Next Article in Journal
Evaluation of Surgical Treatment of Oroantral Fistulae in Smokers Versus Non-Smokers
Next Article in Special Issue
UHPLC-HRMS and GC-MS Screening of a Selection of Synthetic Cannabinoids and Metabolites in Urine of Consumers
Previous Article in Journal
Rates of Intracranial Hemorrhage in Mild Head Trauma Patients Presenting to Emergency Department and Their Management: A Comparison of Direct Oral Anticoagulant Drugs with Vitamin K Antagonists
Previous Article in Special Issue
Herbal Preparations of Medical Cannabis: A Vademecum for Prescribing Doctors
 
 
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

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

1
Clinical Pharmacology Department, Hospital Universitari Germans Trias i Pujol and Institut de Recerca Germans Trias (HUGTiP-IGTP), 08916 Badalona, Spain
2
Departments of Pharmacology, Therapeutics and Toxicology and Department of Psychiatry, Universitat Autònoma de Barcelona, 08193 Cerdanyola del Vallés, Spain
3
Pharmacy Department, Hospital Universitari Germans Trias i Pujol and Institut de Recerca Germans Trias (HUGTiP-IGTP), 08916 Badalona, Spain
4
Drug Addiction Program, Institut de Neuropsiquiatria, Parc de Salut Mar and Institut Hospital del Mar de Recerca Mèdica (PSMAR-IMIM), 08003 Barcelona, Spain
5
Department of Excellence-Biomedical Sciences and Public Health, Università Politecnica delle Marche, 60121 Ancona, Italy
*
Author to whom correspondence should be addressed.
These authors shared first authorship.
These authors shared senior authorship.
Medicina 2020, 56(6), 309; https://doi.org/10.3390/medicina56060309
Received: 15 May 2020 / Revised: 13 June 2020 / Accepted: 17 June 2020 / Published: 23 June 2020
(This article belongs to the Special Issue Use of Medicinal Cannabis and Synthetic Cannabinoids)

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.
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 (R2) of 0.8596 (Table 5, Figure 2). The THC Cmax increased proportionally by increasing the doses of THC.

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 R2 = 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).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. United Nations Office on Drugs and Crime (UNODC). World Drug Report 2019. Available online: https://wdr.unodc.org/wdr2019/index.html. (accessed on 5 April 2020).
  2. Morales, P.; Hurst, D.P.; Reggio, P.H. Molecular Targets of the Phytocannabinoids: A Complex Picture. Prog. Chem. Org. Nat. Prod. 2017, 103, 103–131. [Google Scholar] [PubMed][Green Version]
  3. ElSohly, M.A.; Radwan, M.M.; Gul, W.; Chandra, S.; Galal, A. Phytochemistry of Cannabis sativa L. Prog. Chem. Org. Nat. Prod. 2017, 103, 1–36. [Google Scholar] [PubMed]
  4. Kaur, R.; Ambwani, S.R.; Singh, S. Endocannabinoid System: A Multi-Facet Therapeutic Target. Curr. Clin. Pharmacol. 2016, 11, 110–117. [Google Scholar] [CrossRef][Green Version]
  5. Maccarrone, M.; Maldonado, R.; Casas, M.; Henze, T.; Centonze, D. Cannabinoids therapeutic use: What is our current understanding following the introduction of THC, THC:CBD oromucosal spray and others? Expert Rev. Clin. Pharmacol. 2017, 10, 443–455. [Google Scholar] [CrossRef]
  6. Andre, C.M.; Hausman, J.F.; Guerriero, G. Cannabis sativa: The Plant of the Thousand and One Molecules. Front. Plant. Sci. 2016, 7, 19. [Google Scholar] [CrossRef] [PubMed][Green Version]
  7. Pisanti, S.; Malfitano, A.M.; Ciaglia, E.; Lamberti, A.; Ranieri, R.; Cuomo, G.; Abate, M.; Faggiana, G.; Proto, M.C.; Fiore, D.; et al. Cannabidiol: State of the art and new challenges for therapeutic applications. Pharmacol. Ther. 2017, 175, 133–150. [Google Scholar] [CrossRef]
  8. Mannucci, C.; Navarra, M.; Calapai, F.; Spagnolo, E.V.; Busardò, F.P.; Cas, R.D.; Ippolito, F.M.; Calapai, G. Neurological Aspects of Medical Use of Cannabidiol. CNS Neurol. Disord. Drug Targets 2017, 16, 541–553. [Google Scholar] [CrossRef][Green Version]
  9. Laprairie, R.B.; Bagher, A.M.; Kelly, M.E.M.; Denovan-Wright, E.M. Cannabidiol Is a Negative Allosteric Modulator of the Cannabinoid CB1 Receptor. Br. J. Pharmacol. 2015, 172, 4790–4805. [Google Scholar] [CrossRef][Green Version]
  10. Mueller, J.K.; Reuter, A.R.; Lange, B.; Schaefer, A.; Hanke, F.; Pahlisch, F.; Schaefer, C.; Schmidt, A.-M.; Woelfl, T.; Enning, F.; et al. Effects and interaction of delta-9-tetrahydrocannabidiol and cannabidiol on psychopathology, neurocognition, and endocannabinoids in serum of healthy volunteers: Influence on psychopathology. Neuropsychopharmacology 2016, 41, S589. [Google Scholar]
  11. Morgan, C.J.A.; Freeman, T.P.; Hindocha, C.; Schafer, G.; Gardner, C.; Curran, H.V. Individual and combined effects of acute delta-9tetrahydrocannabinol and cannabidiol on psychotomimetic symptoms and memory function. Transl. Psychiatry 2018, 8, 181. [Google Scholar] [CrossRef]
  12. Hindley, G.; Beck, K.; Borgan, F.; Ginestet, C.E.; McCutcheon, R.; Kleinloog, D.; Ganesh, S.; Radhakrishnan, R.; D'Souza, D.C.; Howes, O.D. Psychiatric symptoms caused by cannabis constituents: A systematic review and meta-analysis. Lancet Psychiatry 2020, 7, 344–353. [Google Scholar] [CrossRef]
  13. Arkell, T.R.; Lintzeris, N.; Kevin, R.C.; Ramaekers, J.G.; Vandrey, R.; Irwin, C.; Haber, P.S.; McGregor, I.S. Cannabidiol (CBD) content in vaporized cannabis does not prevent tetrahydrocannabinol (THC)-induced impairment of driving and cognition. Psychopharmacology 2019, 236, 2713–2724. [Google Scholar] [CrossRef] [PubMed][Green Version]
  14. Papaseit, E.; Pérez-Mañá, C.; Pérez-Acevedo, A.P.; Hladun, O.; Torres-Moreno, M.C.; Muga, R.; Torrens, M.; Farré, M. Cannabinoids: From pot to lab. Int. J. Med. Sci. 2018, 6, 1286–1295. [Google Scholar] [CrossRef] [PubMed][Green Version]
  15. Hazekamp, A.; Heerdink, E.R. The prevalence and incidence of medicinal cannabis on prescription in The Netherlands. Eur. J. Clin. Pharmacol. 2013, 69, 1575–1580. [Google Scholar] [CrossRef]
  16. de Hoop, B.; Heerdink, E.R.; Hazekamp, A. Medicinal Cannabis on Prescription in The Netherlands: Statistics for 2003–2016. Cannabis Cannabinoid Res. 2018, 3, 54–55. [Google Scholar] [CrossRef][Green Version]
  17. Shiplo, S.; Asbridge, M.; Leatherdale, S.T.; Hammond, D. Medical cannabis use in Canada: Vapourization and modes of delivery. Harm Reduct. J. 2016, 13, 30. [Google Scholar] [CrossRef][Green Version]
  18. Boehnke, K.F.; Scott, J.R.; Litinas, E.; Sisley, S.; Clauw, D.J.; Goesling, J.; Williams, D.A. Cannabis Use Preferences and Decision-making Among a Cross-sectional Cohort of Medical Cannabis Patients with Chronic Pain. J. Pain 2019, 20, 1362–1372. [Google Scholar] [CrossRef]
  19. Bouso, J.C.; Jiménez-Garrido, D.; Ona, G.; Woźnica, D.; Dos Santos, R.G.; Hallak, J.E.C.; Paranhos, B.A.P.B.; de Almeida Mendes, F.; Yonamine, M.; Alcázar-Córcoles, M.Á.; et al. Quality of life, mental health, personality, and patterns of use in self-medicated cannabis users with chronic diseases: A 12-month longitudinal study. Phytother Res. 2020, 1–8. [Google Scholar] [CrossRef]
  20. Jett, J.; Stone, E.; Warren, G.; Cummings, K.M. Cannabis Use, Lung Cancer, and Related Issues. J. Thorac. Oncol. 2018, 3, 480–487. [Google Scholar] [CrossRef][Green Version]
  21. Abeles, M.; Popofsky, S.; Wen, A.; Valsamis, C.; Webb, A.; Halaby, C.; Pirzada, M. Vaping-associated lung injury caused by inhalation of cannabis oil. Pediatr. Pulmonol. 2020, 55, 226–228. [Google Scholar] [CrossRef]
  22. Thakrar, P.D.; Boyd, K.P.; Swanson, C.P.; Wideburg, E.; Kumbhar, S.S. E-cigarette, or vaping, product use-associated lung injury in adolescents: A review of imaging features. Pediatr. Radiol. 2020, 50, 338–344. [Google Scholar] [CrossRef] [PubMed]
  23. Duffy, B.; Li, L.; Lu, S.; Durocher, L.; Dittmar, M.; Delaney-Baldwin, E.; Panawennage, D.; LeMaster, D.; Navarette, K.; Spink, D. Analysis of Cannabinoid-Containing Fluids in Illicit Vaping Cartridges Recovered from Pulmonary Injury Patients: Identification of Vitamin E Acetate as a Major Diluent. Toxics 2020, 8, 8. [Google Scholar] [CrossRef][Green Version]
  24. Brunetti, P.; Pichini, S.; Pacifici, R.; Busardó, F.P.; del Rio, A. Herbal preparations of medical cannabis: A Vademecum for prescribing doctors. Medicina 2020, 56, 237. [Google Scholar] [CrossRef]
  25. Levinsohn, E.A.; Hill, K.P. Clinical uses of cannabis and cannabinoids in the United States. J. Neurol. Sci. 2020, 411, 116717. [Google Scholar] [CrossRef] [PubMed][Green Version]
  26. Torres-Moreno, M.C.; Papaseit, E.; Torrens, M.; Farré, M. Assessment of Efficacy and Tolerability of Medicinal Cannabinoids in Patients with Multiple Sclerosis: A Systematic Review and Meta-analysis. JAMA Netw. Open 2018, 1, e183485. [Google Scholar] [CrossRef][Green Version]
  27. EMCDDA (European Monitoring Centre for Drugs and Drug Addiction). Medical Use of Cannabis and Cannabinoids. December 2018. Available online: http://www.emcdda.europa.eu/publications/rapid-communications/medical-use-of-cannabis-and-cannabinoids-questions-and-answers-for-policymaking_en. (accessed on 5 April 2020).
  28. Bedrocan Medicinal Cannabis. Available online: https://www.bedrocan.com/ (accessed on 5 April 2020).
  29. Ministero della Salute. Decreto 9 novembre 2015: Funzioni di Organismo Statale per la Cannabis previsto dagli articoli 23 e 28 della convenzione unica sugli stupefacenti del 1961, come modificata nel 1972. Available online: https://www.gazzettaufficiale.it/eli/id/2015/11/30/15A08888/sg (accessed on 5 April 2020).
  30. Pacifici, R.; Marchei, E.; Salvatore, F.; Guandalini, L.; Busardò, F.P.; Pichini, S. Evaluation of cannabinoids concentration and stability in standardized preparations of cannabis tea and cannabis oil by ultra-high performance liquid chromatography tandem mass spectrometry. Clin. Chem. Lab. Med. 2017, 55, 1555–1563. [Google Scholar] [CrossRef]
  31. Pacifici, R.; Marchei, E.; Salvatore, F.; Guandalini, L.; Busardò, F.P.; Pichini, S. Stability of cannabinoids in cannabis FM1 flowering tops and oil preparation evaluated by ultra-high performance liquid chromatography tandem mass spectrometry. Clin. Chem. Lab. Med. 2019, 57, e165–e168. [Google Scholar] [CrossRef] [PubMed]
  32. Ministero della Salute. La produzione nazionale di sostanze attive di origine vegetale a base di Cannabis. Available online: http://www.salute.gov.it/portale/temi/p2_6.jsp?lingua=italiano&id=4588&area=sostanzeStupefacenti&menu=organismo (accessed on 5 April 2020).
  33. Cannimed Medical Cannabis. Available online: https://www.cannimed.ca/ (accessed on 5 April 2020).
  34. Romano, L.L.; Hazekamp, A. Cannabis Oil: Chemical evaluation of an upcoming cannabis-based medicine. Cannabinoids 2013, 1, 1–11. [Google Scholar]
  35. Monte, A.A.; Shelton, S.K.; Mills, E.; Saben, J.; Hopkinson, A.; Sonn, B.; Devivo, M.; Chang, T.; Fox, J.; Brevik, C.; et al. Acute Illness Associated with Cannabis Use, by Route of Exposure: An Observational Study. Mol. Med. 2019, 116, 229. [Google Scholar] [CrossRef]
  36. Moher, D.; Liberati, A.; Tetzlaff, J.; Altman, D.G. Preferred reporting items for systematic reviews and meta-analyses: The PRISMA statement. Ann. Int. Med. 2009, 151, 264–269. [Google Scholar] [CrossRef][Green Version]
  37. Wall, M.E.; Sadler, B.M.; Brine, D.; Taylor, H.; Perez-Reyes, M. Metabolism, disposition, and kinetics of delta-9-tetrahydrocannabinol in men and women. Clin. Pharmacol. Ther. 1983, 34, 352–363. [Google Scholar] [CrossRef] [PubMed]
  38. Haney, M.; Bisaga, A.; Foltin, R.W. Interaction between naltrexone and oral THC in heavy marijuana smokers. Psychopharmacology 2003, 166, 77–85. [Google Scholar] [CrossRef] [PubMed]
  39. Naef, M.; Curatolo, M.; Petersen-Felix, S.; Arendt-Nielsen, L.; Zbinden, A.; Brenneisen, R. The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions. Pain 2003, 105, 79–88. [Google Scholar] [CrossRef]
  40. Guy, G.W.; Robson, P.J. A Phase I, Open Label, Four-Way Crossover Study to Compare the Pharmacokinetic Profiles of a Single Dose of 20 mg of a Cannabis Based Medicine Extract (CBME) Administered on 3 Different Areas of the Buccal Mucosa and to Investigate the Pharmacokinetics of CBME per Oral in Healthy Male and Female Volunteers (GWPK0112). J. Cannabis Ther. 2004, 3, 79–120. [Google Scholar]
  41. Ménétrey, A.; Augsburger, M.; Favrat, B.; Pin, M.A.; Rothuizen, L.E.; Appenzeller, M.; Buclin, T.; Mangin, P.; Giroud, C. Assessment of driving capability through the use of clinical and psychomotor tests in relation to blood cannabinoids levels following oral administration of 20 mg dronabinol or of a cannabis decoction made with 20 or 60 mg Delta9-THC. J. Anal. Toxicol. 2005, 29, 327–338. [Google Scholar] [CrossRef] [PubMed][Green Version]
  42. Nadulski, T.; Sporkert, F.; Schnelle, M.; Stadelmann, A.M.; Roser, P.; Schefter, T.; Pragst, F. Simultaneous and sensitive analysis of THC, 11-OH-THC, THC-COOH, CBD, and CBN by GC-MS in plasma after oral application of small doses of THC and cannabis extract. J. Anal. Toxicol. 2005, 29, 782–789. [Google Scholar] [CrossRef][Green Version]
  43. Goodwin, R.S.; Gustafson, R.A.; Barnes, A.; Nebro, W.; Moolchan, E.T.; Huestis, M.A. Delta(9)-tetrahydrocannabinol, 11-hydroxy-delta(9)-tetrahydrocannabinol and 11-nor-9-carboxy-delta(9)-tetrahydrocannabinol in human plasma after controlled oral administration of cannabinoids. Ther. Drug Monit. 2006, 28, 545–551. [Google Scholar] [CrossRef]
  44. Schwilke, E.W.; Schwope, D.M.; Karschner, E.L.; Lowe, R.H.; Darwin, W.D.; Kelly, D.L.; Goodwin, R.S.; Gorelick, D.A.; Huestis, M.A. Delta9-tetrahydrocannabinol (THC), 11-hydroxy-THC, and 11-nor-9-carboxy-THC plasma pharmacokinetics during and after continuous high-dose oral THC. Clin. Chem. 2009, 55, 2180–2189. [Google Scholar] [CrossRef][Green Version]
  45. Karschner, E.L.; Darwin, W.D.; Goodwin, R.S.; Wright, S.; Huestis, M.A. Plasma cannabinoid pharmacokinetics following controlled oral delta9-tetrahydrocannabinol and oromucosal cannabis extract administration. Clin. Chem. 2011, 57, 66–75. [Google Scholar] [CrossRef]
  46. Karschner, E.L.; Schwope, D.M.; Schwilke, E.W.; Goodwin, R.S.; Kelly, D.L.; Gorelick, D.A.; Huestis, M.A. Predictive model accuracy in estimating last Δ9-tetrahydrocannabinol (THC) intake from plasma and whole blood cannabinoid concentrations in chronic, daily cannabis smokers administered subchronic oral THC. Drug Alcohol Depend. 2012, 125, 313–319. [Google Scholar] [CrossRef][Green Version]
  47. Martin-Santos, R.; Crippa, J.A.; Batalla, A.; Bhattacharyya, S.; Atakan, Z.; Borgwardt, S.; Allen, P.; Seal, M.; Langohr, K.; Farre, M.; et al. Acute effects of a single, oral dose of d9-tetrahydrocannabinol (THC) and cannabidiol (CBD) administration in healthy volunteers. Curr. Pharm. Des. 2012, 18, 4966–4979. [Google Scholar] [CrossRef]
  48. Eichler, M.; Spinedi, L.; Unfer-Grauwiler, S.; Bodmer, M.; Surber, C.; Luedi, M.; Drewe, J. Heat exposure of Cannabis sativa extracts affects the pharmacokinetic and metabolic profile in healthy male subjects. Planta Med. 2012, 78, 686–691. [Google Scholar] [CrossRef][Green Version]
  49. Lile, J.A.; Kelly, T.H.; Charnigo, R.J.; Stinchcomb, A.L.; Hays, L.R. Pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of Δ(9)-THC in cannabis users. J. Clin. Pharmacol. 2013, 53, 680–690. [Google Scholar] [CrossRef] [PubMed][Green Version]
  50. Parikh, N.; Kramer, W.G.; Khurana, V.; Cognata Smith, C.; Vetticaden, S. Bioavailability study of dronabinol oral solution versus dronabinol capsules in healthy volunteers. Clin. Pharmacol. 2016, 12, 155–162. [Google Scholar] [CrossRef] [PubMed][Green Version]
  51. Cherniakov, I.; Izgelov, D.; Barasch, D.; Davidson, E.; Domb, A.J.; Hoffman, A. Piperine-pro-nanolipospheres as a novel oral delivery system of cannabinoids: Pharmacokinetic evaluation in healthy volunteers in comparison to buccal spray administration. J. Control. Release 2017, 28, 1–7. [Google Scholar] [CrossRef] [PubMed]
  52. Pellesi, L.; Licata, M.; Verri, P.; Vandelli, D.; Palazzoli, F.; Marchesi, F.; Cainazzo, M.M.; Pini, L.A.; Guerzoni, S. Pharmacokinetics and tolerability of oral cannabis preparations in patients with medication overuse headache (MOH)-a pilot study. Eur J. Clin. Pharmacol. 2018, 74, 1427–1436. [Google Scholar] [CrossRef]
  53. Pichini, S.; Mannocchi, G.; Gottardi, M.; Pérez-Acevedo, A.P.; Poyatos, L.; Papaseit, E.; Pérez-Mañá, C.; Farré, M.; Pacifici, R.; Busardò, F.P. Fast and sensitive UHPLC-MS/MS analysis of cannabinoids and their acid precursors in pharmaceutical preparations of medical cannabis and their metabolites in conventional and non-conventional biological matrices of treated individual. Talanta 2020, 209, 120537. [Google Scholar] [CrossRef]
  54. Timpone, J.G.; Wright, D.J.; Li, N.; Egorin, M.J.; Enama, M.E.; Mayers, J.; Galetto, G. The safety and pharmacokinetics of single-agent and combination therapy with megestrol acetate and dronabinol for the treatment of HIV wasting syndrome. The DATRI 004 Study Group. Division of AIDS Treatment Research Initiative. AIDS Res. Hum. Retroviruses 1997, 13, 305–315. [Google Scholar] [CrossRef] [PubMed]
  55. Klumpers, L.E.; Beumer, T.L.; van Hasselt, J.G.; Lipplaa, A.; Karger, L.B.; Kleinloog, H.D.; Freijer, J.I.; de Kam, M.L.; van Gerven, J.M. Novel Δ-(9)-tetrahydrocannabinol formulation Namisol® has beneficial pharmacokinetics and promising pharmacodynamic effects. Br. J. Clin. Pharmacol. 2012, 74, 42–53. [Google Scholar] [CrossRef]
  56. Ahmed, A.I.; van den Elsen, G.A.; Colbers, A.; van der Marck, M.A.; Burger, D.M.; Feuth, T.B.; Rikkert, M.G.; Kramers, C. Safety and pharmacokinetics of oral delta-9-tetrahydrocannabinol in healthy older subjects: A randomized controlled trial. Eur. Neuropsychopharmacol. 2014, 24, 1475–1482. [Google Scholar] [CrossRef]
  57. de Vries, M.; Van Rijckevorsel, D.C.; Vissers, K.C.; Wilder-Smith, O.H.; Van Goor, H. Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: Analgesic efficacy, pharmacokinetics and tolerability. Br. J. Clin. Pharmacol. 2016, 81, 525–537. [Google Scholar] [CrossRef] [PubMed][Green Version]
  58. Ohlsson, A.; Lindgren, J.E.; Wahlen, A.; Agurell, S.; Hollister, L.E.; Gillespie, H.K. Plasma delta-9 tetrahydrocannabinol concentrations and clinical effects after oral and intravenous administration and smoking. Clin. Pharmacol. Ther. 1980, 28, 409–416. [Google Scholar] [CrossRef] [PubMed]
  59. Wachtel, S.R.; ElSohly, M.A.; Ross, S.A.; Ambre, J.; de Wit, H. Comparison of the subjective effects of Delta(9)-tetrahydrocannabinol and marijuana in humans. Psychopharmacology 2002, 161, 331–339. [Google Scholar] [PubMed]
  60. Newmeyer, M.N.; Swortwood, M.J.; Barnes, A.J.; Abulseoud, O.A.; Scheidweiler, K.B.; Huestis, M.A. Free and Glucuronide Whole Blood Cannabinoids' Pharmacokinetics after Controlled Smoked, Vaporized, and Oral Cannabis Administration in Frequent and Occasional Cannabis Users: Identification of Recent Cannabis Intake. Clin. Chem. 2016, 62, 1579–1592. [Google Scholar] [CrossRef][Green Version]
  61. Newmeyer, M.N.; Swortwood, M.J.; Andersson, M.; Abulseoud, O.A.; Scheidweiler, K.B.; Huestis, M.A. Cannabis Edibles: Blood and Oral Fluid Cannabinoid Pharmacokinetics and Evaluation of Oral Fluid Screening Devices for Predicting Δ9-Tetrahydrocannabinol in Blood and Oral Fluid following Cannabis Brownie Administration. Clin. Chem. 2017, 63, 647–662. [Google Scholar] [CrossRef]
  62. Vandrey, R.; Herrmann, E.S.; Mitchell, J.M.; Bigelow, G.E.; Flegel, R.; LoDico, C.; Cone, E.J. Pharmacokinetic Profile of Oral Cannabis in Humans: Blood and Oral Fluid Disposition and Relation to Pharmacodynamic Outcomes. J. Anal. Toxicol. 2017, 41, 83–99. [Google Scholar] [CrossRef]
  63. Badowski, M.E. A review of oral cannabinoids and medical marijuana for the treatment of chemotherapy-induced nausea and vomiting: A focus on pharmacokinetic variability and pharmacodynamics. Cancer Chemother. Pharmacol. 2017, 80, 441–449. [Google Scholar] [CrossRef][Green Version]
  64. Millar, S.A.; Stone, N.L.; Yates, A.S.; O’Sullivan, S.E. A Systematic Review on the Pharmacokinetics of Cannabidiol in Humans. Front. Pharmacol. 2018, 9, 1365. [Google Scholar] [CrossRef]
Figure 1. Flow chart for the study retrieval and selection.
Figure 1. Flow chart for the study retrieval and selection.
Medicina 56 00309 g001
Figure 2. 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).
Figure 2. 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).
Medicina 56 00309 g002
Table 1. Summary of studies included in this systematic review reporting the pharmacokinetic parameters of Δ-9-tetrahydrocannabinol (THC) following capsule administration.
Table 1. Summary of studies included in this systematic review reporting the pharmacokinetic parameters of Δ-9-tetrahydrocannabinol (THC) following capsule administration.
ReferencesStudy DesignParticipantsRoute of AdministrationFormulationDoseCmax (ng/mL)
Mean ± SD, Median (Range)
Tmax (h)Pharmacological Effects
Wall et al., 1983 [37]OL, NP6 M, 6 FOralCapsules20 mg THC (men)MenMenEffects were not assessed.
THC: 14 ± 9.7 bTHC: 2.5
11-OH-THC: 6.6 ± 3.4 b11-OH-THC: 2.0
15 mg THC (women)WomenWomen
THC: 9.4 ± 4.5 bTHC: 1.75
11-OH-THC: 5.9 ± 2.8 b11-OH-THC: 1.75
Intravenous (infusion pump)Human serum albumin4 mg THC (men)MenMen
THC: 71 ± 34 bTHC: 0.42
11-OH-THC: 3.7 ± 2.3 b11-OH-THC: 0.5
2.2 mg THC (women)WomenWomen
THC: 85 ± 26 bTHC: 0.17
11-OH-THC: 3.8 ± 2.8 b11-OH-THC: 0.33
Haney et al., 2003 [38]R, DB, P, C7 M
Cannabis smokers
OralCapsules (Marinol®)30 mg THC29, Placebo naltrexoneTHC: 29.9 ± 9.5 bTHC: 4 bSubjective effects
Increase in ratings of Good Drug Effect, High, and Stimulated.
Vital effects
Decreased HR.
Worsened psychomotor performance.
THC-COOH: 121.9 ± 43.5 bTHC-COOH: 2 b
OralCapsules (Marinol®)30 mg THC
50 mg naltrexone
THC: 21.2 ± 8.6 bTHC: 2 b
THC-COOH: 139.0 ± 36.2 bTHC-COOH: 3 b
Naef et al., 2003 [39]R, DB, P, C6 M, 6 F
Cannabis naïve
OralCapsules (Marinol®)20 mg THCTHC: 7.2 ± 6.9 b, eTHC: 1-2 b, eSubjective 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, e11-OH-THC: 2 b, e
11-COOH-THC: 241.4 ± 73. b, e11-COOH-THC: 2–4 b, e
OralCapsules20 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-
OralCapsules (placebo)30 mg morphine HCl
OralCapsules (placebo)
Guy et al., 2004 [40]R, OL, C
followed by an NR oral dose
6 M, 6 F
Previous experience of cannabis use
OralCapsules10 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)
SublingualLiquid 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)
BuccalLiquid 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-pharyngealLiquid 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, C24OralCapsules10 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)
OralCapsules10 mg THCTHC: 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)
OralCapsulesPlacebo
Goodwin et al., 2006 [43] See also Table 2 for results on capsules and oil administration.
Schwilke et al., 2009 [44]NR, OL, NP, MD6 M
Daily smokers (positive in cannabinoids, smoked within the previous 24 h)
OralCapsules (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 ± 3.4THC: 2.8 (0.33)
11-OH-THC: 8.2 ± 2.011-OH-THC: 2.5 (0.18)
THC-COOH: 75.8 ± 9.4THC-COOH: 3.3 (0.56)
Karschner et al., 2011 [45]R, DB, P, DD6 M, 3 F
Cannabis smokers
OralCapsules (dronabinol)5 mg THCTHC: 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)
OralCapsules (dronabinol)15 mg THCTHC: 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)
SublingualSpray (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)
SublingualSpray (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, MD10 M
Daily smokers (positive cannabinoids, smoked within the previous 24 h)
OralCapsules (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, C16 M
Previous experience of cannabis use (less than 15 times in their lifetime)
OralCapsules10 mg THCTHC: 0.67 ± 0.66 b
THC-COOH: ≈ 5.6 b, d
11-OH-THC: ≈ 0.73 b, d
THC: 2 h bSubjective 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.
OralCapsules600 mg CBD
OralCapsules (placebo)
Eichler et al., 2012 [48]R, DB, C9 M
Non smokers
OralCapsules (Marinol®)20 mg THCTHC: 1.03 ± 1.65, 0.48 e, gTHC: 1.06 ± 0.19, 1.0 eSubjective effects
Mild psychotropic effects, with no significant differences between treatments.
CBD: 0.00 ± 0.00, 0.0 e, gCBD: NA
11-OH-THC: 0.99 ± 0.63, 0.84 e, g11-OH-THC: 1.67 ± 0.51, 2.0 e
THC-COOH: 7.13 ± 5.64, 7.61 e, gTHC-COOH: 1.78 ± 0.96, 2.0 e
CBN: 0.64 ± 0.72, 0.37 e, gCBN: 1.06 ± 0.57, 1.0 e
OralCapsules (extract from heated Herba Cannabis)17.6 mg THC
27.8 mg CBD
THC: 0.42 ± 0.39, 0.25 e, gTHC: 0.78 ± 0.27, 1.0 e
CBD: 0.30 ± 0.21, 0.27 e, gCBD: 0.83 ± 0.51, 0.5 e
11-OH-THC: 0.73 ± 0.69, 0.50 e, g11-OH-THC: 1.44 ± 0.69, 2.0 e
THC-COOH: 5.81 ± 7.59, 3.46 e, gTHC-COOH: 2.89 ± 1.05, 2.0 e
CBN: 0.60 ± 0.36, 0.56 e, gCBN: 0.94 ± 0.45, 1.0 e
OralCapsules (extract from unheated Herba Cannabis)10.4 mg THC
14.8 mg CBD
THC: 1.02 ± 0.78, 0.71 e, gTHC: 1.17 ± 0.66, 1.0 e
CBD: 1.24 ± 0.87, 0.96 e, gCBD: 1.17 ± 1.17, 1.0 e
11-OH-THC: 0.57 ± 0.42, 0.50 e, g11-OH-THC: 1.00 ± 0.42, 1.0 e
THC-COOH: 1.94 ± 1.11, 2.28 e, gTHC-COOH: 2.11 ± 0.78, 2.0 e
CBN: 0.54 ± 0.30, 0.58 e, gCBN: 1.00 ± 0.42, 1.0 e
Lile JA et al., 2013 [49]B, P, C4 M, 3 F
Only 5 completed all doses
Regular cannabis use
OralCapsules (Marinol®)15 mg THCTHC: ≈5 dTHC: 3 dVital 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 d11-OH-THC: 3 d
OralCapsules (Marinol®)30 mg THCTHC: ≈10 dTHC: 3 d
11-OH-THC: ≈5 d11-OH-THC: 3 d
OralCapsules (Marinol®)45 mg THCTHC: ≈17–18 dTHC: 2.5 d
11-OH-THC: ≈8–9 d11-OH-THC: 2 d
OralCapsules (Marinol®)60 mg THCTHC: ≈45 dTHC: 3.5 d
11-OH-THC: ≈11 d11-OH-THC: 3 d
OralCapsules (Marinol®)75 mg THCTHC: ≈42–43 dTHC: 4 d
11-OH-THC: ≈12–13 d11-OH-THC: 4 d
OralCapsules (Marinol®)90 mg THCTHC: ≈53 dTHC: 4 d
11-OH-THC: ≈20 d11-OH-THC: 4 d
OralCapsules (placebo)
Parikh et al., 2016 [50]R, OL, C51 MF
No cannabis use in the previous 90 days
OralOral solution (Dronabinol)4.25 mg THCTHC Replicate 1: 1.81 ± 1.26THC Replicate 1: 1.50 (0.50–4.00)Effects were not assessed.
THC Replicate 2: 2.08 ± 1.30THC Replicate 2: 1.00 (0.50–3.02)
11-OH-THC Replicate 1: 2.53 ± 1.3811-OH-THC Replicate 1: 1.50 (0.75–4.00)
11-OH-THC Replicate 2: 3.01 ± 1.5611-OH-THC Replicate 2: 1.50 (0.50–3.02)
OralCapsules (Dronabinol)5 mg THCTHC 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, C9 M
Not exposed within the previous 4 weeks
SublingualSpray (Sativex®)10.8 mg THC
10.0 mg CBD
THC: 1.8 ± 0.2THC: 2 (1–4)Effects were not assessed.
CBD: 0.5 ± 0.1CBD: 3 (1–5)
OralTHC-CBD-piperine-PNL capsule10.8 mg THC
10.0 mg CBD
THC: 5.4 ± 0.01THC: 1 (1–1.5)
CBD: 2.1 ± 0.4CBD: 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.
Table 2. Summary of studies included in this systematic review reporting the pharmacokinetic parameters for THC following oil or decoction administration.
ReferencesStudy DesignParticipantsRoute of AdministrationFormulationDoseCmax (ng/mL)
Mean ± SD, Median (Range)
Tmax (h)Pharmacological Effects
Menetrey et al., 2005 [41]R, DB, P, C 8 M
Occasional cannabis smokers
OralMilk decoction16.5 mg THCTHC: 3.8 (1.5–8.3) b THC: 1 bSubjective 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) b11-OH-THC: 1 b
THC-COOH: 27.8 (14.1–42.4) b THC-COOH: 4 b
OralMilk decoction45.7 mg THC THC: 8.4 (3.9–13.1) bTHC: 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
OralCapsules (Marinol®)20 mg THCTHC: 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) bTHC-COOH: 5.5 b
OralDecoction (placebo)0.8 mg THC
OralCapsules (placebo)
Goodwin et al., 2006 [43]R, DB, P, DD, MD (5 days)6
Previous experience of cannabis use
OralHemp oil0.39 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/dayTHC: 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)
OralCapsules (dronabinol)7.5 mg THC/dayTHC: 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/dayTHC: 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)
OralPlacebo
Pellesi et al., 2018 [52]OL, C6 M, 7 F
Patients with medication overuse headaches
OralDecoction1.85 ± 1.6 mg THC THC: 1.38 ± 0.75 THC: 1.28 ± 0.51Subjective 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-ATHCA: 48.92 ± 26.34 THCA: 1.22 ± 0.26
1.93 ± 1.17 mg CBDCBD: 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
OralOil 2.2 mg THCTHC: 3.29 ± 1.39THC: 1.28 ± 0.36
2.3 mg THCA-ATHCA: 65.36 ± 20.40 THCA: 1.33 ± 0.35
2.4 mg CBDCBD: 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 MOral Decoction 0.36 mg THC
1.6 mg THCA-A
0.42 mg CBD
4 mg CBDA
BloodBlood Effects were not reported.
THC: 1.0 THC: 2.0
THCA-A: 72.4THCA-A: 2.0
CBD: 1.5CBD: 3.0
CBDA: 94.3CBDA: 0.5
11-OH-THC: 1.211-OH-THC: 2.0
THC-COOH: 17.1THC-COOH: 3.0
THC-COOH-GLUC: 40.2THC-COOH-GLUC: 4.0
Oral fluidOral 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: 0.2THC: 2
THCA: 1.0THCA-A: 2
CBD: 0.6CBD: 2
CBDA: 14.3CBDA: 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.
Table 3. Summary of studies included in this systematic review reporting the pharmacokinetic parameters of THC following tablet administration.
ReferencesStudy Design Participants Route of AdministrationFormulation DoseCmax (ng/mL)
Mean ± SD, Median (Range)
Tmax (h)Pharmacological Effects
Timpone et al., 1997 [54]R, OL7 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.
OralTablets (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 THC2.30 ± 1.01 e1.24 ± 0.65 eSubjective 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.
OralTablets (Namisol®)5.0 mg THC2.92 ± 1.49 e0.93 ± 0.68 e
OralTablets (Namisol®)6.5 mg THC4.43 ± 1.86 e0.66 ± 0.13 e
OralTablets (Namisol®)8.0 mg THC4.69 ± 2.91 e0.73 ± 0.19 e
OralTablets (placebo)
Ahmed et al., 2014 [56]R, DB, P, DD, C6 M, 5 FOral Tablets (Namisol®)3 mg THC1.42 (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.
OralTablets (Namisol®)5 mg THC3.15 (1.54–6.95)0.92 (0.67–0.92)
Oral Tablets (Namisol®)6.5 mg THC4.57 (2.11–8.65)0.67 (0.67–0.92)
OralTablets (placebo)
De Vries et al., 2016 [57]R, DB, P, C15 M, 9 F
Patients diagnosed with chronic pancreatitis
No cannabis use in previous year
Oral Tablets (Namisol®)8 mg THCTHC: 4.01 ± 3.392.05 + 1.47Subjective 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 ± 1.502.26 ± 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.
Table 4. Summary of studies included in this systematic review reporting the pharmacokinetic parameters for THC following baked goods’ administration.
ReferencesStudy Design Participants Route of AdministrationFormulation DoseCmax (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)
SmokedCigarette19 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 cookie20 mg THC4.4–11 a 1–1.5
IntravenousNormal saline ethanolic solution 5 mg THC219, 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, dSubjective 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.
OralCannabis (plant) brownie16.9 mg THC≈ 6.8 b, d2.5 b, d
Oral THC (synthetic) brownie8.4 mg THC≈ 4.8 b, d2.5 b, d
OralTHC (synthetic) brownie16.9 mg THC≈ 9 b, d 2.5 b, d
Smoked Cannabis (plant) cigarette8.4 mg THC≈ 36 b, d 0.08 b, d
SmokedCannabis (plant) cigarette16.9 mg THC≈ 60 b, d0.08 b, d
SmokedTHC (synthetic) cigarette8.4 mg THC≈ 31 b, d 0.08 b, d
SmokedTHC (synthetic) cigarette16.9 mg THC≈ 56 b, d0.08 b, d
Oral Brownie (placebo)
SmokedCigarette (placebo)
Newmeyer et al., 2016 [60]R, DB, P, DD, C9 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 Volcano50.6 mg THC (ad libitum)
1.5 mg CBD
3.3 mg CBN
Frequent smokersFrequent 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 smokersOccasional 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)
SmokedCigarette (placebo)
Inhaled Vaporizer (placebo)
Newmeyer et al., 2017 [61]Optional dosing session under the same clinical protocol followed in Newmeyer et al., 20169 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 smokersFrequent smokersEffects were not assessed.
BloodBlood
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 fluidOral 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 smokersOccasional smokers
BloodBlood
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 fluidOral 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 Brownie10 mg THCBloodBloodSubjective 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 Brownie25 mg THCBloodBlood
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)
OralBrownie50 mg THCBloodBlood
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.
Table 5. Correlation between doses of THC and the maximum plasma concentration (Cmax) values in each formulation group.
Table 5. Correlation between doses of THC and the maximum plasma concentration (Cmax) values in each formulation group.
CapsulesDecoctionOilTabletsBaked Goods
Pearson’s r0.92710.99970.38060.91780.6365
95% confidence interval0.8492 to 0.96560.9851 to 1.000−0.9154 to 0.98240.6032 to 0.98530.09838 to 0.8866
p value (two-tailed)<0.00010,00030.61940.00130.0261
R20.85960.99940.14480.84230.4051

Share and Cite

MDPI and ACS Style

Poyatos, L.; Pérez-Acevedo, A.P.; Papaseit, E.; Pérez-Mañá, C.; Martin, S.; Hladun, O.; Siles, A.; Torrens, M.; Busardo, F.P.; Farré, M. Oral Administration of Cannabis and Δ-9-tetrahydrocannabinol (THC) Preparations: A Systematic Review. Medicina 2020, 56, 309. https://doi.org/10.3390/medicina56060309

AMA Style

Poyatos L, Pérez-Acevedo AP, Papaseit E, Pérez-Mañá C, Martin S, Hladun O, Siles A, Torrens M, Busardo FP, Farré M. Oral Administration of Cannabis and Δ-9-tetrahydrocannabinol (THC) Preparations: A Systematic Review. Medicina. 2020; 56(6):309. https://doi.org/10.3390/medicina56060309

Chicago/Turabian Style

Poyatos, Lourdes, Ana Pilar Pérez-Acevedo, Esther Papaseit, Clara Pérez-Mañá, Soraya Martin, Olga Hladun, Adrià Siles, Marta Torrens, Francesco Paolo Busardo, and Magí Farré. 2020. "Oral Administration of Cannabis and Δ-9-tetrahydrocannabinol (THC) Preparations: A Systematic Review" Medicina 56, no. 6: 309. https://doi.org/10.3390/medicina56060309

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop