cbd oil for oral use

Oral Administration of Cannabis and Δ-9-tetrahydrocannabinol (THC) Preparations: A Systematic Review

2 Departments of Pharmacology, Therapeutics and Toxicology and Department of Psychiatry, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Spain; [email protected]

Ana Pilar Pérez-Acevedo

2 Departments of Pharmacology, Therapeutics and Toxicology and Department of Psychiatry, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Spain; [email protected]

Esther Papaseit

2 Departments of Pharmacology, Therapeutics and Toxicology and Department of Psychiatry, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Spain; [email protected]

Clara Pérez-Mañá

2 Departments of Pharmacology, Therapeutics and Toxicology and Department of Psychiatry, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Spain; [email protected]

Soraya Martin

Olga Hladun

2 Departments of Pharmacology, Therapeutics and Toxicology and Department of Psychiatry, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Spain; [email protected]

Adrià Siles

3 Pharmacy Department, Hospital Universitari Germans Trias i Pujol and Institut de Recerca Germans Trias (HUGTiP-IGTP), 08916 Badalona, Spain; [email protected]

Marta Torrens

2 Departments of Pharmacology, Therapeutics and Toxicology and Department of Psychiatry, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Spain; [email protected]

4 Drug Addiction Program, Institut de Neuropsiquiatria, Parc de Salut Mar and Institut Hospital del Mar de Recerca Mèdica (PSMAR-IMIM), 08003 Barcelona, Spain

Francesco Paolo Busardo

5 Department of Excellence-Biomedical Sciences and Public Health, Università Politecnica delle Marche, 60121 Ancona, Italy; [email protected]

Magí Farré

2 Departments of Pharmacology, Therapeutics and Toxicology and Department of Psychiatry, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Spain; [email protected]

Abstract

Background and objective: Changes in cannabis legalization regimes in several countries have influenced the diversification of cannabis use. There is an ever-increasing number of cannabis forms available, which are gaining popularity for both recreational and therapeutic use. From a therapeutic perspective, oral cannabis containing Δ-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is a promising route of administration but there is still little information about its pharmacokinetics (PK) effects in humans. The purpose of this systematic review is to provide a general overview of the available PK data on cannabis and THC after oral administration. Materials and Methods: A search of the published literature was conducted using the PubMed database to collect available articles describing the PK data of THC after oral administration in humans. Results: The literature search yielded 363 results, 26 of which met our inclusion criteria. The PK of oral THC has been studied using capsules (including oil content), tablets, baked goods (brownies and cookies), and oil and tea (decoctions). Capsules and tablets, which mainly correspond to pharmaceutical forms, were found to be the oral formulations most commonly studied. Overall, the results reflect the high variability in the THC absorption of oral formulations, with delayed peak plasma concentrations compared to other routes of administration. Conclusions: Oral THC has a highly variable PK profile that differs between formulations, with seemingly higher variability in baked goods and oil forms. Overall, there is limited information available in this field. Therefore, further investigations are required to unravel the unpredictability of oral THC administration to increase the effectiveness and safety of oral formulations in medicinal use.

1. Introduction

1.1. Cannabinoids

Cannabis is the most widely used illicit drug worldwide, only surpassed by alcohol and tobacco when also considering legal substances. Recent investigations have highlighted the therapeutic potential of cannabis, resulting in a resurgence of its consumption for medical purposes. Although cannabis continues to be used mostly for recreational purposes, people increasingly consume it to benefit from its therapeutic properties [1,2,3].

Δ-9-Tetrahydrocannabinol (THC) is the principal source of the psychoactive effects associated with cannabis use [3]. These effects result from the activity of THC as a partial agonist of the cannabinoid receptor CB1, which is primarily located in the central nervous system, and CB2, which is predominantly expressed in the peripheral tissues [4]. THC has observable effects on behavior, nociception, and appetite, as well as anti-inflammatory, antitumor, and antiemetic properties. THC is also responsible for the psychotropic effects and addictive and reinforcing properties of cannabis [5].

The other predominant component in the cannabis plant is cannabidiol (CBD), which is the primary cannabinoid in fiber-type hemps. Unlike THC, CBD does not have a direct effect on the receptors (CB1 and CB2) responsible for cannabis’ psychoactive effects [6,7,8], although recent evidence has demonstrated the negative allosteric activity of CBD on CB1 [9].

CBD is believed to attenuate THC’s psychotropic effects, thereby enhancing the safety (or safety profile) of cannabis products containing both cannabinoids. However, this interaction is not fully understood. Previous studies found that CBD does not alter THC’s subjective effects [10,11,12], but a recent study reported an increase in plasma THC concentration and a slight exacerbation of THC-induced impairment in the presence of CBD [13].

Other cannabinoids may play a role in the overall effects of cannabis, such as Δ-8-tetrahydrocannabinol, cannabinol (CBN), cannabicyclol (CBL), cannabichromene (CBC), and cannabigerol (CBG). However, these cannabinoids have fewer psychotropic effects than THC [14].

1.2. Therapeutic Uses of Cannabis

Cannabinoids exert most of their biological effects through interactions with the endocannabinoid system. Their wide range of effects makes cannabinoids good candidates for treating many ailments, including nausea, loss of appetite, neuropathic pain spasticity, epilepsy, chronic pain, etc. [5]. However, cannabinoids are currently typically prescribed as adjuvant treatments or after a patient does not respond well to first-line treatments.

The number of countries that have legalized therapeutic cannabis use (medical cannabis) has grown in recent years. In the Netherlands, the drastic increase in the prevalence of medical cannabis prescriptions can be explained by the emergence of new formulations, especially cannabis oils [15], which have become the preferred option for therapeutic use [16].

When considering the purpose of consumption, for medical cannabis users, edible cannabis is one of the most common consumption modes, along with vaporization [17,18,19], contrary to recreational users, who are more likely to smoke or vaporize [18].

1.3. Oral Cannabis and THC and other Routes of Administration

Recreational cannabis is mainly consumed by smoking, which involves combusting the herbal cannabis present in a joint, blunt, pipe, bubbler, or bong/water pipe, among other forms. The psychoactive effects of THC appear in less than a minute after consumption. From the limited evidence available, it appears that smoking cannabis may be associated with respiratory diseases, as smoked cannabis contains several toxins and carcinogens also found in tobacco smoke [20]. No country that has authorized the medical use of cannabis recommends smoking as a method of consumption.

An alternative inhalation-based form that has become popular in recent years is using a vaporizer. This technique is considered less noxious than regular smoking, as vaporizing does not produce the pyrolytic compounds derived from combustion of the dried herb or extract, such as polycyclic aromatic hydrocarbons. However, vaporizers have been recently associated with acute respiratory illness, now referred to as e-cigarette or vaping product-use associated lung injury (EVALI) [21,22]. The cause of this condition is currently under investigation, although there is evidence implicating the vitamin E acetate used as a diluent in vaporizer liquids [23].

Changes in cannabis legalization in several countries have influenced the emergence of a variety of edible products containing cannabis, which have increasing popularity. At present, edible products are now available in new formats resembling sugary snacks (hard and soft candies) and baked goods (brownies, cookies), which appeal especially to young people. From a therapeutic perspective, oral cannabis intake is promising due to its long-lasting drug effects, easy administration, and reduced toxicity derived from pyrolytic by-products. To date, the limited information available describes a slow and erratic absorption, seemingly showing higher bioavailability in oil formulations [24].

1.4. Oral Cannabinoid Preparations

Medical cannabis refers to a broad range of products and preparations that contain cannabis and cannabinoids for therapeutic purposes. Several medical products with marketing authorization contain THC as their main component, including dronabinol (synthetic THC), commercialized as oral capsules (Marinol ® ) or as an oral solution (Syndros ® ), and nabilone (a synthetic THC analogue), which is marketed as oral capsules (Cesamet ® or Canemes ® ). Nabiximols (Sativex ® ), available as a buccal spray, also includes CBD in its formulation [14,24,25,26]. However, few cannabis products have sufficient evidence to obtain approval for therapeutic use in the USA and several European countries.

Formulations derived from the Cannabis sativa plant that do not have marketing authorization for medical use are known as “cannabis preparations”. This term encompasses raw cannabis, compound preparations, and standardized cannabis preparations, which include cannabis flowers, granulates, and oil extracts [27].

In the Netherlands, cannabis is produced in five standardized strains that are commercially available and classified by their THC and CBD content [28]. In Italy, the Ministry of Health authorized the commercialization of standardized cannabis (FM2, 5–8% THC and 7–12% CBD) for medical purposes, which is produced by the Military Pharmaceutical Institute in Florence [29]. As per recommendations, this medical cannabis is consumed in decoctions or oils following standardized indications [30]. In 2018, a new strain of medical cannabis began production (FM1, 13–20% THC and <1% CBD), but no therapeutic indications are currently authorized for this new strain [31,32]. In Canada, medical cannabis is manufactured under a public license, mostly in the form of oil. Cannimed ® can be purchased as oil capsules, oil, dried flowers, or in a topical form, allowing oral, vaporized, or topical administration [33,34].

Edible cannabis is associated with a high rate of emergency department visits, mainly due to gastrointestinal symptoms, intoxication, and psychiatric effects [35]. The high variability of oral THC absorption and the delayed onset of effects can lead to the overconsumption of edible preparations, especially among naive users.

Considering that cannabinoids are proposed to alleviate a wide range of ailments, the identification and interpretation of their pharmacokinetics (PK) are essential for their use as pharmaceutical products. The purpose of this review was to examine the available data on THC PK after the oral administration of cannabis and THC, as reported in humans.

2. Materials and Methods

This systematic review was performed according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines [36].

Potential studies were systematically searched and identified by one of the authors (L.P.). The study selection was jointly conducted by two of the authors (L.P. and M.F.). After reading the summary of each study, in case of a disagreement, the final decision was reached by consensus. The data were collected by the author L.P. and reviewed by the other authors (M.F. and A.P.P.).

A search of the published literature was conducted using the PubMed database up to March 2020. The keywords used for the search were “oral cannabis”, “edible cannabis”, “oral THC”, “pharmacokinetic”, “blood collection”, “dronabinol”, “synthetic THC”, “plasma levels”, and “Cmax”. To be included, studies had to follow a pharmacokinetic model, include at least the maximum plasma concentration values (Cmax) and time needed to reach the maximum concentrations (Tmax) as PK parameters, and examine oral administration, although they could also include other routes of administration. Single-dose studies were preferred, but multiple-dose studies were included if the blood was collected at various time points following initial dosing. Only articles whose abstracts met our selected criteria were selected. Animal studies, articles focusing on routes of administration other than oral, nabilone (a synthetic cannabinoid), nabiximols, and studies of CBD administration were excluded from the review. Studies featuring the administration of nabiximols were only included if their preparations were compared to those of other oral cannabis/THC preparations.

Only articles written in English were selected. All articles were reviewed independently by the authors to determine their relevance in the framework of the current study.

The following data were collected from the reviewed articles: Design of the study, number of participants, gender, previous experience with cannabis, route of administration, product containing THC, dose of THC, basic PK measurements (maximum concentration, or Cmax, and time to achieve maximum concentrations, or Tmax) in plasma or blood, and pharmacological effects (if measured).

In order to evaluate a relationship between the administered dose and peak concentrations (Cmax), Spearman correlations were conducted between doses of THC and Cmax values in each formulation group. A linear regression procedure that allows for the calculation of correlation coefficients was used. Analyses were performed using GraphPad Prism 5.

3. Results

The literature search yielded a total of 363 results, 26 of which met our inclusion criteria ( Figure 1 ) [37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62]. These studies are summarized in Table 1 , Table 2 , Table 3 and Table 4 . Besides the oral administration route, cannabis was taken in by other routes in eight of the studies, including sublingual, respiratory/inhaled, buccal, intravenous, and oropharyngeal routes. THC can be present in various dosage forms, each with different PK properties, which are crucial to know for a molecule intended for therapeutic applications. The oral absorption of THC was studied using oil capsules, tablets, baked goods (brownies and cookies), oils, and decoctions. However, there was no information on other products containing cannabis, including candies and chocolates.

Flow chart for the study retrieval and selection.

Table 1

Summary of studies included in this systematic review reporting the pharmacokinetic parameters of Δ-9-tetrahydrocannabinol (THC) following capsule administration.

References Study Design Participants Route of Administration Formulation Dose Cmax (ng/mL)
Mean ± SD, Median (Range)
Tmax (h) Pharmacological Effects
Wall et al., 1983 [37] OL, NP 6 M, 6 F Oral Capsules 20 mg THC (men) Men Men Effects were not assessed.
THC: 14 ± 9.7 b THC: 2.5
11-OH-THC: 6.6 ± 3.4 b 11-OH-THC: 2.0
15 mg THC (women) Women Women
THC: 9.4 ± 4.5 b THC: 1.75
11-OH-THC: 5.9 ± 2.8 b 11-OH-THC: 1.75
Intravenous (infusion pump) Human serum albumin 4 mg THC (men) Men Men
THC: 71 ± 34 b THC: 0.42
11-OH-THC: 3.7 ± 2.3 b 11-OH-THC: 0.5
2.2 mg THC (women) Women Women
THC: 85 ± 26 b THC: 0.17
11-OH-THC: 3.8 ± 2.8 b 11-OH-THC: 0.33
Haney et al., 2003 [38] R, DB, P, C 7 M
Cannabis smokers
Oral Capsules (Marinol ® ) 30 mg THC29, Placebo naltrexone THC: 29.9 ± 9.5 b THC: 4 b Subjective effects
Increase in ratings of Good Drug Effect, High, and Stimulated.
Vital effects
Decreased HR.
Worsened psychomotor performance.
THC-COOH: 121.9 ± 43.5 b THC-COOH: 2 b
Oral Capsules (Marinol ® ) 30 mg THC
50 mg naltrexone
THC: 21.2 ± 8.6 b THC: 2 b
THC-COOH: 139.0 ± 36.2 b THC-COOH: 3 b
Naef et al., 2003 [39] R, DB, P, C 6 M, 6 F
Cannabis naïve
Oral Capsules (Marinol ® ) 20 mg THC THC: 7.2 ± 6.9 b, e THC: 1-2 b, e Subjective effects
Psychotropic and somatic side-effects were common but usually mild.
Paint tests
No significant reduction in pain.
11-OH-THC: 19.7 ± 6.9 b, e 11-OH-THC: 2 b, e
11-COOH-THC: 241.4 ± 73. b, e 11-COOH-THC: 2–4 b, e
Oral Capsules 20 mg THC
30 mg morphine HCl
THC: 6.7 ± 7.3 b, e
11-OH-THC: 7.9 ± 8.3 b, e
11-COOH-THC: 134.7 ± 65.12 b, e
Oral Capsules (placebo) 30 mg morphine HCl
Oral Capsules (placebo)
Guy et al., 2004 [40] R, OL, C
followed by an NR oral dose
6 M, 6 F
Previous experience of cannabis use
Oral Capsules 10 mg THC
10 mg CBD
THC: 6.35 ± 3.12 (3.04–4.55) THC: 1.05 ± 0.65 (0.5–2.75) Effects were not assessed.
CBD: 2.47 ± 2.23 (0.47–7.55) CBD: 1.27 ± 0.84 (0.5–3)
11-OH-THC: 7.87 ± 2.96 (4.79–13.64) 11-OH-THC: 1.36 ± 0.63 (0.75–3)
Sublingual Liquid spray (Sativex ® ) 10 mg THC
10 mg CBD
THC: 5.54 ± 3.35 (1.14–12.13) THC: 1.63 ± 0.59 (1–3)
CBD: 2.50 ± 1.83 (0.27–6.55) CBD: 1.63 ± 0.68 (0.75–3)
11-OH-THC: 6.24 ± 2.74 (2.67–10.77) 11-OH-THC: 1.58 ± 0.44 (1–2.75)
Buccal Liquid spray (Sativex ® ) 10 mg THC
10 mg CBD
THC: 6.14 ± 5.37 (0.88–19.78) THC: 2.40 ± 1.08 (1–4.5)
CBD: 3.02 ± 3.15 (0.29–9.91) CBD: 2.78 ± 1.31 (1–4.5)
11-OH-THC: 6.13 ± 2.88 (1.83–11.25) 11-OH-THC: 2.40 ± 1.17 (1–4.5)
Oro-pharyngeal Liquid spray (Sativex ® ) 10 mg THC
10 mg CBD
THC: 6.11 ± 4.00 (1.94–15.68) THC: 2.23 ± 1.52 (0.75–5)
CBD: 2.61 ± 1.91 (0.41–6.36) CBD: 2.04 ± 1.13 (0.75–5)
11-OH-THC: 6.45 ± 2.91 (2.95–13.49) 11-OH-THC: 2.40 ± 1.22 (1.25–5)
Menetrey et al., 2005 [41] See also Table 2 for results on capsules and decoction administration.
Nadulski et al., 2005 [42] DB, P, C 24 Oral Capsules 10 mg THC
5.4 mg CBD
THC: 4.05 (1.18–10.27) THC: 0.93 (0.55–2.08) Effects were not assessed.
CBD: 0.95 (0.30–2.57) CBD: 0.99 (0.5–2)
11-OH-THC: 4.88 (1.83–12.34) 11-OH-THC: 1.67 (0.62–2.17)
THC-COOH:35.46 (19.2–70.6) THC-COOH: 1.92 (1.08–3.83)
Oral Capsules 10 mg THC THC: 3.20 (0.67–7.99) THC: 1.06 (0.5–3.05)
11-OH-THC: 4.48 (1.12–11.14) 11-OH-THC: 1.5 (0.5–3.17)
THC-COOH: 32.9 (12.03–57.63) THC-COOH: 2.07 (0.62–3.92)
Oral Capsules Placebo
Goodwin et al., 2006 [43] See also Table 2 for results on capsules and oil administration.
Schwilke et al., 2009 [44] NR, OL, NP, MD 6 M
Daily smokers (positive in cannabinoids, smoked within the previous 24 h)
Oral Capsules (Marinol ® ) Escalating total daily doses (40-120 mg) for 7 days
First dose 20 mg THC
After 1st dose (single dose): After 1st dose: Effects were not assessed.
THC: 12.4 ± 3.4 THC: 2.8 (0.33)
11-OH-THC: 8.2 ± 2.0 11-OH-THC: 2.5 (0.18)
THC-COOH: 75.8 ± 9.4 THC-COOH: 3.3 (0.56)
Karschner et al., 2011 [45] R, DB, P, DD 6 M, 3 F
Cannabis smokers
Oral Capsules (dronabinol) 5 mg THC THC: 4.7 ± 0.9, 4.6 (1.4–10.4) THC: 3.2 ± 0.3, 3.1 (1.5–4.5) Effects were not assessed.
11-OH-THC: 3.0 ± 0.4, 2.6 (1.8–5.9) 11-OH-THC: 3.3 ± 0.4, 3.3 (1.5–5.6)
THC-COOH: 69.3 ± 17.6, 57.1 (15.9–179.7) THC-COOH: 4.4 ± 0.5, 4.3 (2.7–7.5)
Oral Capsules (dronabinol) 15 mg THC THC: 14.3 ± 2.7, 11.2 (3.3–28.5) THC: 3.4 ± 0.5, 3.4 (1.2–5.5)
11-OH-THC: 11.1 ± 2.0, 9.3 (3.6–19.5) 11-OH-THC: 3.4 ± 0.4, 3.6 (1.0–5.5)
THC-COOH: 133.6 ± 36.3, 102.1 (44.5–409.0) THC-COOH: 4.9 ± 0.5, 5.5 (2.4–7.5)
Sublingual Spray (Sativex ® ) 5.4 mg THC
5.0 mg CBD
THC: 5.1 ± 1.0, 5.1 (1.2–9.6) THC: 3.3 ± 0.3, 3.5 (1.2–4.5)
CBD: 1.6 ± 0.4, 1.2 (0.6–3.9) CBD: 3.7 ± 0.5, 3.6 (1.0–5.5)
11-OH-THC: 4.2 ± 0.7, 3.7 (2.1– 7.5) 11-OH-THC: 3.6 ± 0.6, 3.3 (1.0–7.5)
THC-COOH: 108.0 ± 30.5, 79.8 (19.1–281.6) THC-COOH: 4.4 ± 0.7, 4.5 (1.2–7.5)
Sublingual Spray (Sativex ® ) 16.2 mg THC
15.0 mg CBD
THC: 15.3 ± 3.4, 14.5 (3.2–38.2) THC: 4.0 ± 0.5, 4.5 (1.2–5.6)
CBD: 6.7 ± 2.0, 3.7 (2.0–20.5) CBD: 4.0 ± 0.5, 4.5 (1.2–5.6)
11-OH-THC: 8.4 ± 1.2, 7.6 (3.8–13.7) 11-OH-THC: 3.9 ± 0.5, 3.7 (1.2–5.6)
THC-COOH: 126.6 ± 25.9, 92.4 (55.9–304.1) THC-COOH: 4.8 ± 0.3, 5.0 (2.6–5.6)
Karschner et al., 2012 [46] NR, OL, NP, MD 10 M
Daily smokers (positive cannabinoids, smoked within the previous 24 h)
Oral Capsules (Marinol ® ) Escalating total daily doses (40-120 mg) for 7 days
Each dose of 20 mg THC
After 1st dose (single dose): After 1st dose: Effects were not assessed.
THC: 8.7 ± 4.8, 6.4 (4.1–17.5) THC: 3.0 ± 0.9, 3.0 (2.0–4.0)
11-OH-THC: 4.0 ± 2.1, 3.4 (1.8–7.8) 11-OH-THC: 2.8 ± 0.9, 3.0 (2.0–5.0)
THC-COOH: 38.4 ± 15.9, 36.6 (19.7–68.7) THC-COOH: 3.1 ± 1.0, 3.0 (2.0–5.0)
Martin-santos et al., 2012 [47] R, DB, P, C 16 M
Previous experience of cannabis use (less than 15 times in their lifetime)
Oral Capsules 10 mg THC THC: 0.67 ± 0.66 b
THC-COOH: ≈ 5.6 b, d
11-OH-THC: ≈ 0.73 b, d
THC: 2 h b Subjective effects
Significant changes in PANSS, anxiety (STAI-S), dysphoria (ARCI), sedation (VAMS, ARCI), and the level of subjective intoxication (ASI, ARCI).
Vital effects
Significant increase in HR
No significant differences in SBP and DBP.
Oral Capsules 600 mg CBD
Oral Capsules (placebo)
Eichler et al., 2012 [48] R, DB, C 9 M
Non smokers
Oral Capsules (Marinol ® ) 20 mg THC THC: 1.03 ± 1.65, 0.48 e, g THC: 1.06 ± 0.19, 1.0 e Subjective effects
Mild psychotropic effects, with no significant differences between treatments.
CBD: 0.00 ± 0.00, 0.0 e, g CBD: NA
11-OH-THC: 0.99 ± 0.63, 0.84 e, g 11-OH-THC: 1.67 ± 0.51, 2.0 e
THC-COOH: 7.13 ± 5.64, 7.61 e, g THC-COOH: 1.78 ± 0.96, 2.0 e
CBN: 0.64 ± 0.72, 0.37 e, g CBN: 1.06 ± 0.57, 1.0 e
Oral Capsules (extract from heated Herba Cannabis) 17.6 mg THC
27.8 mg CBD
THC: 0.42 ± 0.39, 0.25 e, g THC: 0.78 ± 0.27, 1.0 e
CBD: 0.30 ± 0.21, 0.27 e, g CBD: 0.83 ± 0.51, 0.5 e
11-OH-THC: 0.73 ± 0.69, 0.50 e, g 11-OH-THC: 1.44 ± 0.69, 2.0 e
THC-COOH: 5.81 ± 7.59, 3.46 e, g THC-COOH: 2.89 ± 1.05, 2.0 e
CBN: 0.60 ± 0.36, 0.56 e, g CBN: 0.94 ± 0.45, 1.0 e
Oral Capsules (extract from unheated Herba Cannabis) 10.4 mg THC
14.8 mg CBD
THC: 1.02 ± 0.78, 0.71 e, g THC: 1.17 ± 0.66, 1.0 e
CBD: 1.24 ± 0.87, 0.96 e, g CBD: 1.17 ± 1.17, 1.0 e
11-OH-THC: 0.57 ± 0.42, 0.50 e, g 11-OH-THC: 1.00 ± 0.42, 1.0 e
THC-COOH: 1.94 ± 1.11, 2.28 e, g THC-COOH: 2.11 ± 0.78, 2.0 e
CBN: 0.54 ± 0.30, 0.58 e, g CBN: 1.00 ± 0.42, 1.0 e
Lile JA et al., 2013 [49] B, P, C 4 M, 3 F
Only 5 completed all doses
Regular cannabis use
Oral Capsules (Marinol ® ) 15 mg THC THC: ≈5 d THC: 3 d Vital effects
Increase in HR.
SBP decreased after 30 mg dose but increased after 75 and 90 mg doses.
No changes in DBP.
Decrease in finger temperature.
Psychomotor performance
Worsened psychomotor performance.
11-OH-THC: ≈2-3 d 11-OH-THC: 3 d
Oral Capsules (Marinol ® ) 30 mg THC THC: ≈10 d THC: 3 d
11-OH-THC: ≈5 d 11-OH-THC: 3 d
Oral Capsules (Marinol ® ) 45 mg THC THC: ≈17–18 d THC: 2.5 d
11-OH-THC: ≈8–9 d 11-OH-THC: 2 d
Oral Capsules (Marinol ® ) 60 mg THC THC: ≈45 d THC: 3.5 d
11-OH-THC: ≈11 d 11-OH-THC: 3 d
Oral Capsules (Marinol ® ) 75 mg THC THC: ≈42–43 d THC: 4 d
11-OH-THC: ≈12–13 d 11-OH-THC: 4 d
Oral Capsules (Marinol ® ) 90 mg THC THC: ≈53 d THC: 4 d
11-OH-THC: ≈20 d 11-OH-THC: 4 d
Oral Capsules (placebo)
Parikh et al., 2016 [50] R, OL, C 51 MF
No cannabis use in the previous 90 days
Oral Oral solution (Dronabinol) 4.25 mg THC THC Replicate 1: 1.81 ± 1.26 THC Replicate 1: 1.50 (0.50–4.00) Effects were not assessed.
THC Replicate 2: 2.08 ± 1.30 THC Replicate 2: 1.00 (0.50–3.02)
11-OH-THC Replicate 1: 2.53 ± 1.38 11-OH-THC Replicate 1: 1.50 (0.75–4.00)
11-OH-THC Replicate 2: 3.01 ± 1.56 11-OH-THC Replicate 2: 1.50 (0.50–3.02)
Oral Capsules (Dronabinol) 5 mg THC THC Replicate 1: 2.20 ± 1.51
THC Replicate 2: 2.61 ± 1.69
11-OH-THC Replicate: 3.28 ± 1.78 11-11-OH-THC Replicate 2: 3.98 ± 2.51
THC Replicate 1: 1.00 (0.50–6.00)
THC Replicate 2: 1.50 (0.50–6.00)
11-OH-THC Replicate 1: 1.60 (0.75–6.00)
11-OH-THC Replicate 2: 1.50 (0.50–6.00)
Cherniakov et al., 2017 [51] OL, C 9 M
Not exposed within the previous 4 weeks
Sublingual Spray (Sativex ® ) 10.8 mg THC
10.0 mg CBD
THC: 1.8 ± 0.2 THC: 2 (1–4) Effects were not assessed.
CBD: 0.5 ± 0.1 CBD: 3 (1–5)
Oral THC-CBD-piperine-PNL capsule 10.8 mg THC
10.0 mg CBD
THC: 5.4 ± 0.01 THC: 1 (1–1.5)
CBD: 2.1 ± 0.4 CBD: 1 (0.5–1.5)

Abbreviations: Cmax, maximum concentration after administration; SD, standard deviations; R, randomized; NR, not-randomized; OL, open label; DB, double-blind; B, blind; P, placebo-controlled; NP, not placebo-controlled; C, crossover; DD, double-dummy; MD, multiple dose; M, male; F, female; THC, Δ-9 tetrahydrocannabinol; THCA, Δ-9-tetrahydrocannabinolic acid A; CBD, cannabidiol; CBDA, cannabidiolic acid; 11-OH-THC, 11-hydroxy-THC; THC-COOH, 11-nor-9-carboxy-THC; THC-COOH-gluc, THC–COOH–glucuronide; THCV-COOH, 11-nor-9-carboxy-tetrahydrocannabivarin; BP, blood pressure; SBP, systolic blood pressure; DBP, diastolic blood pressure; HR, heart rate; ARCI, Addiction Research Center Inventory; VAS, visual analogue scales; VAMS, visual analogue mood scale; PANSS, Positive And Negative Symptom Scale; STAI, State-Trait Anxiety Inventory; ASI, Addiction Severity Index. a Range corresponds to the range of Cmax. b The maximum value of the time-course of plasma THC. c , the median instead of mean. d , data deduced from a figure. e , the original values for values presented as the standard error or coefficient of variation of the mean have been transformed in the table to standard deviation. f , the mean values have been calculated from the values reported in the article. g , values converted from pmol/mL to ng/mL.

Table 2

Summary of studies included in this systematic review reporting the pharmacokinetic parameters for THC following oil or decoction administration.

References Study Design Participants Route of Administration Formulation Dose Cmax (ng/mL)
Mean ± SD, Median (Range)
Tmax (h) Pharmacological Effects
Menetrey et al., 2005 [41] R, DB, P, C 8 M
Occasional cannabis smokers
Oral Milk decoction 16.5 mg THC THC: 3.8 (1.5–8.3) b THC: 1 b Subjective effects
Prototypical effects of THC with a strong feeling of highness.
Vital effects
Slight to moderate conjunctival reddening.
Slight to moderate tachycardia
Increase of HR after decoction.
11-OH-THC: 4.7 (2.9–7.0) b 11-OH-THC: 1 b
THC-COOH: 27.8 (14.1–42.4) b THC-COOH: 4 b
Oral Milk decoction 45.7 mg THC THC: 8.4 (3.9–13.1) b THC: 1 b
11-OH-THC: 12.8 (3.4–24.7) b 11-OH-THC: 2.5 b
THC-COOH: 66.2 (29.0–99) b THC-COOH: 2.5 b
Oral Capsules (Marinol ® ) 20 mg THC THC: 2.8 (nd–5.6) b THC: 1 b
11-OH-THC: 3.9 (1.4–8.5) b 11-OH-THC: 4 b
THC-COOH: 27.8 (5.4–55.4) b THC-COOH: 5.5 b
Oral Decoction (placebo) 0.8 mg THC
Oral Capsules (placebo)
Goodwin et al., 2006 [43] R, DB, P, DD, MD (5 days) 6
Previous experience of cannabis use
Oral Hemp oil 0.39 mg THC/day (tablespoon) THC: 0 f (0.0–0.0) THC: 0.0 f (0.0–0.0) Subjective effects
Mild prototypical effects of THC.
Vital effects
No difference in BP, HR, and respiratory rate.
11-OH-THC: 0 f (0.0–0.0) 11-OH-THC: 0.0 f (0.0–0.0)
THC-COOH: 1.1 f (0.0–3.1) THC-COOH: 49.7 f (4.5–121)
Oral Capsules (hemp oil) 0.47 mg THC/day THC: 0.0 f (0.0–0.0) THC: 0.0 f (0.0–0.0)
11-OH-THC: 0.0 f (0.0–0.0) 11-OH-THC: 0.0 f (0.0–0.0)
THC-COOH: 1.4 f (0.0–2.6) THC-COOH: 65.3 f (11.0–107)
Oral Capsules (dronabinol) 7.5 mg THC/day THC: 1.5 f (0.6–3.8) THC: 57.6 f (6.5–107)
11-OH-THC: 1.6 f (0.0–2.6) 11-OH-THC: 85.9 f (1.5–107)
THC-COOH: 19.8 f (10.6–43.0) THC-COOH: 107 f (107–107)
Oral Hemp oil 14,8 mg THC/day THC: 2.1 f (0.7–6.1) THC: 56.5 f (9–107)
11-OH-THC: 1.7 f (0.0–5.6) 11-OH-THC: 28.6 f (6.5–107)
THC-COOH: 12.7 f (11.0–15.2) THC-COOH: 91.5 f (11.5–121)
Oral Placebo
Pellesi et al., 2018 [52] OL, C 6 M, 7 F
Patients with medication overuse headaches
Oral Decoction 1.85 ± 1.6 mg THC THC: 1.38 ± 0.75 THC: 1.28 ± 0.51 Subjective effects
Intensity of subjective effects was similar in both formulations. Increased drowsiness after cannabis oil administration.
Vital effects
No changes in BP and HR.
2.22 ± 0.66 mg THCA-A THCA: 48.92 ± 26.34 THCA: 1.22 ± 0.26
1.93 ± 1.17 mg CBD CBD: 4.39 ± 3.01 CBD: 0.56 ± 0.17
8.82 ± 2.02 mg CBDA CBDA: 74.61 ± 25.15 CBDA: 0.83 ± 0.35
Oral Oil 2.2 mg THC THC: 3.29 ± 1.39 THC: 1.28 ± 0.36
2.3 mg THCA-A THCA: 65.36 ± 20.40 THCA: 1.33 ± 0.35
2.4 mg CBD CBD: 3.14 ± 2.58 CBD:1 ± 0.25
4.4 mg CBDA CBDA: 55.03 ± 29.45 CBDA: 1.06 ± 0.3
Pichini et al., 2020 [53] NR, OL, NP
Pilot
1 M Oral Decoction 0.36 mg THC
1.6 mg THCA-A
0.42 mg CBD
4 mg CBDA
Blood Blood Effects were not reported.
THC: 1.0 THC: 2.0
THCA-A: 72.4 THCA-A: 2.0
CBD: 1.5 CBD: 3.0
CBDA: 94.3 CBDA: 0.5
11-OH-THC: 1.2 11-OH-THC: 2.0
THC-COOH: 17.1 THC-COOH: 3.0
THC-COOH-GLUC: 40.2 THC-COOH-GLUC: 4.0
Oral fluid Oral fluid
THC: 0.2 THC: 0.5
THCA-A: 5.1 THCA-A: 0.5
CBD: 0.8 CBD: 0.5
CBDA: 145.2 CBDA: 0.5
Oral Oil 0.95 mg THC
1.5 mg THCA-A
0.86 mg CBD
2.8 mg CBDA
Blood Blood
THC: 0.5 THC: 2.0
THCA: 40.3 THCA-A: 2.0
CBD: 0.3 CBD: 2.0
CBDA: 32.4 CBDA: 1.5
11-OH-THC: 0.7 11-OH-THC: 2.0
THC-COOH: 4.3 THC-COOH: 2.0
THC-COOH-GLUC: 7.7 THC-COOH-GLUC: 3.0
Oral fluid Oral fluid
THC: 0.2 THC: 2
THCA: 1.0 THCA-A: 2
CBD: 0.6 CBD: 2
CBDA: 14.3 CBDA: 1

For abbreviations see Table 1 .

Table 3

Summary of studies included in this systematic review reporting the pharmacokinetic parameters of THC following tablet administration.

References Study Design Participants Route of Administration Formulation Dose Cmax (ng/mL)
Mean ± SD, Median (Range)
Tmax (h) Pharmacological Effects
Timpone et al., 1997 [54] R, OL 7 M/F
4 M/F
9 M/F
Patients with HIV wasting syndrome
Oral Tablets (Marinol ® ) 2.5 mg THC Data from all 20 patients Data from all 20 patients Subjective effects
Increase in VAS for hunger.
No differences in VAS for mood and nausea.
Oral Tablets (Marinol ® ) 2.5 mg THC
750 mg megestrol
THC: 2.01 c (0.58–12.48) THC: 2.07 b (0.66–8.26)
Oral Tablets (Marinol ® ) 2.5 mg THC
250 mg megestrol
11-OH-THC: 4.61 c (0.52–37.5) 11-OH-THC: 2.07 b (0.49–8.00)
Klumpers et al., 2011 [55] R, DB, DD, P, C 4 M, 5 F
(in panel 1, 13 subjects)
Previous experience of cannabis use (maximum 1 use per week)
Sublingual Tablets (Namisol ® ) 5.0 mg THC 2.30 ± 1.01 e 1.24 ± 0.65 e Subjective effects
Highest oral doses increased body sway and VAS for calmness, external perception, and feeling high and decreased VAS for alertness.
Vital effects
No significant differences in PD parameters between oral and sublingual administration.
Significant increase in HR.
Oral Tablets (Namisol ® ) 5.0 mg THC 2.92 ± 1.49 e 0.93 ± 0.68 e
Oral Tablets (Namisol ® ) 6.5 mg THC 4.43 ± 1.86 e 0.66 ± 0.13 e
Oral Tablets (Namisol ® ) 8.0 mg THC 4.69 ± 2.91 e 0.73 ± 0.19 e
Oral Tablets (placebo)
Ahmed et al., 2014 [56] R, DB, P, DD, C 6 M, 5 F Oral Tablets (Namisol ® ) 3 mg THC 1.42 (0.53–3.48) 0.92 (0.67–0.92) Subjective effects
No subjective effects (exc. 4 subjects “felt high”)
Vital effects
Mild PD effects.
No changes in SBP, DBP, and HR.
Psychomotor performance
No changes in psychomotor performance.
Oral Tablets (Namisol ® ) 5 mg THC 3.15 (1.54–6.95) 0.92 (0.67–0.92)
Oral Tablets (Namisol ® ) 6.5 mg THC 4.57 (2.11–8.65) 0.67 (0.67–0.92)
Oral Tablets (placebo)
De Vries et al., 2016 [57] R, DB, P, C 15 M, 9 F
Patients diagnosed with chronic pancreatitis
No cannabis use in previous year
Oral Tablets (Namisol ® ) 8 mg THC THC: 4.01 ± 3.39 2.05 + 1.47 Subjective effects
No differences in subjective effects (alertness, mood, calmness, or balance) between treatments. Anxiousness, somnolence, dry mouth, dizziness, and euphoric mood after THC administration.
Vital effects
No changes in SBP and DBP. THC induced an increase in HR compared to diazepam.
11-OH-THC: 4.38 ± 1.50 2.26 ± 1.29
Oral Tablet (active placebo) 5 mg diazepam to non-opioid group/10 mg diazepam to opioid group

For abbreviations see Table 1 .

Table 4

Summary of studies included in this systematic review reporting the pharmacokinetic parameters for THC following baked goods’ administration.

References Study Design Participants Route of Administration Formulation Dose Cmax (ng/mL)
Mean ± SD, Median (Range)
Tmax (h) Pharmacological Effects
Ohlsson et al., 1980 [58] R, OL, NP, C 11 M
Previous experience of cannabis use (from infrequent to frequent use)
Smoked Cigarette 19 mg THC (ad libitum) (mean = 13.0 mg) 77, 33–118 a Subjective effects
Increase in high effect.
Vital effects
Increase in HR.
Conjunctival reddening
Oral Chocolate cookie 20 mg THC 4.4–11 a 1–1.5
Intravenous Normal saline ethanolic solution 5 mg THC 219, 161–316 a
Watchel et al., 2002 [59] DB, P, C 7 M, 5 F
7 M, 6 F
Previous experience of cannabis use
Oral Cannabis (plant) brownie 8.4 mg THC ≈ 4.1 b, d 3 b, d Subjective effects
Both drugs increased VAS sedation and ARCI PCAG scale scores, and decreased the ARCI BG scale scores at higher doses.
Cannabis in high doses increased VAS for sedation, drowsiness, and tiredness.
THC in high doses increased ARCI A scale scores, MBG (euphoria), and LSD (dysphoria).
Vital effects
No effects on physiological or behavioral measures.
Oral Cannabis (plant) brownie 16.9 mg THC ≈ 6.8 b, d 2.5 b, d
Oral THC (synthetic) brownie 8.4 mg THC ≈ 4.8 b, d 2.5 b, d
Oral THC (synthetic) brownie 16.9 mg THC ≈ 9 b, d 2.5 b, d
Smoked Cannabis (plant) cigarette 8.4 mg THC ≈ 36 b, d 0.08 b, d
Smoked Cannabis (plant) cigarette 16.9 mg THC ≈ 60 b, d 0.08 b, d
Smoked THC (synthetic) cigarette 8.4 mg THC ≈ 31 b, d 0.08 b, d
Smoked THC (synthetic) cigarette 16.9 mg THC ≈ 56 b, d 0.08 b, d
Oral Brownie (placebo)
Smoked Cigarette (placebo)
Newmeyer et al., 2016 [60] R, DB, P, DD, C 9 M, 2 F frequent smokers
6 M, 3 F occasional smokers
Oral Brownie 50.6 mg THC (ad libitum)
1.5 mg CBD
3.3 mg CBN
Frequent smokers Frequent smokers Effects were not described.
THC: 15.3, 14.3 (1.4–32.4) THC: 2.5, 2.5 (1.5–3.5)
11-OH-THC: 7.3, 6.2 (0.9–13.7) 11-OH-THC: 2.3, 2.5 (1.5–3.5)
THC-COOH: 36.4, 35.3 (4.3–99.4) THC-COOH: 2.7, 2.5 (2.5–3.5)
THCV-COOH: 2.1, 2.0 (1.1–3.4) THCV-COOH: 3.0, 3.0 (2.5–3.5)
THC-COOH-gluc: 53.0, 57.1 (10.3–75.7) THCOOH-gluc: 3.4, 3.5 (1.5–5.0)
Occasional smokers Occasional smokers
THC: 10.3, 10.1 (3.6–22.5) THC: 2.3, 2.5 (1.5–3.5)
11-OH-THC: 5.5, 5.1 (2.4–11.0) 11-OH-THC: 2.4, 2.5 (1.5–3.5)
THC-COOH: 39.8, 37.8 (12.5–70.4) THC-COOH: 2.9, 3.5 (1.5–3.5)
THCV-COOH: 1.9, 1.9 (1.1–2.7) THCV-COOH: 2.6, 2.5 (1.5–3.5)
THC-COOH-gluc: 124, 124 (70.9–178) THC-COOH-gluc: 4.7, 5.0 (3.5–5.0)
Smoked Cigarette 50.6 mg THC (ad libitum)
1.5 mg CBD
3.3 mg CBN
Frequent smokers Frequent smokers
THC: 151, 114 (51.6–467) THC: 0.12, 0.13 (0.00–0.17)
11-OH-THC: 9.0, 6.5 (1.9–30.2) 11-OH-THC: 0.21, 0.20 (0.10–0.50)
THC-COOH: 23.5, 20.0 (5.7–64.9) THC-COOH: 0.28, 0.25 (0.00–0.50)
THCV-COOH: 2.4, 2.4 (1.8–3.1) THCV-COOH: 0.22, 0.23 (0.17–0.25)
THC-COOH-gluc: 25.8, 14.1 (5.0–70.7) THC-COOH-gluc: 1.1, 0.5 (0.0–3.5)
Occasional smokers Occasional smokers
THC: 51.6, 44.4 (1.3–174) THC: 0.11, 0.10 (0.07–0.17)
11-OH-THC: 2.8, 1.9 (0.5–8.7) 11-OH-THC: 0.22, 0.19 (0.10–0.50)
THC-COOH: 8.4, 7.4 (0.7–17.5) THC-COOH: 0.31, 0.25 (0.10–0.50)
THCV-COOH: – THCVCOOH: –
THC-COOH-gluc: 19.4, 21.4 (11.8–25.0) THC-COOH-gluc: 2.1, 1.5 (1.5–3.5)
Inhaled Vaporizer Volcano 50.6 mg THC (ad libitum)
1.5 mg CBD
3.3 mg CBN
Frequent smokers Frequent smokers
THC: 84.7, 83.1 (23.5–169) THC: 0.09, 0.10 (0.03–0.17)
11-OH-THC: 4.8, 4.2 (1.6–9.8) 11-OH-THC: 0.19, 0.17 (0.10–0.50)
THC-COOH: 13.0, 12.5 (4.1–31.3) THC-COOH: 0.25, 0.25 (0.13–0.50)
THCV-COOH: 1.7, 1.8 (1.2–2.1) THCV-COOH: 0.52, 0.21 (0.17–1.5)
THC-COOH-gluc: 10.9, 10.6 (0.8–23.8) THC-COOH-gluc: 1.8, 1.5 (0.03–3.5)
Occasional smokers Occasional smokers
THC: 47.8, 34.8 (5.2–137) THC: 0.11, 0.10 (0.03–0.17)
11-OH-THC: 2.0, 1.6 (0.7–3.5) 11-OH-THC: 0.15, 0.15 (0.10–0.20)
THC-COOH: 7.2, 5.3 (1.4–15.9) THC-COOH: 0.33, 0.25 (0.20–0.50)
THCV-COOH: – THCV-COOH: –
THC-COOH-gluc: 15.1, 16.1 (5.3–23.7) THC-COOH-gluc: 1.9, 2.5 (0.5–2.5)
Oral Brownie (placebo)
Smoked Cigarette (placebo)
Inhaled Vaporizer (placebo)
Newmeyer et al., 2017 [61] Optional dosing session under the same clinical protocol followed in Newmeyer et al., 2016 9 M frequent smokers
5 M, 2 F occasional smokers
Oral Brownie 50.6 mg THC
1.5 mg CBD
3.3 mg CBN
(ad libitum)
Frequent smokers Frequent smokers Effects were not assessed.
Blood Blood
THC: 16.2, 12.8 (5.3–34.6) THC: 2.5, 3.5 (1.0–3.5)
11-OH-THC: 58.4, 50.0 (27.8–152) 11-OH-THC: 2.8, 3.5 (1.0–3.5)
THC-COOH: 58.4, 50.0 (27.8–152) THC-COOH: 3.3, 3.5 (1.5–3.5)
THCV-COOH: 1.9, 1.6 (1.1–3.9) THCV-COOH: 3.1, 3.5 (1.5–3.5)
THC-COOH-gluc: 68.5, 61.2 (50.6–110) THC-COOH-gluc: 4.8, 5.0 (3.5–8.0)
Oral fluid Oral fluid
THC: 573, 464 (39.3–2111) THC: 0.33
11-OH-THC: 0.6, 0.7 (0.2–1.2) 11-OH-THC: 0.40, 0.33 (0.33–1.0)
THC-COOH: 285, 186 (123–849) THC-COOH: 12, 5 (3.5–48)
THCV-COOH: 7.4, 6.8 (1.3–19.4) THCV-COOH: 0.33
Occasional smokers Occasional smokers
Blood Blood
THC: 8.2, 8.6 (3.2–14.3) THC: 2.2, 1.5 (1.0–5.0)
11-OH-THC: 5.6, 5.2 (4.1–8.6) 11-OH-THC: 2.6, 3.5 (1.5–3.5)
THC-COOH: 39.7, 38.2 (26.5–61.2) THC-COOH: 3.2, 3.5 (1.5–3.5)
THCV-COOH: 1.6, 1.6 (1.1–2.1) THCVCOOH: 2.3, 1.5 (1.0–3.5)
THC-COOH-gluc: 86.2, 73.5 (43.1–183) THCOOH-gluc: 4.6, 5.0 (3.5–6.0)
Oral fluid Oral fluid
THC: 362, 392 (115–696) THC: 0.33
11-OH-THC: 0.4, 0.4 (0.3–0.6) 11-OH-THC: 0.60, 0.33 (0.33–1.5)
THC-COOH: 315, 191 (27.9–1263) THC-COOH: 10, 10 (0.33–20)
THCV-COOH: 5.4, 4.7 (1.6–10.6) THCV-COOH: 0.33
Vandrey et al., 2017 [62] R, DB, NP 9 M, 9 F
Previous experience of cannabis use but not exposed within the previous 3 months
Oral Brownie 10 mg THC Blood Blood Subjective effects
Significant subjective and cognitive drug effects at the 25 and 50 mg doses.
Vital effects
Significant PD effects.
Psychomotor performance
Significant effects on psychomotor performance at the 25 and 50 mg doses.
THC: 1.0 (0–3) THC: 0.9 (0–2)
11-OH-THC: 1.0 (0–2) 11-OH-THC: 1.3 (0–3)
THC-COOH: 7.2 (5–14) THC-COOH: 3.2 (2–4)
Oral fluid Oral fluid
THC: 191.5 (47–412) THC: 0.2 (0.2–0.5)
THC-COOH: 0.051 (0–0.231) THC-COOH: 1.0 (0–3)
Oral Brownie 25 mg THC Blood Blood
THC: 3.5 (3.0–4) THC: 2.6 (1.0–4)
11-OH-THC: 3.3 (2–5) 11-OH-THC: 3.0 (1.5–4)
THC-COOH: 21.3 (12–39) THC-COOH: 3.3 (1.5–6)
Oral fluid Oral fluid
THC: 477.5 (70–1128) THC: 0.2 (0.2–0.5)
THC-COOH: 0.140 (0.023–0.251) THC-COOH: 9.8 (3–30)
Oral Brownie 50 mg THC Blood Blood
THC: 3.3 (1.0–5) THC: 2.3 (1.0–6)
11-OH-THC: 3.2 (2–4) 11-OH-THC: 1.8 (1–3)
THC-COOH: 29.3 (16–44) THC-COOH: 3.3 (1.5–6)
Oral fluid Oral fluid
THC: 597.5 (350–1010) THC: 0.2 (0.2–0.5)
THC-COOH: 0.314 (0–0.822) THC-COOH: 17.4 (0–54)

For abbreviations, see Table 1 .

Overall, these studies showed remarkable heterogeneity in their designs and the conditions under which they were conducted. Most studies included small sample sizes, and not all of them included subjects of both genders. There were also discrepancies in the cannabis experience levels of the participants and their health statuses, since patients with diverse pathologies (HIV, chronic pancreatitis, and medication overuse-related headaches) were targeted in several studies. Most of the studies involved THC administration alone, although THC was administered in combination with CBD in eight studies. Apart from other cannabinoids, THC was also administered combined with other drugs, such as megestrol acetate, naltrexone, and morphine.

Some studies included evaluations of physiological and/or subjective effects after administration of the different preparations. THC/cannabis was found to produce its prototypical effects, presenting mild changes in blood pressure or heart rate, increases in scores of high and positive effects, increased feelings of sedation/drowsiness, and mild impairment of psychomotor performance. See Table 1 , Table 2 , Table 3 and Table 4 for detailed descriptions of these effects in different studies according to various formulations.

3.1. Capsules

Cannabis capsules usually contain cannabis or synthetic THC (dronabinol) in oil due to its higher bioavailability (see also the oil section). In our search, 14 studies investigated cannabis/THC/dronabinol administration dissolved in oil capsules, thus representing the most frequently studied dosage form among all oral formulations [37,38,39,40,41,42,43,44,45,46,47,48,49,50].

The dose of THC contained in the oil capsules in single-dose studies ranged from 5 to 90 mg. The Cmax in plasma ranged from 0.42 to 29.9 ng/mL, and the Tmax ranged from 0.78 to 4 h. PK differences were examined after administering the same cannabinoid doses (10.8 mg of THC and 10.0 mg of CBD) using THC and CBD-piperine-pro-nanolipospheres (THC-CBD-PNL) capsules, which are an alternative to oil capsules, and an oromucosal spray (Sativex ® ). THC-CBD-PNL produced a three-fold increase in Cmax compared to Sativex ® (5.4 and 1.8 ng/mL of THC, respectively) and a faster absorption of cannabinoids (a Tmax of 1 h and 2 h for THC and of 1 h and 2 h for CBD, respectively) [51]. See Table 1 for the specific results.

The correlation between the administered dose and Cmax resulted in a Pearson’s r value of 0.9271 and a coefficient of determination (R 2 ) of 0.8596 ( Table 5 , Figure 2 ). The THC Cmax increased proportionally by increasing the doses of THC.

The correlation between the dose of administered THC and the maximum concentration (Cmax) of THC in plasma following administration of capsules (a), decoctions (b), oils (c), tablets (d), and baked goods (e).

Table 5

Correlation between doses of THC and the maximum plasma concentration (Cmax) values in each formulation group.

Capsules Decoction Oil Tablets Baked Goods
Pearson’s r 0.9271 0.9997 0.3806 0.9178 0.6365
95% confidence interval 0.8492 to 0.9656 0.9851 to 1.000 −0.9154 to 0.9824 0.6032 to 0.9853 0.09838 to 0.8866
p value (two-tailed) <0.0001 0,0003 0.6194 0.0013 0.0261
R 2 0.8596 0.9994 0.1448 0.8423 0.4051

3.2. Oil

In previous studies, oil extracts showed greater cannabinoid extraction efficiency than water [31]. In addition to a higher bioavailability, oil formulations are considered suitable solvents to compose a THC therapeutic preparation. In this section, we only considered the administration of oil-based cannabis (see above for capsules containing oil). Only three studies were found in which oil was directly ingested [43,52,53]. Among these three studies, only two reported single-dose administrations. In one of these studies, subjects received 2.2 mg of THC and 2.3 mg of Δ-9-tetrahydrocannabinolic acid A (THCA-A), obtaining a Cmax of 3.29 and 65.36 ng/mL, respectively, and a Tmax of 1.28 and 1.33 h in plasma [52]. The other study reported data on one healthy individual treated with a cannabis decoction and oil (pilot study). The subject received 0.45 mL of oil containing 0.95 mg of THC, 1.5 mg of THCA-A, 0.86 mg of CBD, and 2.8 mg of cannabidiolic acid (CBDA). The THC and THCA-A Cmax in serum following oil administration were 0.5 and 40.3 ng/mL, respectively, with a Tmax of 2.0 h for both cannabinoids [53]. See Table 2 for the specific results.

In this formulation, among the three studies included, the administered dose of THC showed a weak and not significant correlation with the Cmax (Pearson’s r = 0.3806, p value = 0.6194) ( Table 5 , Figure 2 ).

3.3. Decoctions

Decoctions are also called “tea” in several articles. Only three studies examining cannabinoid PK after cannabis decoction administration were retrieved, including one study with a milk decoction [41,52,53]. For the milk decoction, two doses were selected—a low THC dose of 16.5 mg and a high dose of 45.7 mg, achieving a Cmax of 3.8 and 8.4 ng/mL, respectively, and a Tmax of 1 h in plasma for both doses [41]. In another study, cannabis was boiled in water, obtaining a decoction composed of 1.85 mg THC and 2.22 mg of THCA-A. After consumption of this decoction, the THC reached a mean Cmax of 1.38 ng/mL with a Tmax of 1.28 h, whereas THCA-A reached a mean Cmax of 48.92 ng/mL in plasma with a Tmax of 1.22 h [52]. In the pilot study mentioned in the Oil section, the subject received 100 mL of a cannabis decoction containing 0.36 mg of THC, 1.6 mg of THCA-A, 0.42 mg of CBD, and 4 mg of CBDA. This oral dose resulted in a Cmax in the serum of 1.0 ng/mL of THC and 72.4 ng/mL of THCA-A, with a Tmax of 2.0 h [53]. See Table 2 for the specific results.

Despite the few studies found, cannabis decoctions showed a significant strong correlation between the dose of THC and peak plasma, with a Pearson’s r of 0.9997 and a correlation coefficient of >0.99 ( Table 5 , Figure 2 ).

3.4. Tablets

Like oral capsules, tablets are also a stable dosage form that is considered practical for patient use. Four studies were retrieved. Two of them focused on Namisol, a patented tablet formulation of pure THC under investigation [54,55,56,57]. The PK data for THC doses varied from 2.5 to 8 mg, producing a Cmax of 1.42–4.69 ng/mL and a Tmax of 0.66–2.07 h in plasma. See Table 3 for the specific results.

Tablet administration showed a strong correlation between the administered THC dose and the Cmax, with a Pearson’s r of 0.9178 and a correlation coefficient of 0.8423 ( Table 5 , Figure 2 ).

3.5. Baked Goods

Five studies evaluated the THC PK after brownie or cookie consumption [38,40,58,59,61]. The THC doses in these edibles ranged from 8.4 to 50.6 mg, resulting in a Cmax of 1–16.2 ng/mL and a Tmax of 0.9–2.6 h in plasma. See Table 4 for specific results.

Brownies and cookies showed a weaker correlation between the dose of THC and the Cmax compared to other formulations, resulting in a Pearson’s r of 0.6365 and a correlation coefficient of 0.4051 ( Table 5 , Figure 2 ).

4. Discussion

The purpose of this present review was to provide a general overview of the available THC PK data after oral administration. In our literature review, we found that human PK studies studying the administration of THC in oral forms were scarce, despite their increasing popularity. Most of these studies focused on pharmaceutical forms, such as capsules and tablets. Despite being recommended formulations for the therapeutic use of cannabis in some countries, there were few data on the cannabinoid PK after the ingestion of cannabis oils or decoctions. The only complete, published study comparing these two formulations in patients with medication overuse-related headaches found high variability in the cannabinoid content of these formulations and in the THC recovery after administration. Each preparation showed differences in cannabinoid and metabolite absorption. For instance, cannabis decoctions offered a higher bioavailability of CBDA, while cannabis oil provided a higher bioavailability of THC and its metabolites, 11-hydroxy-Δ-9-tetrahidrocannabinol (11-OH-THC) and 11-nor-9-carboxy-Δ-9-tetrahidrocannabinol (THC-COOH) [52]. Contrary to these results, a published pilot study that also compared oil and decoction formulations obtained higher CBDA, THC, 11-OH-THC, and THC-COOH Cmax values after the administration of decoctions [53]. However, this pilot only presented data from one subject; results from a larger number of participants would likely strengthen comparisons between these two studies.

In our review, we found three studies that compared the oral administration of THC with that of smoking/inhalation, the most common route of administration. In Ohlsson et al. [58], subjects smoked 19.0 mg of THC (ad libitum, with a mean of 13.0 mg of THC) and took an oral dose of 20 mg of THC via a chocolate cookie. Despite being administered in a similar dose, the Cmax obtained after smoking (33–118 ng/mL) was significantly higher than the oral administration (4.4–11 ng/mL). These results showed the low systemic bioavailability of oral THC, which is about a third of that from smoked THC. Similarly, in Watchel et al. [59], the same doses of synthetic or plant-derived THC were orally administered and smoked, but the Cmax obtained was six times higher after smoking than after oral administration. As expected, the oral form achieved a delayed Tmax since absorption is slower when cannabinoids are ingested. Newmeyer et al. [60] reported minimal differences between smoked and vaporized cannabis administration, observing similar delivery. However, the THC Cmax after oral administration (brownie) was significantly lower than that of other routes, in addition to having a delayed Tmax, which agrees with previous observations.

For capsules, a wider range of doses was evaluated compared to other forms. Lile et al. administered the highest dose of THC (90 mg) out of all the studies and consequently reported the highest THC Cmax mean value obtained after administration (approx. 53 ng/mL) [49].

Oral THC doses were moderately to highly correlated (Pearson’s r = 0.6365–0.9997 and R 2 = 0.4051–0.9994), with peak plasma concentrations of THC found in capsules, decoctions, tablets, and baked goods formulations ( Table 5 , Figure 2 ). This correlation was stronger for capsules, decoctions, and oil compared to baked goods, which appeared to have higher variability in the peak plasma value obtained after certain THC doses. Interestingly, for oil, the correlation was not significant, thereby suggesting a more irregular absorption profile ( Figure 2 ). Since THC is a highly lipophilic molecule, it is expected that its absorption will increase in oil-based formulations. More studies on cannabis oil PK could determine whether this lack of linear correlation, as proven in other formulations, persists due to a high variability in the THC absorption of cannabis oil.

The management of dosing is critical for the treatment of patients, as there is a balance between the desired medical effects of THC and the prevention of adverse effects. Analyzing and understanding the PK of oral THC preparations is essential for the selection of optimal formulations, given their high variability. For instance, dronabinol in a solution exhibits lower intra-individual variability and a faster onset of detectable concentrations compared to capsule formulations [24,50].

We found that most studies on oral PK are focused on synthetic forms and analogues of THC, without considering the other cannabinoids usually present in plant-derived products, thus disregarding their possible therapeutic contributions. Moreover, the presence of CBD and other cannabinoids contained in oral cannabis preparations may be involved in alterations of THC PK properties [14].

In 2017, a review examining the PK and pharmacodynamics (PD) of oral cannabinoids for the treatment of chemotherapy-induced nausea and vomiting emphasized the high variability in the PK/PD profiles of capsules [63] and how they differ from other routes, such as smoking and intravenous delivery. The authors remarked on the efficacy of oral cannabinoids in the management of nausea and vomiting, which is similar, or even superior, to conventional antiemetic drugs. Interestingly, participants showed a preference for cannabis-based medicines over conventional medicines in trials where the two options were compared.

Similarly, a systematic review was recently conducted on CBD PK in humans, regardless of the administration route. Contrary to THC, CBD PK has been more thoroughly studied after oral and oromucosal administration (e.g., oral capsules and oromucosal sprays) than other routes of administration, such as smoking or vaporization. The most commonly studied form of administration was oromucosal spray, which contained CBD in combination with THC. Indeed, the administration of CBD alone in cannabinoid PK studies appeared less frequently than THC alone. Thus, like THC, the authors concluded that the limited available data presented some discrepancies in the PK of CBD [64].

The main limitation of the present systematic review is its use of only the PubMed database, the inclusion of only publications in English, and the exclusion of studies on the oromucosal sprays nabilone and those that administer only CBD.

5. Conclusions

In conclusion, oral THC has a highly variable PK profile, which differs between formulations, with seemingly higher variability in baked goods and oil forms. Considering the rapidly changing landscape of medical cannabis laws, there is an evident need for solid PK data after oral administration, especially in dosage forms other than capsules. Particularly, there is a lack of PK data on decoctions (tea) and oils, which are recommended methods of ingestion for medical use. Insufficient studies may lead to future failures of cannabis as a therapeutic compound if its therapeutic window is not defined.

The present review collects all published data on the oral administration of THC and cannabis in humans. Our results show high variability between oral formulations but a positive dose–concentration relationship for THC in most preparations.

Further investigations are required to provide more data on cannabinoid PK in the oral administration of THC, as well as other cannabinoids, to increase the accuracy when defining a therapeutic dosage for every patient.

Author Contributions

Conceptualization, L.P., A.P.P.-A., E.P., C.P.-M., A.S., M.T., F.P.B., and M.F.; methodology, L.P., A.P.P.-A., M.T., and M.F.; data curation, L.P., A.P.P.-A., S.M., O.H., A.S., and M.F.; writing—original draft preparation, L.P., A.P.P.-A., and M.F.; writing—review and editing, all authors. All authors have read and agreed to the published version of the manuscript.

Funding

The investigation was partially carried out with the funding of grants from the Instituto de Salud Carlos III (ISCIII, Fondo Investigación sanitaria (FIS)-Fondo Europeo de Desarrollo Regional (FEDER), FIS PI14/00715 and FIS PI17/01962, predoctoral PFIS FI18/00179 (L. Poyatos), ISCIII-Red de Trastornos Adictivos RTA RD16/0017/0003 and RD16/0017/0010), Ministerio de Sanidad, Política Social e Igualdad (Plan Nacional Sobre Drogas-PNSD, 2015I054 and 2019I010), and Agencia de Gestión de Ayudas Universitarias y de Investigación (AGAUR) Gencat Suport Grups Recerca (2017 SGR 316 and 2017 SGR 530).

How Cannabidiol Can Impact Your Dental Health

The legalization of cannabis (or marijuana) use in Canada in 2018 has lead to the rise of its use in the country. At present, marijuana is mostly used for pain management as an effective and less dangerous alternative to opioids. Although more research is necessary, initial studies have shown that medical marijuana can positively impact the physical and psychological health of an individual.

Cannabis — and specifically of one of its compounds, cannabidiol (CBD) — is sometimes viewed as being consequence-free, a kind of “magic bullet” for pain management. This is inaccurate; whether you smoke it, vape it, or use edible cannabis, cannabidiol can impact your dental health both positively and negatively.

Remember: cannabis and cannabidiol are medicines. They can interact with other medications you are taking, and they do have potential adverse side effects for your general and dental health.

Understanding the potential benefits and risks to your dental health associated with cannabidiol will help you to make a more informed decision about using it.

What Is Cannabidiol (CBD)?

CBD is one of the two main cannabinoids present in cannabis. The other component is tetrahydrocannabinol (THC), which is the psychoactive substance that gives marijuana users the characteristic high. While both compounds have their own health benefits and side effects, CBD offers its benefits without the high.

Ways To Consume CBD Include:

  • Inhalation (through vaping or smoking)
  • Sublingual (oils and tinctures under the tongue)
  • Ingestion (edibles)
  • Topical (lotions and creams)
  • Transdermal (skin patches)

The method used to take CBD influences how fast it takes effect, how long the effects last, and how effective it is. Vaping produces the quickest results, taking effect almost immediately but lasting only as long as three hours. Sublingual applications can take approximately five minutes to manifest and can last up to six hours. Edible can take up to an hour, with the effects lasting up to six hours.

Because it has to pass through your digestive tract first, edible cannabis is also the least predictable in terms of potency and effect.

Can CBD Benefit Your Oral Health?

CBD is a non-addictive substance that allows individuals to manage health problems safely. Recent studies have determined the potential of treating certain illnesses, including:

  • Autoimmune diseases (e.g. rheumatoid arthritis and Crohn’s)
  • Neurological disorders (e.g. Parkinson’s and epileptic seizures)
  • Chronic pain (e.g. fibromyalgia)
  • Psychological problems (e.g. anxiety and depression)

In terms of your oral health, CBD can help to:

  • Reduce anxiety at the dentist’s office – CBD has a soothing effect and can calm a patient’s anxiety, making them more open to dental treatment and paying regular visits to their dentist.
  • Minimize the risk of gum disease – CBD can counteract the inflammation that leads to gum disease like periodontitis. Periodontitis causes gums to pull away from the teeth, making it more likely to become infected. This can break down the bones and tissues supporting teeth, resulting in tooth loss. The anesthetic and antiseptic qualities of cannabidiol may reduce your risk of gum disease (although not if smoked; see below for details).
  • Relieve tooth pain – CBD can be ingested as a systematic painkiller to relieve tooth pain. However, this particular method does not provide quick relief. CBD be applied directly on the affected area as an oral spray, oil, or tincture.
  • Aid in recovery after surgery – After a surgical operation (whether dental or medical), patients are generally prescribed a list of medications to fight bacteria, inflammation, and pain, some of which are addictive or have an array of possible side effects. Treatment with CBD oil following dental surgery can help patients avoid these side effects and recover safely.

What Are The Risks Of CBD?

As stated, there are also some significant risks that come with CBD usage. Some are general medical risks, like its interactions with anesthetics and painkillers; some are very specific to your dental health.

  • CBD use can impact anesthesia – Regular cannabis users may need twice as much sedation. Cannabis intoxication during dental surgery can increase anesthetic risks. Current research indicates that local anesthetics containing epinephrine can, when combined with cannabis use, significantly prolong rapid heart rates.

When an anesthetic is required, patients must inform their dentist of any cannabis or cannabidiol use before treatment, and are recommended to cease cannabis use altogether at least 12 hours before surgery, or CBD use four hours before surgery.

  • CBD can interact with other medications – CBD is known to interact with the following kinds of medicine:
  • Blood thinners – can increase the risk of bleeding when used with blood thinners like ibuprofen and warfarin.
  • Sedatives – can increase the potency of sedatives, creating several health risks.
  • Dosed medications – CBD may disrupt the effects of medicines that need to be taken at a precise dosage, resulting in either under- or over-medicating.

Because of these potential risks, it is vital that any use of CBD or medical marijuana is included in your current medical history so that your dentist can take steps to manage the risks involved. Otherwise, your dentist may be forced to postpone treatment to ensure your safety.

The Added Risks of Smoking Cannabis

Although CBD can be derived from hemp instead of marijuana, some individuals use the terms interchangeably. Smoking marijuana carries specific health and dental health risks that need to be taken into consideration. Some potential side effects are cosmetic, but some can actually be serious:

  • Xerostomia – “dry mouth” is a well-known side-effect of smoking cannabis. Your saliva aids in digestion and protects your mouth from bacterial growth and plaque. The absence of saliva can lead to tooth decay and gum disease.
  • Demineralization of your enamel – like tobacco, smoking cannabis can stain your teeth. However, it can go one step further and demineralize your enamel, making it that much harder to whiten your teeth.
  • Periodontal disease – While CBD can reduce inflammation and help avoid periodontitis, smoking cannabis can cause gum disease.
  • Leukoplakia – also a well-documented side effect of cannabis smoking, leukoplakia is the formation of white patches inside your mouth (on your gums, the insides of your cheeks, and your tongue). Although most patches are benign, leukoplakia is associated with an elevated risk of oral cancer.

Despite the numerous research done on marijuana, the world’s understanding of this drug and its components remains limited. Further investigation is needed before the dental industry can fully harness its potential with minimal risks.

If you do decide to use CBD or medical marijuana to treat chronic pain, or for other conditions, it is vital that you communicate this with your dentist. As we said earlier, CBD and medical marijuana are drugs and need to be treated with the respect and caution that this entails.

If you are a regular cannabis user or are considering using CBD therapeutically, talk with Dr. Pamela Li. She has the expertise to answer your concerns and inquiries about how CBD and medical marijuana can affect your dental health.

Entrust the dental health of your whole family to Dr. Li; call her clinic at (613) 232-0550.

Cannabis Oil

Cannabis oils or concentrated extracts are obtained by the extraction of cannabinoids from the dried flowers (cannabis flos) of the cannabis plant. The purpose of producing cannabis oil is to make cannabinoids and other components (i.e. terpenes), available in a highly concentrated form.

Oils are typically prepared for oral sublingual administration. They have become increasingly popular in recent years. This is because they are easy to use, compared to inhalation by vaporization. Prescribers and pharmacists are more familiar with oral dosing, which also promotes their use.

Medicinal cannabis oil extracted from Bedrocan’s standardised flos is currently available in the Netherlands and several other countries. It is extracted by pharmacies (as magistral preparations) or pharmaceutical companies using GMP-certified production methods.

Bedrocan does not produce nor sell oil for oral sublingual dosing. Please refer to our contact page for an overview of Dutch compounding pharmacists.

The pharmacist prepares medicinal cannabis oil at the Transvaal Pharmacy, the Netherlands

Unregulated production

The preparation of cannabis oil or cannabis concentrates at home, or the use of unregulated cannabis oils or concentrates is not advised.

Home or unregulated production can pose risks to patients who consume them. The exact composition of different available oils is frequently unknown. They are not checked for quality by external certified laboratories for the presence of residual solvents, or contaminants such as microbes, pesticides, heavy metals or mycotoxins. The lack of standardisation of both the cannabis starting material and oils makes it impossible to fully evaluate their therapeutic effects over time and, hence, their medicinal value.

Consequently, there is a significant need to standardise and control cannabis extracts and to regulate their distribution as potential medicinal products.

CBD oil

In recent years, a large, unregulated market for CBD (cannabidiol) oils has emerged. These products are typically derived from fibre-type cannabis strains (hemp), which contain large concentrations of CBD, but negligible of THC.

In most countries it is forbidden to create concentrates from cannabis, because cannabis is a controlled substance .. Nonetheless, the appearance of numerous CBD-rich extracts have appeared on the global market.

For more information on CBD oil, see our article The problem with CBD oil.