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Published in final edited form as: Drug Alcohol Depend. 2020 Jun 18;213:108129. doi: 10.1016/j.drugalcdep.2020.108129

THC and CBD Blood and Brain Concentrations Following Daily Administration to Adolescent Primates

SL Withey 1, J Bergman 2, MA Huestis 3, SR George 4, BK Madras 5
PMCID: PMC7371526  NIHMSID: NIHMS1603641  PMID: 32593153

Abstract

Background:

Cannabis availability with high concentrations of Δ−9-tetrahydrocannabinol (THC) and a range of THC to cannabidiol (CBD) ratios has increased in parallel with a rise in daily cannabis consumption by adolescents. Unanswered questions in adolescents include: 1) whether THC blood concentrations and THC metabolites remain stable or change with prolonged daily dosing, 2) whether CBD modulates THC pharmacokinetic properties and alters THC accumulation in brain, 3) whether blood THC levels reflect brain concentrations.

Methods:

In adolescent squirrel monkeys (Saimiri boliviensis), we determined whether a four-month regimen of daily THC (1 mg/kg) or CBD (3 mg/kg) + THC (1 mg/kg) administration (IM) affects THC, THC metabolites, and CBD concentrations in blood or brain.

Results:

Blood THC concentrations, THC metabolites and CBD remained stable during chronic treatment. 24 h after the final THC or CBD+THC injection, blood THC and CBD concentrations remained relatively high (THC: 6.0 – 11 ng/mL; CBD: 9.7–19 ng/mL). THC concentrations in cerebellum and occipital cortex were approximately twice those in blood 24 h after the last dose and did not significantly differ in subjects given THC or CBD+THC.

Conclusions:

In adolescent monkeys, blood levels of THC, its metabolites or CBD remain stable after daily dosing for four months. Our model suggests that any pharmacological interactions between CBD and THC are unlikely to result from CBD modulation of THC pharmacokinetics. Finally, detection of relatively high brain THC concentrations 24 h after the final dose of THC suggests that the prolonged actions of THC may contribute to persistent cognitive and psychomotor disruption after THC- or cannabis-induced euphoria wane.

Keywords: cannabis, marijuana, cannabidiol, CBD, THC, pharmacokinetics, adolescent monkeys, THC brain, THC blood, CBD blood, CBD brain, THC metabolites, 11-OH-THC, THC-COOH

1. Introduction

The cannabis plant (Cannabis sativa) contains at least 140 cannabinoids (Hanuš et al., 2016), of which Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are particularly relevant to cannabis use. THC and CBD engender markedly different pharmacological effects in humans and animals. THC has reinforcing effects when examined under experimental conditions in primates (Justinova et al., 2003; Tanda et al., 2000) or humans (Hart et al., 2005). THC can also precipitate psychosis in humans (Murray et al., 2017, Hindley et al., 2020), promote or attenuate anxiety in rats, humans, humans (Fokos and Panagis, 2010; Hindley et al., 2020; Van Ameringen et al., 2020, respectively), and compromise cognition and motor coordination in humans (Broyd et al., 2016; Crean et al., 2011; Doss et al., 2018; Weinstein et al., 2008). The pharmacological effects of THC are largely attributed to its high affinity and partial agonist activity at the CB1 cannabinoid receptor. In contrast, CBD has little or no orthosteric activity at CB1 or CB2 receptors (McPartland et al., 2015) and CBD has no demonstrable abuse liability (Babalonis et al., 2017). Furthermore, CBD does not engender robust cognition-impairing effects in either human or non-human subjects (reviewed in Boggs et al., 2018), and may dose-dependently enhance or attenuate THC effects such as intoxication in humans (Solowij et al., 2019), or other adverse behavioral, biological and molecular responses elicited by THC in rodents, primates or humans (Boggs et al., 2018; Freeman et al., 2019; Hasbi et al., 2020; Morgan and Curran 2008; Schubart et al., 2011). Based on THC concentrations, the current potency of cannabis “flower” is increasing (20.6% THC), with the average potency of cannabis extracts and concentrates even greater (e.g. 68.7% THC, in Washington state samples, Smart et al., 2017). In high potency cannabis, CBD concentrations have declined substantially (Chandra et al., 2019), but consumption of CBD alone or CBD preparations with various CBD:THC ratios has risen (Leas et al., 2019; Madras, 2019). Research on interactive effects between these cannabinoids is lagging, especially in preparations in which CBD:THC ratios exceed 1:1.

These newly manufactured or strain-selected products are available without guidance or adequate information on their biological effects or dose-specific pharmacokinetic properties (Milman et al., 2011). This scarcity of data is noteworthy, especially in light of increased consumption of cannabis among youthful users (Johnston et al., 2020; Monitoring the Future, 2019). Human adolescents reportedly are more susceptible to the adverse consequences of cannabis (Barrington-Trimis et al., 2020; Mason et al., 2020; Wright et al., 2020), yet adolescent cannabis research lags far behind these new realities. Among the knowledge gaps of cannabis consumption in adolescents are the unknown pharmacokinetic and pharmacodynamic properties of THC alone or in combination with CBD in this vulnerable population. Filling this void is especially compelling, as adolescent-adult differences in pharmacokinetic properties have been reported for other drugs (Oh and Crean, 2015). To the best of our knowledge, no reports exist of whether blood concentrations of THC or THC metabolites fluctuate with prolonged daily use among adolescents (Bergamaschi et al., 2013; Karschner et al., 2012; Lindgren et al., 1981), or whether brain concentrations mirror blood concentrations and are relevant to impaired driving or cognition (Broyd et al., 2016; Grotenhermen et al., 2007; Hartman and Huestis, 2013; Ramaekers et al., 2006) or to the development of tolerance to the psychomotor and cognitive impairing effects of THC (Ramaekers et al., 2006, 2009). As CBD putatively mitigates some, but not all THC-induced effects in rodents, primates or humans (Boggs et al., 2018; Freeman et al., 2019; Haney et al., 2016; Hasbi et al., 2020), CBD conceivably modulates concentrations of THC or THC metabolites in adolescent blood or brain following long-term daily exposure.

To fill some of these gaps, we addressed these questions in a unique primate study, which to the best of our knowledge has not been performed previously either in adolescent humans or nonhuman primates. Nonhuman primates are more relevant for translation to human pharmacology than rodents, because of the marked differences in rodent and human THC pharmacokinetics, behavior and metabolism (Boggs et al., 2018). The study also circumvented the ethical barrier of conducting a placebo-controlled trial of daily adolescent exposure to high dose THC and the issue of accuracy in subject’s self-reported use of THC or CBD at unknown doses, dosing frequency, or poly-substance use.

Our study enabled access to brain tissue, rigorous control of dose and daily dosing regimen (Verrico et al., 2019). As daily use is rising among high school students (Johnston et al., 2020), it is a growing concern because frequency of use is correlated with adverse effects, such as psychotic symptoms (Di Forti et al., 2019). THC or THC combined with CBD were administered weekly at escalating doses, and then daily to previously drug-naïve adolescent squirrel monkeys for four months. We determined whether blood THC or metabolite concentrations fluctuated over time, whether blood and brain concentrations of THC were comparable, and whether CBD modulated blood and brain concentrations of THC when co-administered.

2. Materials and Methods

2.1. Subjects

12 adolescent (2 – 2.5 years) male squirrel monkeys (Saimiri boliviensis) were divided into three treatment groups (n=4) that received either 1 mg/kg THC, 3 mg/kg CBD: 1 mg/kg THC or vehicle according to the dosing regimen described below. All subjects were drug and experimentally naïve prior to this study. Subjects were individually housed in a temperature- and humidity-controlled vivarium with a 12-hour light/12-hour dark cycle (7 AM to 7PM) and had unlimited access to water in the home cage. Subjects were maintained at approximate free-feeding weights by post session feedings of a nutritionally balanced diet of high protein chow (Purina Monkey Chow, St Louis, MO). In addition, fresh fruit and environmental enrichment were provided daily. Subjects were maintained in a facility licensed by the U.S. Department of Agriculture. The experimental protocol for the present studies was approved by the Institutional Animal Care and Use Committee at McLean Hospital and were in accord with the Guidelines for the Care and Use of Mammals in Neuroscience and Behavioral Research Committee of the Institute of Laboratory Animals Resources, Commission on Life Sciences, National Research Council (National Research Council, 2011).

2.2. Dosing Regimen

Subjects were divided randomly into three treatment groups and varied equally between groups for home cage position (top/bottom, left/middle/right) and date of entry into the colony (first or second cohort). The three groups were treated with either THC, THC+CBD (1:3) or vehicle as described in figure 1. Doses were progressively increased over a three-week period where the animals received a low dose on a single day during week 1, an intermediate dose on a single day in week 2, and a high dose on a single day in week 3. The escalating weekly doses of THC were 0.1, 0.3 and 1.0 mg/kg, and the escalating weekly doses of CBD given in combination with THC were 0.3, 1.0 and 3.0 mg/kg, respectively. On day 1 of week 4, the animals began daily treatment with the high dose they experienced the previous week (1.0 mg/kg THC or 3.0 mg/kg CBD + 1.0 mg/kg THC) and daily injections continued for 114 or 117 days. Vehicle treated subjects received a single 20:20:60 injection mixture of 95% ethanol, polysorbate-80 (Tween-80; sigma-Aldrich, St Louis, MO) and saline on each of the weekly injection days in line with the drug treated subjects. Vehicle treated subjects received the first daily vehicle injection on day 1 of week 4 and daily injections continued for 114 or 117 days.

Figure 1.

Figure 1.

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Timeline of blood draws

2.3. Collection of Blood Samples

Femoral venous blood (>1.5 mL) was collected in 3 mL vacutainers containing potassium oxalate as an anticoagulant and sodium fluoride as a preservative. After blood collection, the vacutainers were immediately put on ice and stored at −20°C until analysis. Initial blood samples were collected three days after the final weekly injection and prior to daily administration. On day one, blood samples were collected 3 h after the first daily injection for each of the three groups (THC, THC+CBD, vehicle). Further blood samples were taken on day 50 and day 100 of daily treatment. The fifth and final blood sample was taken approximately 24 h after the last daily dose was administered.

2.4. Collection and Preparation of Brain Tissue for Assay

Approximately 24 h after the final daily dose all subjects were euthanized. Each of the subjects received an IM injection of ketamine (20 mg/kg) followed by 3.0 mL IV Beuthanasia-D (pentobarbital-based euthanasia solution). Brains were rapidly removed and bisected along the midline, the left hemisphere was dissected into distinct brain regions, and snap frozen over liquid nitrogen fumes. The occipital cortex and cerebellum were chosen for cannabinoid assays, for two reasons: (1) to accurately analyze cannabinoids in brain tissue, 250 mg of tissue was required. In squirrel monkey, both the cerebellum and occipital cortex are of relatively high weight and enabled collection of 250mg of tissue. (2) The density of CB1 receptors in the cerebellum is high, but moderate in the occipital cortex, enabling cannabinoid concentrations to be compared in brain regions with different CB1 receptor densities.

Brain regions were then stored at −80°C until use. Before samples were analyzed, brain regions were homogenized in dH2O at a concentration of approximately 250 mg/mL. Concentrations of cannabinoids were corrected for exact tissue weights after processing.

2.5. Quantification of THC, CBD, and THC metabolites 11-OH-THC and THCCOOH

Blood and brain analyses were performed by NMS Labs (NMS Labs, Horsham, PA) using High Performance Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS). Detailed methods are included as supplemental information (Supplementary material can be found by accessing the online version of this paper at http://dx.doi.org and by entering doi….). Detection limits of each compound were as follows: THC: 0.5 ng/mL, CBD: 0.1 ng/mL, 11-hydroxy-THC (11-OH-THC): 1 ng/mL, and 11-nor-9-carboxy-THC (THCCOOH): 5 ng/mL. CBD concentrations were not measured in brain tissue.

2.6. Drugs

THC and CBD were provided by the National Institute on Drug Abuse Supply Program (Rockville, MD). All drugs were prepared for administration in a 20:20:60 mixture of 95% ethanol, polysorbate-80 (Tween-80; sigma-Aldrich, St Louis, MO), and saline. All drug solutions were refrigerated and protected from light. Injections of drug or vehicle were prepared in volumes of 0.3 mL/kg body weight or less and administered in alternating thigh muscles (i.m.). The i.m. route of THC administration was chosen based on previous studies using i.m. THC and reports that THC administered to nonhuman primates via either i.v. or i.m. routes of administration elicit behavioral responses similar to humans (Evans and Wenger, 1992; Kamien et al., 1994; Winsauer et al., 1999, Jacobs et al., 2016, see also Adam et al., 2020).

2.7. Data Analysis

Data from four individual subjects in each treatment group is presented as mean ± SEM. Unpaired multiple t-tests were used to analyze differences between treatment groups at each time point.

3. Results

3.1. Blood cannabinoid concentrations prior to daily dosing

As expected, CBD, THC and its metabolites were not detected at any time point in subjects that received daily injections of vehicle. Vehicle control data are not included in graphs for clarity, but blood levels of all four compounds were 0 ng/mL at every time point. The mean concentration of CBD, THC and its metabolites, 11-OH-THC and THCCOOH were monitored in blood samples at various times after cannabinoid administration. Three days after the last of three weekly escalating injections of THC alone, blood THC and metabolites were below the limits of detection. In the CBD+THC group treated weekly with increasing doses, THC was detectable albeit at low concentrations, in one of four subjects 3 days after the last weekly dose (group average: 0.6 ± 0.5 ng/mL; Figure 2A), reflecting large individual differences in THC clearance rates. Also, in the CBD+THC group, CBD concentrations were quantifiable in all four subjects 3 days after the last weekly dose (1.3 ± 0.5 ng/mL, Figure 2B).

Figure 2.

Figure 2.

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Blood concentrations (ng/mL) of THC (A, top left), CBD (B, top right), 11-OH-THC (C, bottom left) and THCCOOH (D, bottom right) 3 h after daily injection of THC (1 mg/kg; filled bars) or CBD:THC (3 mg/kg + 1 mg/kg; shaded bars). Data shown as mean ± SEM.

3.2. Blood cannabinoid concentrations with daily THC or THC+CBD Dosing

The 4-month daily dosing regimen of THC (1 mg/kg) or CBD:THC (3:1 mg/kg) began seven days after the last weekly dose, with blood samples consistently taken 3 h after drug administration. On the first of daily THC (1 mg/kg) doses, THC Cmax was 44 ± 6.3 ng/mL and co-administration of CBD did not significantly affect blood THC Cmax (35 ± 4.7 ng/mL). On days 50 and 100, blood THC concentrations appeared to increase compared with day 1, but these differences were not statistically significant (Figure 2A). As anticipated, CBD was only detected in subjects administered CBD and assigned to the CBD:THC treatment group (Figure 2B). On day 1 of the daily treatment regimen, blood CBD concentrations were more variable (mean 92 ± 40 ng/mL), predominantly due to one individual subject, but individual differences stabilized thereafter (77 ± 16 ng/mL and 76 ± 8.2 ng/mL; days 50 and 100, respectively). On the first day of daily treatment, the active THC metabolite 11-OH-THC was significantly lower in the CBD+THC group than the THC group (3.4 ± 0.4 ng/mL vs. 5.8 ± 0.8 mg/mL, respectively; p=0.035; Figure 2C). By days 50 or 100, CBD did not significantly affect 11-OH-THC. On the first day of daily treatment, the inactive THC metabolite THCCOOH reached 8.8 ± 1.0 ng/mL in subjects treated with THC alone and co-administration of CBD did not significantly affect blood THCCOOH concentrations (8.0 ± 1.0 ng/mL; Figure 2D). On days 50 and 100, blood THCCOOH concentrations in the subjects treated with THC alone appeared to increase compared with the first day, but these differences were not statistically significant. In the subjects treated with CBD:THC, there was an insignificant increase in THCCOOH on day 100.

3.3. Brain and blood cannabinoid concentrations one day after final dose

Twenty-four h after the last daily dose, and just prior to euthanasia, blood samples were taken from THC- and CBD+THC-treated subjects (Figure 3). Following THC alone, mean THC concentrations (8.1 ± 1.2 ng/mL) were approximately 10 times higher than those of 11-OH-THC (0.6 ± 0.3 ng/mL). In CBD+THC-treated subjects, THC was detected in blood 24 h after the last dose (5.5 ± 0.6 ng/mL), as was CBD (13 ± 2.2 ng/mL), but THC metabolites were below detectable limits. To compare brain and blood concentrations of THC and whether CBD alters this dynamic, THC and its metabolites were measured in cerebellum (Moreno-Rius, 2019) and occipital cortex (Abbas et al., 2015). These regions were selected to compare a region that expresses high (cerebellum) and one that expresses moderate densities of the CB1 cannabinoid receptor. In THC treated subjects, THC was detected in both brain regions 24 h after the last dose. In cerebellum and occipital cortex, THC concentrations were 1.7 and 1.9 times higher (respectively) than in blood (cerebellum, 13.6 ± 3.9 ng/mL, ns; occipital cortex, 15.3 ± 2.0 ng/mL, p < 0.037 compared with blood concentrations). In CBD+THC-treated subjects, THC concentrations in cerebellum and occipital cortex were approximately twice the concentration detected in blood (11.4 ± 1.8; p = 0.053 and 12.0± 2.0; p = 0.052, respectively). THC metabolites were non-detectable in cerebellum and occipital cortex in all CBD+THC-treated subjects, and for all THC-treated subjects, with the exception of occipital cortex of one animal, in which the 11-OH-THC concentration was 1.3 ng/mL

Figure 3.

Figure 3.

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Blood and brain concentrations of THC (ng/mL) 24 h after last injection. Filled bars represent THC-treated subjects, shaded bars represent CBD:THC 3:1 treated subjects. Data shown as mean ± SEM. Cereb (Cerebellum), Occ Ctx (Occipital cortex).

To determine whether individual THC concentrations in brain were correlated with THC concentrations in blood at 24 h, individual data after the final daily injection were plotted for THC in cerebellum and occipital cortex against THC in blood (Figure 4). Blood and brain THC concentrations were negatively correlated in subjects treated with THC alone (r = −0.8443 [−0.9712 to – 0.3445; P = 0.0084]), but not in subjects that received CBD+THC (r = −0.3688 [−0.8520 to 0.4538]).

Figure 4.

Figure 4.

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Correlation of blood and brain concentrations of THC 24 h after final daily injections. Filled circles represent THC-treated subjects, circles with X represent CBD+THC treated subjects. Both cerebellum and occipital cortex concentrations are included for brain THC concentrations and are correlated to the respective blood concentration.

4. Discussion

Daily cannabis use is rising among adolescents, especially high THC content cannabis, along with consumption of CBD in oil-based cannabis extracts (Hoffenberg et al., 2019; Hamilton et al., 2019; Johnston et al., 2020). These upward trends continue even though human adolescents appear to be more vulnerable to the adverse effects of cannabis (Barrington-Trimis et al., 2020; Gobbi et al., 2019; Mashoon et al., 2019; Mason et al., 2020; Silins et al., 2014; Wright et al., 2020). As the pharmacokinetic properties of THC alone or combined with CBD in adolescents is unknown, the current study measured blood and brain distribution of a relatively high daily dose of THC and a high CBD:THC ratio in adolescent nonhuman primates.

The dose of THC selected (1 mg/kg) was based on the current percent dose of THC in a standard cannabis joint equivalent or CJE (Manthey et al., 2020) or 20.6% THC in a 0.26 – 0.32 g CJE. An average THC cigarette currently contains approximately 60 mg THC, equivalent to 0.85 mg/kg for a 70 kg person, notwithstanding THC bioavailability, which is driven by smoking efficiency, frequency and mode of delivery (Grotenhermen, 2003). THC vaping cartridges, a mode of cannabis consumption that is expanding in popularity (e.g. Washington state), deliver higher THC doses more efficiently (Davenport, 2019), with products averaging 366 mg of THC or approximately 5 mg/kg. Accordingly, THC doses in the current study, which at one time might have been considered high, fall within the current range of retail THC products. The CBD dose and ratio were based on a range of CBD doses or CBD:THC ratios in the retail market or administered experimentally to human subjects or nonhuman primates (Arndt and de Wit, 2017; Bonn-Miller et al., 2017; Hundal et al., 2018; McMahon, 2016; Morgan et al., 2018; Zuardi et al., 1993).

THC was not detectable in the blood of most subjects three days after the last of three weekly escalating doses. Blood THC was detected in only one subject co-administered CBD, highlighting the diverse THC pharmacokinetics among individuals. In naturalistic or laboratory human studies, pharmacokinetic processes are dynamic and affected by the route of administration, frequency and magnitude of drug exposure, period of abstinence, or individual differences in blood and oral fluids (Bergamaschi et al., 2013; Fabritius et al., 2013; Newmeyer et al., 2017). Within blood, approximately 90% of THC is localized to plasma and largely bound to plasma proteins, lipoproteins, albumin, with a smaller fraction compartmentalized in red blood cells (for review see Grotenhermen, 2003). However, the absence of blood THC in the present study is not an indicator of the absence of THC in other compartments. Smoking is the most common entry route in humans, with THC distributing to multiple compartments in the body (body fluids, fat and protein bound storage sites).

After initiation of daily dosing, blood sampling showed relative stability of blood THC and its two major metabolites over the course of 4 months. As blood THC and metabolite concentrations in frequent cannabis users reportedly are higher than in occasional users (Huestis et al., 1992), our THC stability data are germane to frequent or daily, rather than occasional users. In agreement with previous studies in monkey, human and monkey, respectively (Ginsburg et al., 2014; Hunt and Jones, 1980; Slikker et al., 1991), the stability of blood THC levels implies that pharmacokinetic tolerance does not develop. Accordingly, behavioral and functional tolerance that develops in frequent human cannabis users or in monkeys exposed to THC (Ramaekers et al., 2009, Verrico et al., 2019), is more likely a consequence of pharmacodynamic tolerance in humans (Huestis, 2007).

THC persisted in blood and brain for at least 24 hours after repeated daily use. Blood THC concentrations ranged from 6–11 ng/mL but were twice as high in cerebellum and occipital cortex. Brain-blood discrepancies reflect a challenge in establishing biometric standards for cannabis intoxication (Logan et al., 2018). In agreement with our data in adolescent primates, THC concentrations in human post-mortem brain were approximately 2–5 times higher than blood concentrations, and in several cases, THC was detectable in brain but not in blood (Mura et al., 2005). One case within this series showed that THC distribution in various brain regions was similar, except for higher concentrations in substantia nigra (“locus niger”), corpus callosum and spinal cord. Conceivably, the euphoriant/intoxicating effects of smoked cannabis, which peak within 1 h and subside by 4 h, require higher brain concentrations than concentrations that impair cognition or motor coordination. Residual pharmacological effects have been detected 12 h or longer after the intoxicating effects of cannabis waned, e.g. piloting in a flight simulator (Leirer et al., 1989), or in some, but not all, simulated driving experiments (Brands et al., 2019; Dahlgren et al., 2020). The relationship between THC presence or THC-induced neuroadaptive changes in human or nonhuman primate brain and behavioral, cognitive deficits, or CB1 cannabinoid receptor down-regulation after cessation are unknown (Bosker et al., 2013; Hasbi et al., 2020; Hirvonen et al., 2012). However, following exposure in adolescent rodents, THC has been reported to adversely influence brain biology and behavior long after it has cleared from the body (Hurd et al., 2019).

As CBD reportedly attenuates some, but not all THC-induced adverse effects and molecular adaptations in various species, including humans (Boggs et al., 2018; Freeman et al., 2019; Hasbi et al., 2020; Morgan et al., 2008; Schubart et al., 2011), we investigated CBD effects on THC pharmacokinetics. CBD did not significantly affect blood THC pharmacokinetics, except on the first day of daily treatment, when the active THC metabolite 11-OH-THC was lower in the CBD+THC treated subjects. With some exceptions in humans (van de Donk et al., 2019; Topp et al., 1976), and using different doses, ratios, routes of administration, others have not detected CBD modulation of THC blood pharmacokinetics in humans (Agurell et al., 1981; Karschner et al., 2011; Nadulski et al., 2005). Similar conclusions can be drawn from results in brain tissues. Twenty-four h after the final dose in subjects co-administered THC and CBD, THC concentrations in two brain regions were lower, but not significantly so, compared with animals administered THC alone. Distinctly opposite effects were reported in a rodent study, as THC concentrations were significantly higher in brain tissue if treated with THC and CBD, compared with THC treatment alone (Klein et al., 2011). This discrepancy may arise from species differences, doses or pretreatment with CBD instead of co-administration. The rodent study used higher THC doses (1–10 mg/kg, IP) and failed to detect CBD in the blood samples taken 30 and 50 mins after acute treatment with CBD and THC. Our findings indicate that the reported pharmacological interactions of these cannabinoids do not result from CBD modulation of THC distribution or metabolism. However, several features of the present work including the size and composition of the sample (previously drug-naïve males) as well as the study of a single CBD:THC ratio in the absence of other cannabis constituents, administered parenterally and assayed only in blood, indicates the need for further study to confirm the broad applicability of these findings.

5. Summary and conclusions.

In conclusion, results from adolescent nonhuman primates treated daily for four months with THC or CBD+THC (3:1) strongly suggest that THC and CBD have a long-lasting presence in blood, detectable at least 24 h after the final dose. Brain THC concentrations 24 h after the last dose were approximately twice as high as blood concentrations. Over the course of chronic treatment, concentrations of THC, CBD and THC metabolites remained relatively stable without any large excursions in blood concentrations. At the dose studied, CBD did not appear to attenuate or enhance THC concentrations in blood or THC entry into the brain. Blood concentrations of THC and CBD do not necessarily reflect brain concentrations, adding further complexity to the issue of accurately defining a legal THC limit based on blood analysis of either drug and or predicting the effects of THC on brain function from blood levels. Detection of relatively high brain THC concentrations 24 h after the final dose of THC may offer an underlying reason for persistent cognitive and psychomotor disruption long after the euphoriant effects of THC, or cannabis wane.

Supplementary Material

Supplementary Material

Highlights.

  • Adolescent primates dosed daily show stable THC, CBD blood levels for 4 months.

  • Pharmacokinetic tolerance does not develop to THC or CBD.

  • CBD did not modulate THC pharmacokinetics during daily dosing.

  • THC concentrations in brain were higher than blood 24 h after the final daily dose.

  • Prolonged presence of THC in brain may contribute to persistent behavioral disruption.

Acknowledgments:

The authors acknowledge the helpful assistance of Dr. Gabriele Chelini and Jessica Eisold.

Funding and Disclosure: This study was supported by NIH-NIDA grant R01 DA042178 (BKM).

Footnotes

Authors report no conflict of interests

Supplementary material can be found by accessing the online version of this paper at http://dx.doi.org and by entering doi: …

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