29)	0.443	0.809	0.541
	Male	0.24 ± 0.2	0.23 ± 0.19(0.05)	0.19 ± 0.13(0.25)	0.17 ± 0.10(0.35)	0.19 ± 0.16	0.24 ± 0.29(0.31)	0.20 ± 0.20(0.06)	0.23 ± 0.22(0.25)	0.219	0.141	0.494
	Female	0.15 ± 0.10	0.17 ± 0.07(0.20)	0.20 ± 0.12(0.50)	0.47 ± 1.00(3.2)	0.17 ± 0.13	0.18 ± 0.09(0.08)	0.23 ± 0.19(0.46)	0.21 ± 0.20(0.31)	0.399	0.397	0.439
Basophils (10^3/μL)	Overall	0.07 ± 0.14	0.06 ± 0.10(0.07)	0.04 ± 0.02(0.21)	0.05 ± 0.08(0.14)	0.04 ± 0.02	0.04 ± 0.03(0.00)	0.05 ± 0.03(0.5)	0.04 ± 0.03(0.00)	0.588	0.535	0.400
	Male	0.03 ± 0.02	0.06 ± 0.10(1.50)	0.03 ± 0.01(0.00)	0.07 ± 0.10(2.0)	0.04 ± 0.02	0.04 ± 0.03(0.00)	0.04 ± 0.03(0.00)	0.04 ± 0.03(0.00)	0.567	0.209	0.453
	Female	0.11 ± 0.02	0.07 ± 0.1(2.00)	0.04 ± 0.02(3.50)	0.03 ± 0.02(4.00)	0.04 ± 0.02	0.04 ± 0.02(0.00)	0.05 ± 0.02(0.05)	0.04 ± 0.03(0.00)	0.393	0.497	0.750

Data are presented as mean ± SD(d). All effect sizes (d) are compared to Visit 2 (V2).

*Denotes p < 0.05.

#Denotes p < 0.1.

WBC = white blood cells, RBC = red blood cells, HGB = hemoglobin, HCT = hematocrit, MCV = mean corpuscular volume, MCH = mean corpuscular hemoglobin, MCHC = mean corpuscular hemoglobin concentration, RDW = RBC distribution width, MPV = mean platelet volume, µL = microliter, pg = picogram, g/dL = grams per deciliter, fL= femtoliter.

Table 6. Changes in perceived stress, sleep quality, and body discomfort by group and sex.

Measure	Sex	CBD				Placebo					p-value
		V2	V3	V4	V5	V2	V3	V4	V5	Time	Group	Interaction
CPSS	Overall	14.5 ± 7.6	12.2 ± 7.7(0.30)	13.1 ± 6.6(0.18)	13.4 ± 6.8(0.14)	11.9 ± 5.9	12.7 ± 6.3(0.14)	12.7 ± 6.7(0.14)	12.2 ± 7.5(0.05)	0.792	0.204	0.456
	Male	10.8 ± 5.7	9.9 ± 6.3(0.15)	10.5 ± 6.1(0.05)	10.7 ± 5.0(0.01)	12.0 ± 5.7	11.9 ± 7.0(0.02)	11.6 ± 6.5(0.07)	10.3 ± 5.7(0.30)	0.793	0.954	0.423
	Female	18.0 ± 7.7	14.3 ± 8.5(0.48)	15.4 ± 6.4(0.33)	15.9 ± 7.5(0.27)	11.9 ± 6.4	13.5 ± 5.7(0.25)	13.8 ± 6.9(0.30)	14.2 ± 8.8(0.36)	0.570	0.047*	0.874
PSQI	Overall	5.48 ± 2.99	5.22 ± 2.94(0.09)	5.3 ± 3.12(0.06)	5.07 ± 2.6(0.14)	4.89 ± 2.49	4.26 ± 2.38(0.25)	4.48 ± 2.42(0.16)	4.37 ± 2.79(0.21)	0.815	0.337	0.815
	Male	4.31 ± 2.10	3.62 ± 2.33(0.33)	4.00 ± 2.20(0.15)	3.85 ± 2.08(0.22)	4.57 ± 2.85	4.29 ± 2.52(0.10)	3.86 ± 2.25(0.25)	4.07 ± 2.30(0.18)	0.996	0.864	0.533
	Female	6.57 ± 3.34	6.71 ± 2.70(0.04)	6.50 ± 3.44(0.02)	6.21 ± 2.58(0.11)	5.23 ± 2.09	4.23 ± 2.31(0.48)	5.15 ± 2.51(0.04)	4.69 ± 3.30(0.26)	0.642	0.205	0.395
Body Discomfort	Overall	1.30 ± 1.10	1.26 ± 1.23(0.04)	1.22 ± 1.15(0.07)	1.04 ± 1.13(0.24)	0.81 ± 1.11	1.30 ± 1.38(0.44)	1.11 ± 1.34(0.27)	1.44 ± 1.72(0.57)	0.812	0.090#	0.318
	Male	1.38 ± 1.26	1.23 ± 1.48(0.12)	1.38 ± 1.12(0.00)	1.15 ± 1.28(0.18)	0.79 ± 1.12	1.21 ± 1.42(0.38)	1.36 ± 1.65(0.51)	1.57 ± 2.03(0.70)	0.862	0.108	0.709
	Female	1.21 ± 0.97	1.29 ± 0.99(0.08)	1.07 ± 1.21(0.14)	0.93 ± 1.00(0.29)	0.85 ± 1.14	1.38 ± 1.39(0.46)	0.85 ± 0.90(0.00)	1.31 ± 1.38(0.40)	0.118	0.449	0.249

Data are presented as mean ± SD(d). All effect sizes (d) are compared back to Visit 2 (V2).

*Denotes p < 0.05.

#Denotes p < 0.1.

CPSS= Cohens perceived stress scale, PSQI = Pittsburgh sleep quality index.

Table 7. Changes in profile of mood states total mood disturbance and subscales by group and sex.

Measure	Sex	CBD				Placebo					p-value
		V2	V3	V4	V5	V2	V3	V4	V5	Time	Group	Interaction
Total Mood Disturbance	Overall	19.3 ± 26.7	18.3 ± 28.4(0.04)	23.5 ± 29.0(0.16)	20.4 ± 29.5(0.04)	14.3 ± 23.4	13.3 ± 25.8(0.04)	16.1 ± 25.8(0.08)	17.6 ± 34.3(0.14)	0.298	0.842	0.694
	Male	9.9 ± 25.3	11.0 ± 25.5(0.04)	18.1 ± 28.0(0.32)	17.5 ± 31.1(0.30)	15.0 ± 28.4	12.1 ± 27.7(0.10)	13.0 ± 28.9(0.07)	14.2 ± 30.1(0.03)	0.446	0.396	0.732
	Female	28.1 ± 25.8	25.1 ± 30.3(0.12)	29.4 ± 29.7(0.05)	23.1 ± 28.9(0.19)	13.5 ± 17.7	14.6 ± 24.6(0.06)	19.4 ± 22.7(0.33)	21.2 ± 39.2(0.44)	0.545	0.319	0.509
Anger Hostility	Overall	5.00 ± 4.51	5.11 ± 5.26(0.02)	5.89 ± 5.69(0.20)	5.15 ± 5.77(0.03)	3.63 ± 3.85	3.19 ± 3.37(0.11)	2.96 ± 4.64(0.17)	3.26 ± 4.90(0.10)	0.853	0.178	0.532
	Male	5.62 ± 4.94	6.31 ± 5.60(0.23)	8.15 ± 5.11(0.43)	6.69 ± 5.79(0.19)	4.29 ± 4.53	3.93 ± 3.60(0.12)	3.71 ± 5.33(0.12)	3.64 ± 5.08(0.15)	0.532	0.081#	0.436
	Female	4.43 ± 4.18	4.00 ± 4.85(0.10)	3.79 ± 5.54(0.15)	3.71 ± 5.57(0.17)	2.92 ± 2.99	2.38 ± 3.04(0.18)	2.15 ± 3.80(0.26)	2.85 ± 4.86(0.02)	0.893	0.925	0.811
Confusion Bewilderment	Overall	9.30 ± 6.28	9.04 ± 6.04(0.04)	10.19 ± 6.59(0.14)	9.89 ± 5.81(0.09)	8.26 ± 4.98	8.22 ± 5.67(0.01)	9.15 ± 5.44(0.18)	9.00 ± 6.88(0.15)	0.221	0.839	0.984
	Male	7.38 ± 4.68	7.00 ± 4.76(0.08)	8.23 ± 4.97(0.18)	8.54 ± 4.97(0.25)	8.07 ± 6.11	7.71 ± 5.99(0.06)	8.64 ± 6.34(0.09)	9.07 ± 6.41(0.16)	0.210	0.952	0.984
	Female	11.07 ± 7.18	10.93 ± 6.63(0.02)	12.00 ± 7.53(0.13)	11.14 ± 5.67(0.01)	8.46 ± 3.64	8.77 ± 5.48(0.09)	9.69 ± 4.46(0.34)	8.92 ± 7.61(0.13)	0.539	0.736	0.999
Depression Dejection	Overall	4.67 ± 4.92	5.67 ± 7.50(0.20)	6.15 ± 6.57(0.30)	4.89 ± 7.00(0.04)	4.89 ± 6.22	5.07 ± 6.88(0.03)	4.41 ± 4.65(0.08)	5.81 ± 7.04(0.15)	0.991	0.572	0.181
	Male	3.62 ± 4.23	5.08 ± 5.57(0.35)	6.77 ± 7.25(0.74)	6.00 ± 7.77(0.56)	5.79 ± 8.04	6.43 ± 7.95(0.08)	5.00 ± 5.90(0.10)	6.36 ± 6.98(0.07)	0.909	0.396	0.286
	Female	5.64 ± 5.46	6.21 ± 9.12(0.10)	5.57 ± 6.10(0.01)	3.86 ± 6.31(0.32)	3.92 ± 3.45	3.62 ± 5.45(0.09)	3.77 ± 2.89(0.04)	5.23 ± 7.35(0.38)	0.936	0.645	0.140
Fatigue Inertia	Overall	8.48 ± 6.06	7.85 ± 5.57(0.10)	8.41 + 5.54(0.01)	7.67 ± 5.55(0.13)	6.63 ± 3.41	6.70 ± 3.36(0.02)	6.93 ± 4.36(0.09)	7.15 ± 5.45(0.15)	0.742	0.791	0.635
	Male	6.62 ± 5.80	6.15 ± 5.27(0.08)	6.08 ± 4.31(0.09)	6.15 ± 4.88(0.08)	7.00 ± 3.49	6.50 ± 3.30(0.14)	6.57 ± 4.88(0.12)	6.36 ± 4.5(0.18)	0.993	0.911	0.977
	Female	10.21 ± 5.98	9.43 ± 5.54(0.13)	10.57 ± 5.81(0.06)	9.07 ± 5.93(0.19)	6.23 ± 3.42	6.92 ± 3.55(0.20)	7.31 ± 3.88(0.32)	8.00 ± 6.39(0.52)	0.629	0.429	0.377
Tension Anxiety	Overall	10.93 ± 7.69	10.11 ± 6.89(0.11)	11.15 ± 7.34(0.03)	10.15 ± 7.90(0.10)	9.89 ± 6.46	9.30 ± 6.31(0.09)	9.85 ± 6.50(0.01)	10.30 ± 8.31(0.06)	0.520	0.881	0.582
	Male	6.77 ± 5.28	7.31 ± 5.22(0.10)	8.23 ± 4.90(0.28)	8.38 ± 5.99(0.30)	9.43 ± 7.06	8.14 ± 6.21(0.18)	8.07 ± 6.11(0.19)	9.00 ± 6.97(0.06)	0.551	0.359	0.840
	Female	14.79 ± 7.69	12.71 ± 7.38(0.27)	13.86 ± 8.31(0.12)	11.79 ± 9.26(0.39)	10.38 ± 5.99	10.54 ± 6.41(0.03)	11.77 ± 6.58(0.23)	11.69 ± 9.63(0.22)	0.509	0.077#	0.579
Vigor Activity	Overall	19.1 ± 5.2	19.5 ± 5.5(0.08)	18.3 ± 5.6(0.15)	17.3 ± 5.3(0.35)	19.0 ± 5.7	19.2 ± 6.4(0.04)	17.2 ± 7.3(0.32)	17.9 ± 7.1(0.19)	0.008*	0.789	0.369
	Male	20.2 ± 5.7	20.9 ± 7.0(0.12)	20.4 ± 5.9(0.04)	18.3 ± 6.4(0.33)	19.6 ± 6.1	7.7 ± 6.0(1.95)	8.6 ± 6.3(1.8)	9.1 ± 6.4(1.72)	0.178	0.620	0.114
	Female	18.1 ± 5.0	17.6 ± 5.9(0.10)	16.4 ± 4.7(0.37)	16.4 ± 4.0(0.37)	16.5 ± 5.0	17.6 ± 5.9(0.22)	15.3 ± 7.1(0.24)	15.5 ± 7.2(0.20)	0.038*	0.355	0.964
Friendliness	Overall	16.9 ± 3.6	16.0 ± 3.4(0.25)	16.2 + 4.3(0.19)	15.3 ± 4.0(0.44)	17.9 ± 3.5	17.9 ± 3.7(0.00)	16.9 ± 4.1(0.29)	17.1 ± 3.9(0.23)	0.179	0.204	0.291
	Male	17.3 ± 4.3	16.1 ± 4.7(0.28)	16.7 ± 5.1(0.14)	15.1 ± 5.2(0.51)	17.6 ± 3.3	17.6 ± 3.9(0.00)	16.6 ± 3.4(0.30)	17.4 ± 3.5(0.06)	0.559	0.250	0.156
	Female	16.6 ± 3.0	15.9 ± 1.9(0.23)	15.6 ± 3.5(0.33)	15.6 ± 2.6(0.33)	18.1 ± 3.8	18.2 ± 3.6(0.03)	17.2 ± 4.9(0.24)	16.9 ± 4.5(0.32)	0.218	0.526	0.218

Data are presented as mean ± SD(d). All effect sizes (d) are compared back to Visit 2 (V2).

*Denotes p < 0.05.

#Denotes p < 0.1.

Table 8. Changes in missed productivity by group and sex.

Measure	Sex	CBD			Placebo			p-value
		V2 to V3	V3 to V4	V4 to V5	V2 to V3	V3 to V4	V4 to V5	Time	Group	Interaction
Missed Productivity	Overall	0 ± 0	0 ± 1	0 ± 0	0 ± 0	0 ± 1	0 ± 1	0.326	0.756	0.256
	Male	0 ± 0	0 ± 0	0 ± 0	0 ± 0	0 ± 0	0 ± 1	0.726	0.999	0.726
	Female	0 ± 1	0 ± 1	0 ± 1	0 ± 1	0 ± 1	1 ± 2	0.905	0.709	0.317

Data are presented as mean ± SD.

Table 9. Changes in subscales of foundational pain index by group and sex.

Measure	Sex	CBD				Placebo					p-value
		V2	V3	V4	V5	V2	V3	V4	V5	Time	Group	Interaction
Foundational Pain Index	Overall	11.9 ± 14.4	8.8 ± 11.7(0.22)	13.2 ± 10.4(0.09)	8.8 ± 10.9(0.22)	9.0 ± 14.2	14.4 ± 16.3(0.38)	15.6 ± 14.7(0.46)	12.9 ± 11.5(0.27)	0.116	0.028*	0.669
	Male	11.5 ± 16.8	8.9 ± 12.2(0.15)	13.7 ± 10.3(0.13)	10.7 ± 10.9(0.05)	4.7 ± 9.1	12.9 ± 17.2(0.90)	9.0 ± 13.3(0.47)	11.2 ± 12.7(0.71)	0.971	0.242	0.142
	Female	12.3 ± 12.3	8.7 ± 11.7(0.29)	12.7 ± 10.9(0.03)	6.9 ± 11.0(0.44)	14.0 ± 17.6	16.2 ± 15.7(0.13)	23.4 ± 12.7(0.53)	14.8 ± 10.2(0.05)	0.037*	0.023*	0.833

Data are presented as mean ± SD(d). All effect sizes (d) are compared back to Visit 2 (V2).

*Denotes p < 0.05.