1. bookVolume 71 (2020): Issue 1 (March 2020)
Journal Details
License
Format
Journal
eISSN
1848-6312
First Published
26 Mar 2007
Publication timeframe
4 times per year
Languages
English
access type Open Access

Toxicological properties of Δ9-tetrahydrocannabinol and cannabidiol

Published Online: 09 Apr 2020
Volume & Issue: Volume 71 (2020) - Issue 1 (March 2020)
Page range: 1 - 11
Received: 01 Jun 2019
Accepted: 01 Mar 2020
Journal Details
License
Format
Journal
eISSN
1848-6312
First Published
26 Mar 2007
Publication timeframe
4 times per year
Languages
English
Izvleček

Iz rastline Cannabis sativa L. so do sedaj izolirali že več kot 100 fitokanabinoidov, poleg njih pa obstaja več kot 550 sintetičnih spojin, ki delujejo na kanabinoidne receptorje CB1 in CB2. Prav tako je treba omeniti, da nobeden od ligandov kanabinoidnih receptorjev ni popolnoma CB1- ali CB2-specifičen. Zato se učinki vsakega od njih razlikujejo ne le zaradi različne moči na kanabinoidnih receptorjih, ampak tudi zato, ker lahko delujejo na druga ne-CB1 in ne-CB2 prijemališča. Najpogosteje proučevani kanabinoid je Δ9-tetrahidrokanabinol (THC). THC je delni agonist na obeh kanabinoidnih receptorjih, vendar je njegov psihoaktivni učinek povezan predvsem z aktivacijo receptorjev CB1. Receptor CB1 je eden izmed metabotropnih receptorjev z največjo ekspresijo v osrednjem živčevju, z izjemo možganskega debla. Čeprav so akutni učinki na osrednji živčni sistem THC jasno opredeljeni, je tveganje za ireverzibilne nevropsihološke učinke THC kot neodvisnega dejavnika potrebno nadalje raziskati za pojasnitev povezave. Za razliko od THC, fitokanabinoid kanabidiol (CBD) nima psihoaktivnih učinkov, vendar lahko pri sočasni uporabi vpliva na nekatere učinke THC. CBD, ki nima pomembne afinitete za CB1 in CB2, aktivira ali zavira številne uveljavljene in domnevne farmakološke tarče. CBD je kot aktivna snov v zdravilu Epidiolex® pred kratkim opravil nadzorovana klinična preskušanja, da so ocenili njegovo varnost pri zdravljenju redkih epileptičnih sindromov pri otrocih. Največjo zaskrbljenost glede varnosti so predstavljale povišane vrednosti transaminaz. Zato je treba izvesti postmarketinški nadzor toksičnosti za jetra. Članek bo povzel kar je znano o akutnih in kroničnih toksikoloških učinkih, katere študije še manjkajo in kaj so negotovosti v zvezi z varnostjo eksogenih kanabinoidov.

Keywords

Ključne besede

With the growing interest in the use of cannabinoids for medicinal purposes grows a need for a systematic review of their toxicological properties. There are still many uncertainties and contradictions remaining from the increasing number of published cannabinoid safety studies. This is because these studies vary to extremes in their methodology and quality, rendering results difficult to compare. Moreover, toxicity is not systematically covered, and there are no chronic toxicity data from well-defined exposure settings. Higher quality toxicological data are available for cannabinoid-based medicines that are manufactured today as approved drugs. However, the main indications for their use are serious and/or rare diseases, mostly after all other treatment has failed, so their toxicological profile is less detailed than that of the drugs of first choice (1).

Cannabinoid receptor ligands are a varied group of over 100 chemical compounds isolated from Cannabis sativa L. (2). The best-characterised cannabinoids found in the cannabis plant are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). They can interact with two types of cannabinoid receptors – cannabinoid type 1 (CB1) and cannabinoid type 2 (CB2) – that both belonging to the superfamily of G protein-coupled, seven-transmembrane (7TM) domain receptors (3). None of the cannabinoid receptor ligands, however, are entirely CB1- or CB2-specific. Each of these ligands therefore differs in effect, not only because they have different potency at cannabinoid receptors but also because they can interact with other non-CB1/non-CB2 targets, such as transient receptor potential channel, vanilloid subfamily member 1 (TRPV1, aka capsaicin or vanilloid receptor), G protein-coupled receptors (GPR55 and GPR119), voltage-gated ion channels, and neuronal transporters of catecholamines (4, 5, 6). Despite such diversity, there are only four cannabinoid-based medicines currently on the market: nabiximols (Sativex®), nabilone (Cesamet® or Canemes®), dronabinol (Marinol® or Syndros®), and cannabidiol (Epidiolex®) (7). Still being developed are selective synthetic cannabinoid receptor agonists, antagonists, and modulators, metabolism inhibitors [such as fatty acid amide hydrolase (FAAH) inhibitors] or inhibitors of endocannabinoid reuptake (8).

The aim of this review is to summarise what is known about acute and chronic cannabinoid toxicity, primarily based on animal and clinical studies of medicinal product safety (9). Particular attention will be paid to identifying future studies that could fill in current gaps in knowledge and uncertainties surrounding the safety of exogenous cannabinoids. This review will discuss the toxicology of chemically defined, single compounds that are either synthetic, semisynthetic, or plant-derived. We will also discuss why the combination of THC with CBD has fewer adverse effects than THC alone.

What this review will not discuss is the toxicology of medicinal or recreational cannabis use or the health issues associated with contaminants in plant extracts obtained from uncontrolled sources.

Cannabinoid receptors

THC shares the ability of endocannabinoid ligands anandamide (AEA) and 2-arachidonoylglycerol to activate both the CB1 and CB2 receptor. It is their partial agonist, as it binds to them with Ki values in the low nanomolar range. Both receptors are coupled through Gi/o proteins, negatively to adenylate cyclase and positively to mitogen-activated protein kinase (3). CB1 receptors are mainly located at the terminals of central and peripheral neurons, where they usually mediate inhibition of neurotransmitter release. CB1 is one of the G protein-coupled receptors expressed at the highest level in the central nervous system, with the notable exception of the brain stem (4, 10). This may be why THC is not associated with sudden death due to respiratory depression, which indicates its low acute toxicity. In the brain, CB1 receptors are particularly concentrated in the hippocampus and cerebral cortex (areas involved in memory and cognition), olfactory areas, basal ganglia and cerebellum (areas involved in motor activity and posture control), hypothalamus (area involved in appetite regulation and energy homeostasis), limbic cortex (area involved in sedation), and neocortex (area involved in the executive function). CB1 is also found in peripheral nervous organs (lungs, liver, bowel, thyroid, uterus, placenta, and testicles). Therefore, these sites can also be the targets of cannabinoid effects. CB2 receptors are primarily associated with cells governing the immune function, such as splenocytes, macrophages, monocytes, microglia, and B- and T-cells. Recently, CB2 receptors have also been reported in other cells, often up-regulated under pathological conditions (5). The functions of these receptors include modulation of cytokine release and immune cell migration. CB2 receptors are expressed in the brain by microglia, blood vessels, and by some neurons (4, 10). However, their action has not been elucidated.

In contrast to THC, CBD does not seem to be psychoactive and has low affinity for CB1 and CB2 receptors (4). This is why its research has focused on non-CB1/non-CB2 targets (see THC/CBD interactions below). When interpreting the effects of cannabinoids, we should bear in mind that cannabinoid receptors are members of the rhodopsin-like family of 7TM receptors, at which, according to Kenakin (11), the efficacy of agonist depends on cell type and its condition. Therefore, it is difficult to predict the therapeutic behaviour of cannabinoid receptor agonists. This is probably why higher release of endocannabinoids can be protective in one and damaging in another case.

Toxicological properties of THC

Apart from natural THC, the most reliable toxicological data available to date are for synthetic THC dronabinol and synthetic THC analogue nabilone. Nabilone has a similar chemical structure and is twice as potent as THC at the CB1 and CB2 receptors (12). The main indication for dronabinol and nabilone is nausea and vomiting in adult patients receiving chemotherapy when conventional antiemetics fail to do the job. Dronabinol is also indicated for anorexia in adults with AIDS. There are no safety profiles for dronabinol and nabilone in paediatric (<18 years) and elderly (>65 years) populations. The starting dose of dronabinol is 2.5 mg, administered twice daily as capsules for oral use. The maximum recommended dosage is 20 mg/day (4–6 doses a day). Dronabinol is also administered as a 5 mg/ mL oral solution. The usual nabilone dose is 1 or 2 mg twice a day, and the maximum recommended dosage is 6 mg/day, administered as capsules for oral use (13, 14). Since both are used short-term, data on chronic effects in humans are not available.

Pharmacokinetics/toxicokinetics of THC

The bioavailability of dronabinol is low (4–20 %) because of its high lipid solubility and extensive first-pass hepatic metabolism (15, 16). Its effects do not show clear dose dependence (17). Due to lipid solubility, the apparent volume of distribution is high (10 L/kg). Dronabinol is extensively metabolised in the liver, primarily by cytochrome P450 enzymes CYP2C9 and CYP3A4. CYP2C9 is probably responsible for the formation of the primary active metabolite hydroxy-Δ9-THC. Pharmacogenomics studies indicate two to three times higher plasma THC in individuals with a less active form of CYP2C9, so adverse drug reaction in these individuals may be more frequent and/or severe. The major route of excretion is faeces (65 %), and the minor is urine (20 %) (16). Urinary metabolites of dronabinol are identical to those of marijuana and may be excreted over long time (18).

Nabilone has better bioavailability (at least 60 %) than dronabinol and demonstrates dose linearity (15, 19). Multiple cytochrome P450 enzymes extensively metabolise nabilone to various metabolites, which have not been fully characterised yet. Two major metabolic pathways are probably involved in the biotransformation of nabilone: 1) enzymatic reduction of the 9-keto group to form carbinol metabolites; and 2) direct enzymatic oxidation of the aliphatic side-chain to produce carboxylic and hydroxylic analogues. The formation of carbinol metabolites is a major nabilone metabolic pathway in dog. Hydroxylic analogues appear to be more important in rhesus monkey and man. Carbinols are long-lived metabolites that accumulate in the plasma and concentrate in the brains of treated dogs over time (see chronic toxicity) (20). Nabilone and its metabolites are primarily eliminated in faeces (~65 %) and to a lesser extent in urine (~20 %) (14, 17). Although no accumulation of nabilone was observed after repeated doses, some accumulation was observed for its metabolites (21).

Non-clinical toxicity of THC

Acute oral toxicity of THC in rats is lower in males (LD50=1910 mg/kg) than in females (LD50=1040 mg/kg) (22). The LD50 of oral nabilone is >1000 mg/kg in rats of both sexes (21). The signs of acute toxicity of THC and nabilone are similar and include lower respiratory rate, ataxia, decreased activity, catatonia, hypothermia, hypersensitivity to touch, and generalised body twitching. Death was reported to be due to respiratory arrest (21, 22).

Sub-chronic and chronic effects of THC (5, 15, 50, 150, and 500 mg/kg/day) administered by gavage were assessed in rats in a 13-week study followed by a 9-week recovery period and in a 2-year study (12.5, 25, and 50 mg/kg/day) (23). Briefly, THC-treated rats had lower body weight than controls and exhibited convulsions, hyperactivity, and changes in the reproductive organs of both male and female rats. Reduced body weight was notable even at low dose exposure and was attributed to metabolic changes caused by THC. Weight loss was not associated with lower feed consumption but with increased energy consumption (evidenced by higher plasma corticosterone levels) needed for hyperactivity, adaptation, and detoxification from THC. Convulsions and hyperactivity were observed at all doses. The onset and frequency of convulsions were also dose-related. However, Chan et al. (23) observed no histological changes in brain tissue of rats with a history of THC-related convulsion or seizures. Luthra et al. (24) reported generalised depression, followed by hyperactivity, irritability, aggressiveness, and convulsion in rats treated with THC for 119 days. The highest dose of THC in a sub-chronic study in rats induced testicular atrophy and uterine and ovarian hypoplasia (23). This study also found higher serum FSH and LH at all doses.

Nabilone was assessed in two chronic toxicity studies (21). The one in beagle dogs (0.5, 1.0, 2.0 mg/kg/day) was planned to last one year but was terminated after seven months due to high mortality. Most deaths were preceded by convulsions, and toxicity was attributed to accumulation of carbinol metabolites in the brain over time. In contrast to dogs, nabilone chronic toxicity was minimal in rhesus monkeys receiving doses of up to 2.0 mg/kg/day for one year. Transient periods of anorexia, emesis, and ataxia were observed only at the highest dose.

Chan et al. (23) also evaluated THC carcinogenicity in rats and mice and found no evidence in rats at doses of up to 50 mg/kg/day [~20 times the maximal human recommended dose (MHRD)]. In mice, THC produced thyroid follicular cell adenoma (a common benign neoplasm of the thyroid) in both sexes, but the effect was not dose-dependent, as the hyperplasia was increased compared to control at all doses and in both sexes. It is unclear what these findings mean. Carcinogenicity studies have not been performed with nabilone.

Genotoxicity

THC and nabilone have no mutagenic potential (11, 12, 13, 23). Positive Ames and skin test results in mice for THC in some in vitro tests are attributed to cytotoxic rather than mutagenic action (25).

Reproductive toxicity

THC was evaluated in an oral embryo-foetal developmental study in rats (at doses ranging from 12.5 to 50 mg/kg/day) (26) and in rabbits (0.5, 1.5, 5 and 15 mg/ kg/day) (27). No teratogenic effects were observed in rats. Increased foetal mortality and early resorption were associated with maternal toxicity, which manifested itself as lower weight gain. In rabbits, one third of the foetuses in the high-dose group had multiple anomalies (such as acrania and spina bifida). In a single-generation reproductive study (28), male and female rats received 0.5, 1.5, and 5 mg/ kg/day of THC by gavage. Offspring to mothers receiving 1.5 and 5 mg/kg/day showed a dose-related drop in survival at day 12 of lactation and at weaning.

A reproduction study of nabilone in rats (1.4, and 12 mg/ kg/day) and rabbits (0.7, 1.6, and 3.3 mg/kg/day) (29) showed no teratogenic effects. However, it did find dose-related developmental toxicity, such as embryo death, foetal resorption, decreased foetal weight, and disrupted pregnancy. Another study in rats (24) revealed postnatal developmental toxicity of nabilone at 1.4 and 12 mg/kg/ day), manifested by smaller litter size and lower survival as well as lower initial body weight and hypothermia in pups from the high-dose group.

There are no sufficient data on pregnancy outcomes in women exposed to dronabinol (THC) or nabilone.

THC toxicity in clinical trials

Safety data on dronabinol come from 10 randomised, double-blind, placebo-controlled clinical trials. In one trial (30) patients with AIDS-related anorexia (N=139) were receiving dronabinol as appetite stimulant (5 mg/day), and in nine trials patients with cancer (N=454) were receiving dronabinol as antiemetic in the dose range of 2.5–40 mg/ day (31, 32, 33, 34, 35, 36, 37, 38, 39) for no longer than six weeks. The most frequently reported adverse events (33 %) in patients with AIDS were euphoria, dizziness, somnolence, and thinking abnormalities. The most common adverse events in patients receiving the antiemetic dronabinol were drowsiness, dizziness and transient impairment of sensory and perceptual functions. Patients from both studies (24% in antiemetic and 8% in appetite stimulant) reported dose-related “highs” (elation, laughter, and heightened awareness). The frequency of adverse effects on the central nervous system (CNS) increased with doses, and their severity greatly varied between patients. After oral administration, dronabinol had an action onset of approximately 30 min to one hour and a peak effect at two to four hours (40). Psychoactive effects lasted four to six hours. Other than those affecting the nervous system, the most frequent adverse effects were gastrointestinal (abdominal pain, nausea, and vomiting) and cardiovascular (palpitation, tachycardia, vasodilatation/facial flush) (30, 31, 32, 33, 34, 35, 36, 37, 38, 39). The following were the most serious adverse effects of dronabinol: neuropsychiatric, haemodynamic instability, seizure, paradoxical nausea, vomiting, and abdominal pain. Dronabinol should be discontinued in patients experiencing a psychotic reaction or showing cardiovascular effects (tachycardia, transient changes in blood pressure) and used with caution in patients with a history of epilepsy or recurrent seizures (13).

Nabilone has systematically been evaluated in controlled clinical trials that lasted up to nine weeks (41, 42, 43). The lowest nabilone dose (2 mg) had a few adverse effects, whereas a 3–5 mg dose closely mirrored dronabinol’s (25 mg) effects (18).

THC addiction and dependence

High levels of CB1 receptors are found in the brain areas that are part of the mesocorticolimbic dopaminergic pathway and are implicated in motivational and reward processes (44). Being partial CB1 receptor agonists, THC and its analogues should be tested for their addictive potential (45). Many abused drugs that can lead to addiction increase synaptic dopamine levels in the human limbic striatum. The same was reported for THC in human studies in healthy participants (46, 47, 48). Dopamine release was small compared to amphetamine, cocaine, alcohol (10–15 %), and nicotine (~10 %).

First studies in monkeys (49, 50) failed to show the rewarding effects of THC, but newer studies with intravenous dronabinol injection (1–6 μg/kg) confirmed it in squirrel monkeys (51, 52). Another widely used predictor of a reinforcing (and therefore addictive) effect is the conditional place preference (CCP) test, in which a compartment in a cage is associated (paired) with a tested substance. Lepore et. al. (53) reported that CCP depended on the dose and intervals between administration and that dronabinol doses of 2 or 4 mg/kg every 24 h produced a reliable shift in favour of the dronabinol-paired compartment.

Reinforcing effects have also been observed in humans (12). Nabilone (4–8 mg/day) and dronabinol (10–20 mg/ day) produced stronger marijuana-like subjective effects, such as feeling good, feeling “high”, and feeling “stoned” than placebo. Nabilone had a slower onset of the peak subjective effects.

Chronic therapy with dronabinol can lead to physical dependence. One human study (17) showed that dronabinol doses of 210 mg/day (~10 times higher than MHRD) administered for 12 to 16 consecutive days produced withdrawal syndrome within 12 h after discontinuation. Initial symptoms were irritability, insomnia, and restlessness. By hour 24 of discontinuation, withdrawal symptoms intensified to include “hot flashes”, sweating, rhinorrhoea, loose stool, hiccoughs, and anorexia. We still do not know whether nabilone can also lead to physical dependence. Patients that participated in clinical trials for up to five days showed no withdrawal symptoms after discontinuation of dosing (54).

Toxicological properties of CBD

As a 99 % pure extract from C. sativa, active substance cannabidiol was first approved in June 2018 under proprietary name Epidiolex® (55). The United States Food and Drug Administration (US FDA) and European Medicines Agency (EMA) approved it for the treatment of seizures associated with Lennox-Gestaut (LGS) and Dravet syndrome (DS) in patients two years of age or older. Epidiolex® is administered as a 100 mg/mL oral solution. The starting dose is 2.5 mg/kg twice a day and the maximum recommended dose is 10 mg/kg twice a day (20 mg/kg/day) (55, 56). Considering that Epidiolex® has been approved for treatment in children, CBD has become the most extensively toxicologically tested cannabinoid, and thus the most reliable source of toxicological data. However, because of the seriousness of the indications and failure of patients to respond to existing medication, Epidiolex® was approved in spite of certain deficiencies in the safety assessment (e.g., inadequate safety assessment of major human metabolite 7-COOH-CBD). Additional studies listed in Table 1 should therefore be carried out as part of post-marketing surveillance to obtain a complete safety profile of CBD. Furthermore, no clinical trial with Epidiolex® has been conducted in patients older than 55 years, so its safety profile does not cover the elderly population. General recommendation is to start with the lowest dose (56).

Recommended post-marketing studies to obtain a complete safety profile of cannabidiol (CBD)

Non-clinical toxicity studies
Toxicity studies with CBD metabolite 7-COOH-cannabidiol in rat:

- embryo-foetal developmental study

- pre- and postnatal developmental study

- juvenile animal toxicity study

- 2-year carcinogenicity study with gavage

Toxicity studies with CBD

- 2-year carcinogenicity study in mouse

- 2-year carcinogenicity study in rat with gavage

Clinical studies

- Potential for chronic liver injury

- Effect on glomerular filtration rate

- Pregnancy outcome study

- QT interval prolongation trial at the maximum tolerable dose

Drug-drug interaction trials in healthy volunteers

CBD effect on the pharmacokinetics of:

- caffeine

- sensitive CYP2B6

cytochrome P450

and CYP2C9 substrate

- sensitive UGP1A9

UDP-glucuronosyltransferase

and UGTB7 substrate

Strong CYP3A inhibitor effects on pharmacokinetics of CBD

Strong 2C9 inhibitor effects on pharmacokinetics of CBD

Rifampin effects on pharmacokinetics of CBD

Since CBD is derived from C. sativa, Table 2 presents a thorough assessment of the abuse and dependence potential of Epidiolex® (4, 57, 58, 59). A human study (58) found marginal abuse potential at a higher therapeutic dose (1500 mg/day) and supratherapeutic dose (4500 mg/day), but there is little other evidence that CBD could cause addiction. The results of a human dependence study of CBD were negative (59).

Cannabidiol (CBD) abuse potential

TYPE OF STUDY RESULTS
Receptor binding studies

- cannabinoid receptors no significant affinity

- opioid receptors no significant affinity

Non-clinical studies evaluating general behaviour (similarity to THC)

- tetrad test no meaningful abuse related signal

- drug discrimination study no meaningful abuse related signal

- self-administration study no meaningful abuse related signal

Clinical studies evaluating efficacy and safety in patients with LGS

Lennox-Gastaut syndrome

or DS

Dravet syndrome


- Phase I clinical study no euphoria or other abuse-related signals

- Phase II/III studies could not be evaluated

concomitant use of other seizure drugs and limited capacity of patients


Phase I human abuse potential (HAP) study (N=40, with 35 completers)

randomized, double blind, placebo-controlled trial

subjects: healthy recreational poly-drug users

positive control: THC (10, 30 mg), alprazolam (2 mg)

negative control: placebo

mean DRUG LIKING SCORE

lower therapeutic dose: 750 mg/day not significantly different

higher therapeutic dose: 1500 mg/day significantly different (very small increase)

supra-therapeutic dose: 4500 mg/day significantly different (very small increase)

Human physical dependence study following chronic administration

3 days after discontinuation no withdrawal signs and symptoms
Pharmacokinetics/toxicokinetics of CBD

Plasma CBD concentrations show a nonlinear increase with dose and 6.5 % bioavailability at a 3000-mg dose (60).

CBD absorption increases three times with a high-fat meal and six times with new oral delivery system for lipophilic active compounds (61, 62). Its high estimated volume of distribution (18,800—30,959 L) indicates accumulation of CBD in body fat (63). CBD is extensively metabolised in the liver and gut, mainly by the CYP2C19, CYP3A4, UGT1A7, UGT1A9, and UGT2B7 enzymes (64). Drug interaction trials to assess the effect of CBD on these enzymes in healthy volunteers will be conducted during the post-marketing period (Table 1) (55, 56). The metabolism of CBD is very complex, especially in hepatocytes. The main human metabolite is 7-carboxy-cannabidiol (7-COOH-CBD; ~90 % of all drug-related substances measured in the plasma) (64). Its toxicological profile has not been investigated because experimental animals for toxicological studies (mice, rats, and dogs) do not metabolise CBD to a comparable extent as humans (65). The major concern with 7-COOH-CBD could be its reactive acyl-glucuronide (66) The primary excretion route of CBD is through faeces (84 %), followed by urine (8 %) (63).

Non-clinical toxicology of CBD

In a study of acute effects in rhesus monkeys (67), intravenous CBD caused death by respiratory arrest and cardiac failure at doses above 200 mg/kg (LD50=212 mg/ kg). At the lower dose of 150 mg/kg, survivors recovered in one to three days, and liver weights increased from 19 to 142 %. In the part of the study investigating subchronic effects (after 90 days of oral administration), the authors reported inhibition of spermatogenesis at the highest oral dose of 300 mg/kg (67).

Animal studies of CBD alone described below make part of the Epidiolex® European Public Assessment Report (EPAR, EMA’s scientific monography) (56). To the best of my knowledge, they have not been published and therefore no further detail or original references are currently available. All these studies were conducted in accordance with medicinal product safety standards and protocols and reviewed by the EMA committee (9).

Two oral chronic toxicity studies (referred to in 56) have assessed CBD in Wistar rats (receiving 15, 50, or 150 mg/ kg/day for 6 months) and Beagle dogs (receiving 10, 50, 100 mg/kg/day for 9 months). In both species the primary target organ was the liver. Hepatocellular hypertrophy was detected at all doses, accompanied by an increase in alanine transferase (ALT) and alkaline phosphatase (ALP).

A 104-week oral carcinogenicity study in Wistar rats (referred to in 56) revealed no drug-related neoplastic findings. However, the study had several drawbacks, including impure active substance, excessive effect of body weight, and unknown exposure to the two major human metabolites.

The genotoxic potential of CBD was also investigated in a standard battery of tests, but their results were negative for mutagenicity and clastogenicity (referred to in 56).

A full battery of oral reproductive and developmental studies has been conducted with purified CBD. In an embryo-foetal development study in Wistar rats, litter loss was noted at the highest applied dose of 250 mg/kg. In a prenatal and postnatal development study (referred to in 56) rat exposure to the highest doses (150 and 200 mg/kg/ day) affected reproductive organs (smaller testes in males, reduced fertility index in females). A high dose of 125 mg/ kg also reduced foetal body weight in New Zealand white rabbit, which was related to maternal toxicity. The developmental toxicity in rabbits occurred at maternal plasma concentration similar to human at therapeutic doses (referred to in 56). In rats these concentrations were much higher. No adequate data are available on pregnancy outcome in women exposed to CBD.

A juvenile toxicity study in Wistar rats (referred to in 56) showed neurobehavioral deficits and delayed sexual maturation in males. A no observed effect level (NOAEL) was 150 mg/kg/day.

Clinical toxicology of CBD

Safety data on Epidiolex® were obtained from four randomised, double-blind, placebo-controlled multicentre trials with exposure to CBD doses of 5, 10, and 20 mg/kg/day (68, 69, 70). These phase II studies were conducted in 2 to 55 year-old patients with LGS (N=235) and DS (N=88) for up to 14 weeks.

Additional non-controlled safety data have been obtained from an ongoing open-label Phase III study (Study 1415) in LGS and DS patients (N=644), which is being conducted at 38 sites in the USA and Australia. Since this trial is not finished, an interim analysis of long-term safety was conducted (71, 72).

The most common adverse events in CBD-treated patients affected the following systems: CNS (somnolence, sedation), gastrointestinal tract (lower appetite, diarrhoea), liver (higher transaminase), and the lungs (pneumonia). The severity of these events was generally mild to moderate. Diarrhoea, weight loss, higher ALT, and somnolence/ sedation/lethargy were all dose-related. There were two serious cases of transaminase elevation, two severe events with rash (one consistent with a hypersensitivity reaction) and three severe cases of appetite loss. The CBD-treated and the placebo group did not differ in the rate of respiratory failure. Children had lower weight, which was associated to a certain extent with appetite loss (68, 69, 70, 71).

Treatment with CBD is clearly associated with an increased risk of hepatotoxicity (68, 69, 70, 71). Higher doses of CBD and concomitant use of valproate increase the risk of transaminase elevation in patients. Two patients concomitantly treated with valproate experienced toxic hepatocellular injury, metabolic acidosis, and encephalopathy. There appears to be no pharmacokinetic interaction between CBD and valproate, although a pharmacodynamical interaction is currently being investigated. The potential of CBD to cause chronic liver injury should be evaluated in the post-marketing period (55, 56) (Table 1).

Mechanisms of THC/CBD interactions

In spite of its low affinity for the CB1 and CB2 receptors, CBD can interfere with some THC adverse effects, particularly in the brain, without interfering with the intended THC effects, such as muscle relaxation (73). Understanding pharmacodynamic interactions between THC and CBD can be quite a challenge. CBD is a ligand with very low affinity for the CB1 receptor but can still increase CB1 constitutional or endocannabinoid activity (5), which has been confirmed by. thermodynamic findings that CBD increases membrane fluidity and thereby the activity of the CB1 receptor (74). Another mechanism of action is that CBD increases the levels of primary endocannabinoids AEA and 2-arachidonyl-glycerol (2-AG) (5). CBD may also interfere with THC through interaction with other non-CB1 receptors and enzymes in the ‘expanded endocannabinoid system’ (5). In their systematic review McPartland et al. (5) propose several non-CB1 receptor mechanisms of CBD antagonising or potentiating THC effects. For example, CBD may attenuate the anxiogenic effect of THC by acting as a direct or indirect agonist on serotonin 1A receptors (5-HT1A). In contrast, it can potentiate THC action on CB1 receptors by reducing peripheral hyperalgesia via TRPV1 channels (75). Sativex®, as a mixture of THC and CBD, consequently provided better antinociception than THC given on its own 76).

In terms of pharmacokinetic CBD/THC interaction, CBD may impair THC hydrolysis by CYP450 enzymes (77). The inhibition of THC metabolism may vary with species, timing of administration (CBD pre-administration vs co-administration), and CYP isoenzymes. In rats or mice THC effects are potentiated when CBD is administered 30 min to 24 h before THC but mitigated if co-administered (78). In humans, no pharmacokinetic interactions between THC and CBD at clinically relevant doses have been reported (79). Co-administration of CBD with THC in one study (80) yielded similar maximum plasma levels of THC as when it was administered alone. Whether CBD will antagonise or potentiate THC effects also seems to depend on their administration ratio, and this ratio varies with species (5).

Toxicology of THC/CBD combinations

The combination of THC and CBD in a 1:1 ratio makes the active substance nabiximols of the cannabinoid-based medicine Sativex® (81). It is an oromucosal spray approved for the treatment of multiple sclerosis-associated spasticity in adult patients when all other treatment has failed. There is no safety profile of nabiximols in children (>18 years) and the elderly, even though clinical trials included patients up to 90 years of age. Elderly patients may be more susceptible to some adverse effects in the CNS. The oromucosal (e.g. sub-lingual) route resolves the problem of variable bioavailability (typically 6 to 20 %) of orally administered cannabinoids due to first-pass metabolism. Each 100 μL spray contains 2.7 mg THC and 2.5 mg CBD. The starting dose is two sprays per day and the maximum dose is 10–12 sprays per day (corresponding to 32.4 mg THC and 30 mg CBD) (81).

A study using a rat model of Huntington’s disease showed that nabiximols can up-regulate CB1 gene expression (82). CBD increases the levels of the primary endocannabinoids AEA and 2-arachidonyl-glycerol (2-AG) (6).

The most common adverse effects of nabiximols in clinical trials conducted in patients with multiple sclerosis were dizziness, fatigue and gastrointestinal disorders (e.g. nausea, vomiting, diarrhoea) (82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92). These adverse effects and poor efficacy were the main reasons for some patients to discontinue therapy (88, 90). In patients with multiple sclerosis the risk of accidental injury may be increased (83, 87, 92, 93, 94). There is little evidence of abuse (addiction) or dependence, and the risk of either to develop is small. However, trials to date have mainly used therapeutic doses, and it is possible that supratherapeutic doses could cause addiction and/or dependence (85, 87, 92, 93, 94).

Conclusion

In spite of uncertainties about the safety of cannabinoids, there are no doubts about the acute neurological and cardiovascular effects of THC. However, THC is not associated with sudden death due to respiratory depression as is the case with opioid analgesics. Long-term cognitive, psychological, and endocrine effects of THC are still being investigated.

As for CBD, it can be toxic to the liver and increases the risk of somnolence and sedation, but the most commonly observed adverse events in controlled clinical trials were mild to moderate. However, these clinical trials included a small number of subjects and some aspects require continued pharmacovigilance. Regardless of different views on the subject, cannabinoid-based medicines need to be assessed just as any other substance in terms of quality, efficacy, and safety.

Toksikološke lastnosti kanabinoidov

Recommended post-marketing studies to obtain a complete safety profile of cannabidiol (CBD)

Non-clinical toxicity studies
Toxicity studies with CBD metabolite 7-COOH-cannabidiol in rat:

- embryo-foetal developmental study

- pre- and postnatal developmental study

- juvenile animal toxicity study

- 2-year carcinogenicity study with gavage

Toxicity studies with CBD

- 2-year carcinogenicity study in mouse

- 2-year carcinogenicity study in rat with gavage

Clinical studies

- Potential for chronic liver injury

- Effect on glomerular filtration rate

- Pregnancy outcome study

- QT interval prolongation trial at the maximum tolerable dose

Drug-drug interaction trials in healthy volunteers

CBD effect on the pharmacokinetics of:

- caffeine

- sensitive CYP2B6

cytochrome P450

and CYP2C9 substrate

- sensitive UGP1A9

UDP-glucuronosyltransferase

and UGTB7 substrate

Strong CYP3A inhibitor effects on pharmacokinetics of CBD

Strong 2C9 inhibitor effects on pharmacokinetics of CBD

Rifampin effects on pharmacokinetics of CBD

Cannabidiol (CBD) abuse potential

TYPE OF STUDY RESULTS
Receptor binding studies

- cannabinoid receptors no significant affinity

- opioid receptors no significant affinity

Non-clinical studies evaluating general behaviour (similarity to THC)

- tetrad test no meaningful abuse related signal

- drug discrimination study no meaningful abuse related signal

- self-administration study no meaningful abuse related signal

Clinical studies evaluating efficacy and safety in patients with LGS

Lennox-Gastaut syndrome

or DS

Dravet syndrome


- Phase I clinical study no euphoria or other abuse-related signals

- Phase II/III studies could not be evaluated

concomitant use of other seizure drugs and limited capacity of patients


Phase I human abuse potential (HAP) study (N=40, with 35 completers)

randomized, double blind, placebo-controlled trial

subjects: healthy recreational poly-drug users

positive control: THC (10, 30 mg), alprazolam (2 mg)

negative control: placebo

mean DRUG LIKING SCORE

lower therapeutic dose: 750 mg/day not significantly different

higher therapeutic dose: 1500 mg/day significantly different (very small increase)

supra-therapeutic dose: 4500 mg/day significantly different (very small increase)

Human physical dependence study following chronic administration

3 days after discontinuation no withdrawal signs and symptoms

Murphy SM1, Puwanant A, Griggs RC; Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) and Inherited Neuropathies Consortium (INC) Consortia of the Rare Disease Clinical Research Network. Unintended effects of orphan product designation for rare neurological diseases. Ann Neurol 2012;72:481–90. doi: 10.1002/ana.23672 Murphy SM1 Puwanant A Griggs RC Consortium for Clinical Investigations of Neurological Channelopathies (CINCH) and Inherited Neuropathies Consortium (INC) Consortia of the Rare Disease Clinical Research Network. Unintended effects of orphan product designation for rare neurological diseases Ann Neurol 201272481 90 10.1002/ana.23672Open DOISearch in Google Scholar

ElSohly MA, Radwan MM, Gul W, Chandra S, Galal A. Phytochemistry of Cannabis sativa L. Prog Chem Org Nat Prod 2017;103:1–36. doi: 10.1007/978-3-319-45541-9_1 ElSohly MA Radwan MM Gul W Chandra S Galal A Phytochemistry of Cannabis sativa L Prog Chem Org Nat Prod 20171031 36 10.1007/978-3-319-45541-9_1Open DOISearch in Google Scholar

Pertwee RG. Pharmacological actions of cannabinoids. In: Pertwee RG, editors. Cannabinoids. Handbook of experimental pharmacology. Vol 168. Berlin, Heidelberg: Springer; 2005. p. 1–51. Pertwee RG Pharmacological actions of cannabinoids In Pertwee RG editors Cannabinoids. Handbook of experimental pharmacology. Vol 168 Berlin, Heidelberg Springer 2005 p 15110.1007/3-540-26573-2_1Search in Google Scholar

Pertwee RG. The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin. Br J Pharmacol 2008;153:199–215. doi: 10.1038/sj.bjp.0707617 Pertwee RG The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: Δ9-tetrahydrocannabinol, cannabidiol and Δ9-tetrahydrocannabivarin Br J Pharmacol 2008153199 215 10.1038/sj.bjp.0707617Open DOISearch in Google Scholar

McPartland JM, Duncan M, Di Marzo V, Pertwee R. Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review. Br J Pharmacol 2015;172:737–53. doi: 10.1111/ bph.12944 McPartland JM Duncan M Di Marzo V Pertwee R Are cannabidiol and Δ9-tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review Br J Pharmacol 2015172737 53 10.1111/bph.12944Open DOISearch in Google Scholar

Boggs DL, Nguyen JD, Morgenson D, Taffe MA, Ranganathan M. Clinical and preclinical evidence for functional interactions of cannabidiol and Δ9-tetrahydrocannabinol. Neuropsychopharmacology 2018;43:142–54. doi: 10.1038/npp.2017.209 Boggs DL Nguyen JD Morgenson D Taffe MA Ranganathan M Clinical and preclinical evidence for functional interactions of c a n n a bi d i o l a n d Δ 9-tetrahydrocannabinol Neuropsychopharmacology 201843142 54 10.1038/npp.2017.209Open DOISearch in Google Scholar

Abuhasira R, Shbiro L, Landschaft Y. Medical use of cannabis and cannabinoids containing products - Regulations in Europe and North America. Eur J Intern Med 2018;49:2–6. doi: 10.1016/j.ejim.2018.01.001 Abuhasira R Shbiro L Landschaft Y Medical use of cannabis and cannabinoids containing products - Regulations in Europe and North America Eur J Intern Med 2018492 6 10.1016/j.ejim.2018.01.001Open DOISearch in Google Scholar

Cravatt BF, Lichtman AH. Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system. Curr Opin Chem Biol 2003;7:469–75. doi: 10.1016/S1367-5931(03)00079-6 Cravatt BF Lichtman AH Fatty acid amide hydrolase: an emerging therapeutic target in the endocannabinoid system Curr Opin Chem Biol 20037469 75 10.1016/S1367-5931(03)00079-6Open DOISearch in Google Scholar

Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Annex 1, Analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products. [displayed 05 March 2020]. Available at https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdf Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to medicinal products for human use. Annex 1, Analytical, pharmacotoxicological and clinical standards and protocols in respect of the testing of medicinal products. [displayed 05 March 2020] Available at https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-1/dir_2001_83_consol_2012/dir_2001_83_cons_2012_en.pdfSearch in Google Scholar

Pertwee RG. Emerging strategies for exploiting cannabinoid receptor agonists as medicines. Br J Pharmacol 2009;156:397–411. doi: 10.1111/j.1476-5381.2008.00048.x Pertwee RG Emerging strategies for exploiting cannabinoid receptor agonists as medicines Br J Pharmacol 2009156397 411 10.1111/j.1476-5381.2008.00048.x269768119226257Open DOISearch in Google Scholar

Kenakin T. New concepts in pharmacological efficacy at 7TM receptors: IUPHAR review 2. Br J Pharmacol 2013;168:554–75. doi: 10.1111/j.1476-5381.2012.02223.x Kenakin T New concepts in pharmacological efficacy at 7TM receptors: IUPHAR review 2 Br J Pharmacol 2013168554 75 10.1111/j.1476-5381.2012.02223.x357927922994528Open DOISearch in Google Scholar

Bedi G, Cooper ZD, Haney M. Subjective, cognitive and cardiovascular dose-effect profile of nabilone and dronabinol in marijuana smokers. Addict Biol 2013;18:872–81. doi: 10.1111/j.1369-1600.2011.00427.x Bedi G Cooper ZD Haney M Subjective, cognitive and cardiovascular dose-effect profile of nabilone and dronabinol in marijuana smokers Addict Biol 201318872 81 10.1111/j.1369-1600.2011.00427.xOpen DOISearch in Google Scholar

Abbott laboratorie, Limited. NMarinol® Product Monograph [displayed 14 April 2019]. Available at https://pdf.hres.ca/dpd_pm/00013378.PDF Abbott laboratorie, Limited. NMarinol® Product Monograph [displayed 14 April 2019 Available at https://pdf.hres.ca/dpd_pm/00013378.PDFSearch in Google Scholar

Valeant Canada Limited. NCesamet® Product Monograph [displayed 28 April 2019]. Available at https://pdf.hres.ca/dpd_pm/00007760.PDF Valeant Canada Limited. NCesamet® Product Monograph [displayed 28 April 2019 Available at https://pdf.hres.ca/dpd_pm/00007760.PDFSearch in Google Scholar

Ben Amar M. Cannabinoids in medicine: A review of their therapeutic potential. J Ethnopharmacol 2006;21:1–25. doi: 10.1016/j.jep.2006.02.001 Ben Amar M Cannabinoids in medicine: A review of their therapeutic potential J Ethnopharmacol 2006211 25 10.1016/j.jep.2006.02.001Open DOISearch in Google Scholar

McGilveray IJ. Pharmacokinetics of cannabinoids. Pain Res Manag 2005;10(Suppl):15A-22A. doi: 10.1155/2005/242516 McGilveray IJ. Pharmacokinetics of cannabinoids. Pain Res Manag 200510Suppl15A 22A 10.1155/2005/242516Open DOISearch in Google Scholar

Haney M, Ward AS, Comer SD, Foltin RW, Fischman MW. Abstinence symptoms following oral THC administration to humans. Psychopharmacology (Berl) 1999;141:385–94. doi: 10.1007/s002130050848 Haney M Ward AS Comer SD Foltin RW Fischman MW Abstinence symptoms following oral THC administration to humans Psychopharmacology (Berl) 1999141385 94 10.1007/s002130050848Open DOISearch in Google Scholar

Lile JA, Kelly TH, Hays LR. Substitution profile of the cannabinoid agonist nabilone in human subjects discriminating δ9-tetrahydrocannabinol. Clin Neuropharmacol 2010;33:235–42. doi: 10.1097/WNF.0b013e3181e77428 Lile JA Kelly TH Hays LR Substitution profile of the cannabinoid agonist nabilone in human subjects discriminating δ9-tetrahydrocannabinol Clin Neuropharmacol 201033235 42 10.1097/WNF.0b013e3181e77428Open DOISearch in Google Scholar

Lemberger L, Rubin A, Wolen R, DeSante K, Rowe H, Forney R, Pence P. Pharmacokinetics, metabolism and drug-abuse potential of nabilone. Cancer Treat Rev 1982;9(Suppl B): 17– 23. doi: 10.1016/s0305-7372(82)80031-5 Lemberger L Rubin A Wolen R DeSante K Rowe H Forney R Pence P Pharmacokinetics, metabolism and drug-abuse potential of nabilone Cancer Treat Rev 19829Suppl B 1723 10.1016/s0305-7372(82)80031-5Open DOISearch in Google Scholar

Sullivan HR, Hanasono GK, Miller WM, Wood PG. Species specificity in the metabolism of nabilone. Relationship between toxicity and metabolic routes. Xenobiotica 1987;17:459–68. doi: 10.3109/00498258709043952 Sullivan HR Hanasono GK Miller WM Wood PG Species specificity in the metabolism of nabilone Relationship between toxicity and metabolic routes. Xenobiotica 198717459 68 10.3109/00498258709043952Open DOISearch in Google Scholar

Hanasono GK, Sullivan HR, Gries CL, Jordan WH, Emmerson JL. A species comparison of the toxicity of nabilone, a new synthetic cannabinoid. Fundam Appl Toxicol 1987;9:185–97. doi: 10.1016/0272-0590(87)90042-x Hanasono GK Sullivan HR Gries CL Jordan WH Emmerson JL A species comparison of the toxicity of nabilone, a new synthetic cannabinoid Fundam Appl Toxicol 19879185 97 10.1016/0272-0590(87)90042-xOpen DOISearch in Google Scholar

Thompson GR, Rosenkrantz H, Schaeppi UH, Braude MC. Comparison of acute oral toxicity of cannabinoids in rats, dogs and monkeys. Toxicol Appl Pharmacol 1973;25:363–72. doi: 10.1016/0041-008x(73)90310-4 Thompson GR Rosenkrantz H Schaeppi UH Braude MC Comparison of acute oral toxicity of cannabinoids in rats, dogs and monkeys Toxicol Appl Pharmacol 197325363 72 10.1016/0041-008x(73)90310-4Open DOISearch in Google Scholar

Chan PC, Sills RC, Braun AG, Haseman JK, Bucher JR. Toxicity and carcinogenicity of Δ9-tetrahydrocannabinol in Fischer rats and B6C3F1 mice. Fundam Appl Toxicol 1996;30:109–17. doi: 10.1006/faat.1996.0048 Chan PC Sills RC Braun AG Haseman JK Bucher JR Toxicity and carcinogenicity of Δ9-tetrahydrocannabinol in Fischer rats and B6C3F1 mice Fundam Appl Toxicol 199630109 17 10.1006/faat.1996.00488812248Open DOISearch in Google Scholar

Luthra UL, Rosenkrantz H, Heyman IA, Braude MC. Differential neurochemistry and temporal pattern in rats treated orally with Δ9-tetrahydrocannabinol for periods up to six months. Toxicol Appl Pharmacol 1975;32:418–31. doi: 10.1016/0041-008X(75)90232-X Luthra UL Rosenkrantz H Heyman IA Braude MC Differential neurochemistry and temporal pattern in rats treated orally with Δ9-tetrahydrocannabinol for periods up to six months Toxicol Appl Pharmacol 197532418 31 10.1016/0041-008X(75)90232-XOpen DOISearch in Google Scholar

International Agency for Research on Cancer (IARC). Report of the Advisory Group to Recommend Priorities for IARC Monographs during 2015–2019. IARC Monographs on the Evaluation of Carcinogenic Risk to Humans. Lyon: IARC; 2014. International Agency for Research on Cancer (IARC). Report of the Advisory Group to Recommend Priorities for IARC Monographs during 2015–2019. IARC Monographs on the Evaluation of Carcinogenic Risk to Humans Lyon IARC 2014Search in Google Scholar

Fleischman RW, Hayden DW, Naqvi RH, Rosenkrantz H, Braude MC. The embryotoxic effects of cannabinoids in rats and mice. J Environ Pathol Toxicol 1980;4:471–82. PMID: 6255054 Fleischman RW Hayden DW Naqvi RH Rosenkrantz H Braude MC The embryotoxic effects of cannabinoids in rats and mice J Environ Pathol Toxicol 19804471 82 PMID: 6255054Search in Google Scholar

Haley SL, Wright PL, Plank JB, Keplinger ML, Braude MC, Calendra JC. The effect of natural and synthetic Δ9-tetrahydrocannabinol on fetal development. Toxicol Appl Pharmacol 1973;25:450. Haley SL Wright PL Plank JB Keplinger ML Braude MC Calendra JC The effect of natural and synthetic Δ9-tetrahydrocannabinol on fetal development Toxicol Appl Pharmacol 197325450Search in Google Scholar

Keplinger ML, Wright RL, Haley SL, Plank JB, Braude MC, Calandra JC. The effect of natural and synthetic Δ9-tetrahydrocannabinol on reproductive and lactation performance in albino rats. Toxicol Appl Pharmacol 1973;25:449. Keplinger ML Wright RL Haley SL Plank JB Braude MC Calandra JC The effect of natural and synthetic Δ9-tetrahydrocannabinol on reproductive and lactation performance in albino rats Toxicol Appl Pharmacol 197325449Search in Google Scholar

Brigss GG, Freeman RK, Yaffe SJ. Drugs in Pregnancy and Lactation. Philadelphia (PA): Lippincott Williams and Wilkins; 2011. Brigss GG Freeman RK Yaffe SJ Drugs in Pregnancy and Lactation Philadelphia (PA) Lippincott Williams and Wilkins; 2011Search in Google Scholar

Beal JE, Olson R, Laubenstein L, Morales JO, Bellman P, Yangco B, Lefkowitz L, Plasse TF, Shepard KV. Dronabinol as a treatment for anorexia associated with weight loss in patinets with AIDS. J Pain Symptom Manage 1995;10:89–97. doi: 10.1016/0885-3924(94)00117-4 Beal JE Olson R Laubenstein L Morales JO Bellman P Yangco B Lefkowitz L Plasse TF Shepard KV Dronabinol as a treatment for anorexia associated with weight loss in patinets with AIDS J Pain Symptom Manage 19951089 97 10.1016/0885-3924(94)00117-4Open DOISearch in Google Scholar

Sallan SE, Zinberg NE, Frei E 3rd Antiemetic effect of Δ9-tetrahydrocannabinol in patients receiving cancer chemotherapy. N Engl J Med 1975;293:795–7. doi: 10.1056/ NEJM197510162931603 Sallan SE Zinberg NE Frei E 3rd Antiemetic effect of Δ9-tetrahydrocannabinol in patients receiving cancer chemotherapy N Engl J Med 1975293795 7 10.1056/NEJM197510162931603Open DOISearch in Google Scholar

Frytak S, Moertel CG, O’Fallon JR, Rubin J, Creagan ET, O’Connell MJ, Schutt AJ, Schwartau NW. Δ9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy. A comparison with prochlorperazine and a placebo. Ann Intern Med 1979;91:825–30. doi: 10.7326/0003-4819-91-6-825 Frytak S Moertel CG O’Fallon JR Rubin J Creagan ET O’Connell MJ Schutt AJ Schwartau NW Δ9-tetrahydrocannabinol as an antiemetic for patients receiving cancer chemotherapy A comparison with prochlorperazine and a placebo Ann Intern Med 197991825 30 10.7326/0003-4819-91-6-825Open DOISearch in Google Scholar

Kluin-Neleman JC, Neleman FA, Meuwissen OJ, Maes RA. Δ9-tetrahydrocannabinol (THC) as an antiemetic in patients treated with cancer chemotherapy; a double-blind cross-over trial against placebo. Vet Hum Toxicol 1979;21:338–40. PMID: 516362 Kluin-Neleman JC Neleman FA Meuwissen OJ Maes RA Δ9-tetrahydrocannabinol (THC) as an antiemetic in patients treated with cancer chemotherapy; a double-blind cross-over trial against placebo Vet Hum Toxicol 197921338 40 PMID: 516362Search in Google Scholar

Lucas VS Jr, Laszlo J. Δ9-tetrahydrocannabinol for refractory vomiting induced by cancer chemotherapy. JAMA 1980;243:1241–3. doi: 10.1001/jama.1980.03300380021014 Lucas VS Jr Laszlo J Δ9-tetrahydrocannabinol for refractory vomiting induced by cancer chemotherapy JAMA 19802431241 3 10.1001/jama.1980.03300380021014Open DOISearch in Google Scholar

Orr LE, McKernan JF, Bloome B. Antiemetic effect of tetrahydrocannabinol. Compared with placebo and prochlorperazine in chemotherapy-associated nausea and emesis. Arch Intern Med 1980;140:1431–3. doi: 10.1001/ archinte.140.11.1431 Orr LE McKernan JF Bloome B Antiemetic effect of tetrahydrocannabinol Compared with placebo and prochlorperazine in chemotherapy-associated nausea and emesis Arch Intern Med 19801401431 3 10.1001/archinte.140.11.1431Open DOISearch in Google Scholar

Sallan SE, Cronin C, Zelen M, Zinberg NE. Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of Δ9-tetrahydrocannabinol and prochlorperazine. N Engl J Med 1980;302:135–8. doi: 10.1056/ NEJM198001173020302 Sallan SE Cronin C Zelen M Zinberg NE Antiemetics in patients receiving chemotherapy for cancer: a randomized comparison of Δ9-tetrahydrocannabinol and prochlorperazine N Engl J Med 1980302135 8 10.1056/NEJM198001173020302Open DOISearch in Google Scholar

Neidhart JA, Gagen MM, Wilson HE, Young DC. Comparative trial of the antiemetic effects of THC and haloperidol. J Clin Pharmacol 1981;21 (Suppl 1 ) : 38 S– 42 S . doi : 10.1002/j.1552-4604.1981.tb02571.x Neidhart JA Gagen MM Wilson HE Young DC Comparative trial of the antiemetic effects of THC and haloperidol J Clin Pharmacol 198121 (Sup p l 1 ) : 3 8 S– 4 2 S 10.1002/j.1552-4604.1981.tb02571.xOpen DOISearch in Google Scholar

Citron ML, Herman TS, Vreeland F, Krasnow SH, Fossieck BE Jr, Harwood S, Franklin R, Cohen MH. Antiemetic efficacy of levonantradol compared to Δ9-tetrahydrocannabinol for chemotherapy-induced nausea and vomiting. Cancer Treat Rep 1985;69:109–12. PMID: 2981616 Citron ML Herman TS Vreeland F Krasnow SH Fossieck BE Jr Harwood S Franklin R Cohen MH Antiemetic efficacy of levonantradol compared to Δ9-tetrahydrocannabinol for chemotherapy-induced nausea and vomiting Cancer Treat Rep 198569109 12 PMID 2981616Search in Google Scholar

Lane M, Vogel CL, Ferguson J, Krasnow S, Saiers JL, Hamm J, Salva K, Wiernik PH, Holroyde CP, Hammill S, Shepard K, Plasse T. Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting. J Pain Symptom Manage 1991;6:352–9. doi: 10.1016/0885-3924(91)90026-Z Lane M Vogel CL Ferguson J Krasnow S Saiers JL Hamm J Salva K Wiernik PH Holroyde CP Hammill S Shepard K Plasse T Dronabinol and prochlorperazine in combination for treatment of cancer chemotherapy-induced nausea and vomiting J Pain Symptom Manage 19916352 9 10.1016/0885-3924(91)90026-ZOpen DOISearch in Google Scholar

May MB, Glode AE. Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics. Cancer Manag Res 2016;8:49–55. doi: 10.2147/CMAR.S81425 May MB Glode AE Dronabinol for chemotherapy-induced nausea and vomiting unresponsive to antiemetics Cancer Manag Res 2016849 55 10.2147/CMAR.S81425486961227274310Open DOISearch in Google Scholar

Johansson R, Kilkku P, Groenroos M. A double-blind, controlled trial of nabilone vs. prochlorperazine for refractory emesis induced by cancer chemotherapy. Cancer Treat Rev 1982;9(Suppl 2):25–33. doi: 10.1016/s0305-7372(82)80032-7 Johansson R Kilkku P Groenroos M A double-blind, controlled trial of nabilone vs prochlorperazine for refractory emesis induced by cancer chemotherapy. Cancer Treat Rev 19829Suppl 225 33 10.1016/s0305-7372(82)80032-7Open DOISearch in Google Scholar

Wada JK, Bogdon DL, Gunnell JC, Hum GJ, Gota CH, Rieth TE. Double-blind, randomized, crossover trial of nabilone vs. placebo in cancer chemotherapy. Cancer Treat Rev 1982;9(Suppl 2):39–44. doi: 10.1016/s0305-7372(82)80034-0 Wada JK Bogdon DL Gunnell JC Hum GJ Gota CH Rieth TE Double-blind, randomized, crossover trial of nabilone vs placebo in cancer chemotherapy Cancer Treat Rev 19829Suppl 239 44 10.1016/s0305-7372(82)80034-0Open DOISearch in Google Scholar

Ahmedzai S, Carlyle DL, Calder IT, Moran F. Anti-emetic efficacy and toxicity of nabilone, a synthetic cannabinoid, in lung cancer chemotherapy. Br J Cancer 1983;48:657–63. doi: 10.1038/bjc.1983.247 Ahmedzai S Carlyle DL Calder IT Moran F Anti-emetic efficacy and toxicity of nabilone, a synthetic cannabinoid, in lung cancer chemotherapy Br J Cancer 198348657 63 10.1038/bjc.1983.24720115106315040Open DOISearch in Google Scholar

Panagis G, Mackey B, Vlachou S. Cannabinoid regulation of brain reward processing with an emphasis on the role of CB1 receptors: A step back into the future. Front Psychiatry 2014;5:1–20. doi: 10.3389/fpsyt.2014.00092 Panagis G Mackey B Vlachou S Cannabinoid regulation of brain reward processing with an emphasis on the role of CB1 receptors: A step back into the future Front Psychiatry 201451 20 10.3389/fpsyt.2014.00092411718025132823Open DOISearch in Google Scholar

European Medicines Agency (EMA). Guideline on the non-clinical investigation of the dependence potential of medicinal products [displayed 2 March 2020]. Available at https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-non-clinical-investigation-dependence-potential-medicinal-products_en.pdf European Medicines Agency (EMA). Guideline on the nonclinical investigation of the dependence potential of medicinal products [displayed 2 March 2020 Available at https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-non-clinical-investigation-dependence-potential-medicinal-products_en.pdfSearch in Google Scholar

Brody AL, Mandelkern MA, Olmstead RE, Allen-Martinez Z, Scheibal D, Abrams AL, Costello MR, Farahi J, Saxena S, Monterosso J, London ED. Ventral striatal dopamine release in response to smoking a regular vs a denicotinized cigarette. Neuropsychopharmacology 2009;34:282–9. doi: 10.1038/ npp.2008.87 Brody AL Mandelkern MA Olmstead RE Allen-Martinez Z Scheibal D Abrams AL Costello MR Farahi J Saxena S Monterosso J London ED Ventral striatal dopamine release in response to smoking a regular vs a denicotinized cigarette Neuropsychopharmacology 200934282 9 10.1038/npp.2008.87277799018563061Open DOISearch in Google Scholar

Urban NB, Kegeles LS, Slifstein M, Xu X, Martinez D, Sakr E, Castillo F, Moadel T, O’Malley SS, Krystal JH, Abi-Dargham A. Sex differences in striatal dopamine release in young adults after oral alcohol challenge: apositron emission tomography imaging study with [11C]raclopride. Biol Psychiatry 2010;68:689 – 96.doi:10.1016/j.biopsych.2010.06.005 Urban NB Kegeles LS Slifstein M Xu X Martinez D Sakr E Castillo F Moadel T O’Malley SS Krystal JH Abi-Dargham A Sex differences in striatal dopamine release in young adults after oral alcohol challenge: apositron emission tomography imaging study with [11C]raclopride Biol Psychiatry 2010;68:689–96 10.1016/j.biopsych.2010.06.005294953320678752Open DOISearch in Google Scholar

Bossong MG, Mehta MA, van Berckel BN, Howes OD, Kahn RS, Stokes PR. Further human evidence for striatal dopamine release induced by administration of Δ9-tetrahydrocannabinol (THC): selectivity to limbic striatum. Psychopharmacology (Berl) 2015;232:2723–9. doi: 10.1007/s00213-015-3915-0 Bossong MG Mehta MA van Berckel BN Howes OD Kahn RS Stokes PR Further human evidence for striatal dopamine release induced by administration of Δ9-tetrahydrocannabinol (THC): selectivity to limbic striatum Psychopharmacology (Berl) 20152322723 9 10.1007/s00213-015-3915-0481619625801289Open DOISearch in Google Scholar

Harris RT, Waters W, McLendon D. Evaluation of reinforcing capability of Δ9-tetrahydrocannabinol in rhesus monkeys. Psychopharmacologia 1974;37:23–9. doi: 10.1007/bf00426679 Harris RT Waters W McLendon D Evaluation of reinforcing capability of Δ9-tetrahydrocannabinol in rhesus monkeys Psychopharmacologia 19743723 9 10.1007/bf00426679Open DOISearch in Google Scholar

Mansbach RS, Nicholson KL, Martin BR, Balster RL. Failure of! Δ9-tetrahydrocannabinol and CP 55,940 to maintain intravenous self-administration under a fixed-interval schedule in rhesus monkeys. Behav Pharmacol 1994;5:219–25. doi: 10.1097/00008877-199404000-00014 Mansbach RS Nicholson KL Martin BR Balster RL Failure of! Δ9-tetrahydrocannabinol and CP 55,940 to maintain intravenous self-administration under a fixed-interval schedule in rhesus monkeys Behav Pharmacol 19945219 25 10.1097/00008877-199404000-0001411224271Open DOISearch in Google Scholar

Tanda G, Munzar P, Goldberg SR. Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys. Nat Neurosci 2000;3:1073–4. doi: 10.1038/80577 Tanda G Munzar P Goldberg SR Self-administration behavior is maintained by the psychoactive ingredient of marijuana in squirrel monkeys Nat Neurosci 200031073 4 10.1038/8057711036260Open DOISearch in Google Scholar

Justinova Z, Tanda G, Redhi GH, Goldberg SR. Self-administration of Δ9-tetrahydrocannabinol (THC) by drug naive squirrel monkeys. Psychopharmacology (Berl) 2003;169:135–40. doi: 10.1007/s00213-003-1484-0 Justinova Z Tanda G Redhi GH Goldberg SR Self-administration of Δ9-tetrahydrocannabinol (THC) by drug naive squirrel monkeys Psychopharmacology (Berl) 2003169135 40 10.1007/s00213-003-1484-0Open DOISearch in Google Scholar

Lepore M, Vorel SR, Lowinson J, Gardner EL. Conditioned place preference induced by Δ9-tetrahydrocannabinol: comparison with cocaine, morphine, and food reward. Life Sci 1995;56:2073–80. doi: 10.1016/0024-3205(95)00191-8 Lepore M Vorel SR Lowinson J Gardner EL Conditioned place preference induced by Δ9-tetrahydrocannabinol: comparison with cocaine, morphine, and food reward Life Sci 1995562073 80 10.1016/0024-3205(95)00191-8Open DOISearch in Google Scholar

Herman TS, Einhorn LH, Jones SE, Nagy C, Chester AB, Dean JC, Furnas B, Williams SD, Leigh SA, Dorr RT, Moon TE. Superiority of nabilone over prochlorperazine as an antiemetic in patients receiving cancer chemotherapy. N Engl J Med 1979;300:1295–7. doi: 10.1056/NEJM197906073002302 Herman TS Einhorn LH Jones SE Nagy C Chester AB Dean JC Furnas B Williams SD Leigh SA Dorr RT Moon TE Superiority of nabilone over prochlorperazine as an antiemetic in patients receiving cancer chemotherapy N Engl J Med 19793001295 7 10.1056/NEJM197906073002302Open DOISearch in Google Scholar

Food and Drug Organization (FDA). Center for drug evalution and research. Epidiolex. Summary review [displayed 28 April 2019]. Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210365Orig1s000SumR.pdf Food and Drug Organization (FDA). Center for drug evalution and research. Epidiolex. Summary review [displayed 28 April 2019 Available at https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/210365Orig1s000SumR.pdfSearch in Google Scholar

European Medicines Agency (EMA). European Public Assessment report. Epidyolex, [displayed 05 March 2020]. Available at https://www.ema.europa.eu/en/documents/assessment-report/epidyolex-epar-public-assessment-report_en.pdf European Medicines Agency (EMA). European Public Assessment report. Epidyolex [displayed 05 March 2020 Available at https://www.ema.europa.eu/en/documents/assessment-report/epidyolex-epar-public-assessment-report_en.pdfSearch in Google Scholar

Robert EM, Taylor NL, Martin BR, Wiley JL. Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Δ9-tetrahydrocannabinol. Drug Alcohol Depend 2008;94:191–8. doi: 10.1016/j.drugalcdep.2007.11.017 Robert EM Taylor NL Martin BR Wiley JL Divergent effects of cannabidiol on the discriminative stimulus and place conditioning effects of Δ9-tetrahydrocannabinol Drug Alcohol Depend 200894191 8 10.1016/j.drugalcdep.2007.11.017Open DOISearch in Google Scholar

Schoedel KA, Szeto I, Setnik B, Sellers EM, Levy-Cooperman N, Mills C, Etges T, Sommerville K. Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: A randomized, double-blind, controlled trial. Epilepsy Behav 2018;88:162–171. doi: 10.1016/j.yebeh.2018.07.027 Schoedel KA Szeto I Setnik B Sellers EM Levy-Cooperman N Mills C Etges T Sommerville K Abuse potential assessment of cannabidiol (CBD) in recreational polydrug users: A randomized, double-blind, controlled trial Epilepsy Behav 201888162 171 10.1016/j.yebeh.2018.07.027Open DOISearch in Google Scholar

World Health Organization Expert Committee on Drug Dependence. Cannabidiol (CBD) Pre-Review Report Agenda Item 5.2 and Peer Review, 2017. Available AT https://www.who.int/medicines/access/controlled-substances/5.2_CBD.pdf World Health Organization Expert Committee on Drug Dependence. Cannabidiol (CBD) Pre-Review Report Agenda Item 5.2 and Peer Review 2017 Available AT https://www.who.int/medicines/access/controlled-substances/5.2_CBD.pdfSearch in Google Scholar

Lim SY, Sharan S, Woo S. Model-based analysis of cannabidiol dose-exposure relationship and bioavailability. Pharmacotherapy 2020. doi: 10.1002/phar.2377 Lim SY Sharan S Woo S Model-based analysis of cannabidiol dose-exposure relationship and bioavailability Pharmacotherapy 2020 10.1002/phar.2377Open DOISearch in Google Scholar

Zgair A, Wong JC, Lee JB, Mistry J, Sivak O, Wasan KM, Hennig IM, Barrett DA, Constantinescu CS, Fischer PM, Gershkovich P. Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines. Am J Transl Res 2016;8:3448–59. PMCID: PMC5009397 Zgair A Wong JC Lee JB Mistry J Sivak O Wasan KM Hennig IM Barrett DA Constantinescu CS Fischer PM Gershkovich P Dietary fats and pharmaceutical lipid excipients increase systemic exposure to orally administered cannabis and cannabis-based medicines Am J Transl Res 201683448 59 PMCID: PMC5009397Search in Google Scholar

Cherniakov I, Izgelov D, Domb AJ, Hoffman A. The effect of Pro NanoLipospheres (PNL) formulation containing natural absorption enhancers on the oral bioavailability of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in a rat model. Eur J Pharm Sci 2017;109:21–30. doi: 10.1016/j. ejps.2017.07.003 Cherniakov I Izgelov D Domb AJ Hoffman A The effect of Pro NanoLipospheres (PNL) formulation containing natural absorption enhancers on the oral bioavailability of Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD) in a rat model Eur J Pharm Sci 201710921 30 10.1016/j.ejps.2017.07.003Open DOISearch in Google Scholar

Stott CG, White L, Wright S, Wilbraham D, Guy GW. A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray. Eur J Clin Pharmacol 2013;69:1135–47. doi: 10.1007/s00228-012-1441-0 Stott CG White L Wright S Wilbraham D Guy GW A phase I study to assess the single and multiple dose pharmacokinetics of THC/CBD oromucosal spray Eur J Clin Pharmacol 2013691135 47 10.1007/s00228-012-1441-0Open DOISearch in Google Scholar

Ujváry I, Hanuš L. Human metabolites of cannabidiol: A review on their formation, biological activity, and relevance in therapy. Cannabis Cannabinoid Res 2016;1:90–101. doi: 10.1089/can.2015.0012 Ujváry I Hanuš L Human metabolites of cannabidiol: A review on their formation, biological activity, and relevance in therapy Cannabis Cannabinoid Res 2016190 101 10.1089/can.2015.0012Open DOISearch in Google Scholar

Harvey DJ, Samara E, Mechoulam R. Comparative metabolism of cannabidiol in dog, rat and man. Pharmacol Biochem Behav 1991;40:523–32. doi: 10.1016/0091-3057(91)90358-9 Harvey DJ Samara E Mechoulam R Comparative metabolism of cannabidiol in dog, rat and man Pharmacol Biochem Behav 199140523 32 10.1016/0091-3057(91)90358-9Open DOISearch in Google Scholar

Regan SL, Maggs JL, Hammond TG, Lambert C, Williams DP, Park BK. Acyl glucuronides: the good, the bad and the ugly. Biopharm Drug Dispos 2010;31:367–95. doi: 10.1002/ bdd.720 Regan SL Maggs JL Hammond TG Lambert C Williams DP Park BK Acyl glucuronides: the good, the bad and the ugly Biopharm Drug Dispos 201031367 95 10.1002/bdd.720Open DOISearch in Google Scholar

Rosenkrantz H, Fleischman RW, Grant RJ. Toxicity of short-term administration of cannabinoids to rhesus monkeys. Toxicol Appl Pharmacol 1981;58:118–31. doi: 10.1016/0041-008x(81)90122-8 Rosenkrantz H Fleischman RW Grant RJ Toxicity of short-term administration of cannabinoids to rhesus monkeys Toxicol Appl Pharmacol 198158118 31 10.1016/0041-008x(81)90122-8Open DOISearch in Google Scholar

Devinsky O, Cross JH, Laux L, Marsh E, Miller I, Nabbout R, Scheffer IE, Thiele EA, Wright S. Cannabidiol in Dravet syndrome study group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med 2017;376:2011– 20. doi: 10.1056/NEJMoa1611618 Devinsky O Cross JH Laux L Marsh E Miller I Nabbout R Scheffer IE Thiele EA Wright S Cannabidiol in Dravet syndrome study group. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome N Engl J Med 2017376201120 10.1056/NEJMoa1611618Open DOISearch in Google Scholar

Devinsky O, Patel AD, Cross JH, Villanueva V, Wirrell EC, Privitera M, Greenwood SM, Roberts C, Checketts D, VanLandingham KE, Zuberi SM. Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome. N Engl J Med 2018;378:1888–97. doi: 10.1056/NEJMoa1714631 Devinsky O Patel AD Cross JH Villanueva V Wirrell EC Privitera M Greenwood SM Roberts C Checketts D VanLandingham KE Zuberi SM Effect of cannabidiol on drop seizures in the Lennox-Gastaut syndrome N Engl J Med 20183781888 97 10.1056/NEJMoa1714631Open DOISearch in Google Scholar

Thiele EA, Marsh ED, French JA, Mazurkiewicz-Beldzinska M, Benbadis SR, Joshi C, Lyons PD, Taylor A, Roberts C, Sommerville K. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. Lancet 2018;391:1085–96. doi: 10.1016/S0140-6736(18)30136-3 Thiele EA Marsh ED French JA Mazurkiewicz-Beldzinska M Benbadis SR Joshi C Lyons PD Taylor A Roberts C Sommerville K Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial Lancet 20183911085 96 10.1016/S0140-6736(18)30136-3Open DOISearch in Google Scholar

Laux LC, Bebin EM, Checketts D, Chez M, Flamini R, Marsh ED, Miller I, Nichol K, Park Y, Segal E, Seltzer L, Szaflarski JP, Thiele EA, Weinstock A; CBD EAP study group. Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results. Epilepsy Res 2019;154:13–20. doi: 10.1016/j.eplepsyres.2019.03.015 Laux LC Bebin EM Checketts D Chez M Flamini R Marsh ED Miller I Nichol K Park Y Segal E Seltzer L Szaflarski JP Thiele EA Weinstock A; CBD EAP study group Long-term safety and efficacy of cannabidiol in children and adults with treatment resistant Lennox-Gastaut syndrome or Dravet syndrome: Expanded access program results Epilepsy Res 201915413 20 10.1016/j.eplepsyres.2019.03.015Open DOISearch in Google Scholar

ClinicalTrials.gov database. GWPCARE5 - An Open Label Extension Study of Cannabidiol (GWP42003-P) in Children and Young Adults With Dravet or Lennox-Gastaut Syndromes [displayed 4 March 2020]. Available at https://clinicaltrials.gov/ct2/show/record/NCT02224573 ClinicalTrials.gov database. GWPCARE5 - An Open Label Extension Study of Cannabidiol (GWP42003-P) in Children and Young Adults With Dravet or Lennox-Gastaut Syndromes [displayed 4 March 2020 Available at https://clinicaltrials.gov/ct2/show/record/NCT02224573Search in Google Scholar

Russo E, Guy GW. A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol. Med Hypotheses 2006;66:234–46. doi: 10.1016/j. mehy.2005.08.026 Russo E Guy GW A tale of two cannabinoids: the therapeutic rationale for combining tetrahydrocannabinol and cannabidiol Med Hypotheses 200666234 46 10.1016/j.mehy.2005.08.026Open DOISearch in Google Scholar

Howlett AC, Scott DK, Wilken GH. Regulation of adenylate cyclase by cannabinoid drugs. Insights based n thermodynamic studies. Biochem Pharmacol 1989;38:3297–304. doi: 10.1016/0006-2952(89)90628-x Howlett AC Scott DK Wilken GH Regulation of adenylate cyclase by cannabinoid drugs Insights based n thermodynamic studies Biochem Pharmacol 1989383297 304 10.1016/0006-2952(89)90628-xOpen DOISearch in Google Scholar

Costa B, Giagnoni G, Franke C, Trovato AE, Colleoni M. Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation. Br J Pharmacol 2004;143:247– 50. doi: 10.1038/sj.bjp.0705920 Costa B Giagnoni G Franke C Trovato AE Colleoni M Vanilloid TRPV1 receptor mediates the antihyperalgesic effect of the nonpsychoactive cannabinoid, cannabidiol, in a rat model of acute inflammation Br J Pharmacol 200414324750 10.1038/sj.bjp.0705920157533315313881Open DOISearch in Google Scholar

Comelli F, Giagnoni G, Bettoni I, Colleoni M, Costa B. Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved. Phytother Res 2008;22:1017–24. doi: 10.1002/ptr.2401 Comelli F Giagnoni G Bettoni I Colleoni M Costa B Antihyperalgesic effect of a Cannabis sativa extract in a rat model of neuropathic pain: mechanisms involved Phytother Res 2008221017 24 10.1002/ptr.240118618522Open DOISearch in Google Scholar

Bornheim LM, Kim KY, Li J, Perotti BY, Benet LZ. Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain. Drug Metab Dispos 1995;23:825– 31. PMID: 7493549 Bornheim LM Kim KY Li J Perotti BY Benet LZ Effect of cannabidiol pretreatment on the kinetics of tetrahydrocannabinol metabolites in mouse brain Drug Metab Dispos 19952382531 PMID 7493549Search in Google Scholar

Wright MJ Jr, Vandewater SA, Taffe MA. Cannabidiol attenuates deficits of visuospatial associative memory induced by Δ9-tetrahydrocannabinol. Br J Pharmacol 2013;170:1365–73. doi: 10.1111/bph.12199 Wright MJ Jr Vandewater SA Taffe MA Cannabidiol attenuates deficits of visuospatial associative memory induced by Δ9-tetrahydrocannabinol Br J Pharmacol 20131701365 73 10.1111/bph.12199383868323550724Open DOISearch in Google Scholar

Nadulski T, Pragst F, Weinberg G, Roser P, Schnelle M, Fronk EM, Stadelmann AM. Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of Δ9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract. Ther Drug Monit 2005;27:799–810. doi: 10.1097/01. ftd.0000177223.19294.5c Nadulski T Pragst F Weinberg G Roser P Schnelle M Fronk EM Stadelmann AM Randomized, double-blind, placebo-controlled study about the effects of cannabidiol (CBD) on the pharmacokinetics of Δ9-tetrahydrocannabinol (THC) after oral application of THC verses standardized cannabis extract Ther Drug Monit 200527799 810 10.1097/01.ftd.0000177223.19294.5c16306858Open DOISearch in Google Scholar

Karschner EL, Darwin WD, Goodwin RS, Wright S, Huestis MA. Plasma cannabinoid pharmacokinetics following controlled oral Δ9-tetrahydrocannabinol and oromucosal cannabis extract administration. Clin Chem 2011;57:66–75. doi: 10.1373/clinchem.2010.152439 Karschner EL Darwin WD Goodwin RS Wright S Huestis MA Plasma cannabinoid pharmacokinetics following controlled oral Δ9-tetrahydrocannabinol and oromucosal cannabis extract administration Clin Chem 20115766 75 10.1373/clinchem.2010.152439371733821078841Open DOISearch in Google Scholar

Medicines and Healthcare Products Regulatory Agency (MHRA). Public Assessment Report. Sativex oromucosal Spray [displayed 28 April 2019]. Available at http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con084961.pdf Medicines and Healthcare Products Regulatory Agency (MHRA). Public Assessment Report Sativex oromucosal Spray [displayed 28 April 2019 Available at http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con084961.pdfSearch in Google Scholar

Sagredo O, Pazos MR, Satta V, Ramos JA, Pertwee RG, Fernández-Ruiz J. Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington’s disease. J Neurosci Res 2011;89:1509–18. doi: 10.1002/jnr.22682 Sagredo O Pazos MR Satta V Ramos JA Pertwee RG Fernández-Ruiz J Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington’s disease J Neurosci Res 2011891509 18 10.1002/jnr.2268221674569Open DOISearch in Google Scholar

Vaney C, Heinzel-Gutenbrunner M, Jobin P, Tschopp F, Gattlen B, Hagen U, Schnelle M, Reif M. Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study. Mult Scler 2004;10:417–24. doi: 10.1191/1352458504ms1048oa Vaney C Heinzel-Gutenbrunner M Jobin P Tschopp F Gattlen B Hagen U Schnelle M Reif M Efficacy, safety and tolerability of an orally administered cannabis extract in the treatment of spasticity in patients with multiple sclerosis: a randomized, double-blind, placebo-controlled, crossover study Mult Scler 200410417 24 10.1191/1352458504ms1048oa15327040Open DOISearch in Google Scholar

Wade DT, Makela P, Robson P, House H, Bateman C. Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients. Mult Scler 2004;10:434–41. doi: 10.1191/1352458504ms1082oa Wade DT Makela P Robson P House H Bateman C Do cannabis-based medicinal extracts have general or specific effects on symptoms in multiple sclerosis? A double-blind, randomized, placebo-controlled study on 160 patients Mult Scler 200410434 41 10.1191/1352458504ms1082oa15327042Open DOISearch in Google Scholar

Wade DT, Makela PM, House H, Bateman C, Robson P. Longterm use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis. Mult Scler 2006;12:639–45. doi: 10.1177/1352458505070618 Wade DT Makela PM House H Bateman C Robson P Longterm use of a cannabis-based medicine in the treatment of spasticity and other symptoms in multiple sclerosis Mult Scler 200612639 45 10.1177/135245850507061817086911Open DOISearch in Google Scholar

Collin C, Davies P, Mutiboko IK, Ratcliffe S; Sativex Spasticity in MS Study Group. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis. Eur J Neurol 2007;14(3):290–6. doi: 10.1111/j.1468-1331.2006.01639.x Collin C Davies P Mutiboko IK Ratcliffe S Sativex Spasticity in MS Study Group. Randomized controlled trial of cannabis-based medicine in spasticity caused by multiple sclerosis Eur J Neurol 2007143290 6 10.1111/j.1468-1331.2006.01639.x17355549Open DOISearch in Google Scholar

Serpell MG, Notcutt W, Collin C. Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis. J Neurol 2013;260:285–95. doi: 10.1007/s00415-012-6634-z Serpell MG Notcutt W Collin C Sativex long-term use: an open-label trial in patients with spasticity due to multiple sclerosis J Neurol 2013260285 95 10.1007/s00415-012-6634-z22878432Open DOISearch in Google Scholar

Collin C, Ehler E, Waberzinek G, Alsindi Z, Davies P, Powell K, Notcutt W, O’Leary C, Ratcliffe S, Nováková I, Zapletalova O, Piková J, Ambler Z. A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis. Neurol Res 2010;32:451–9. doi: 10.1179/016164109X12590518685660 Collin C Ehler E Waberzinek G Alsindi Z Davies P Powell K Notcutt W O’Leary C Ratcliffe S Nováková I Zapletalova O Piková J Ambler Z A double-blind, randomized, placebo-controlled, parallel-group study of Sativex, in subjects with symptoms of spasticity due to multiple sclerosis Neurol Res 201032451 9 10.1179/016164109X1259051868566020307378Open DOISearch in Google Scholar

Novotna A, Mares J, Ratcliffe S, Novakova I, Vachova M, Zapletalova O, Gasperini C, Pozzilli C, Cefaro L, Comi G, Rossi P, Ambler Z, Stelmasiak Z, Erdmann A, Montalban X, Klimek A, Davies P; Sativex Spasticity Study Group. A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols (Sativex), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis. Eur J Neurol 2011;18:1122–31. doi: 10.1111/j.1468-1331.2010.03328.x Novotna A Mares J Ratcliffe S Novakova I Vachova M Zapletalova O Gasperini C Pozzilli C Cefaro L Comi G Rossi P Ambler Z Stelmasiak Z Erdmann A Montalban X Klimek A Davies P; Sativex Spasticity Study Group A randomized, double-blind, placebo-controlled, parallel-group, enriched-design study of nabiximols (Sativex), as add-on therapy, in subjects with refractory spasticity caused by multiple sclerosis Eur J Neurol 2011181122 31 10.1111/j.1468-1331.2010.03328.x21362108Open DOISearch in Google Scholar

Langford RM, Mares J, Novotna A, Vachova M, Novakova I, Notcutt W, Ratcliffe S. A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regime, in the relief of central europathic pain in patients with multiple sclerosis. J Neurol 2013;260:984–77. doi: 10.1007/s00415-012-6739-4 Langford RM Mares J Novotna A Vachova M Novakova I Notcutt W Ratcliffe S A double-blind, randomized, placebo-controlled, parallel-group study of THC/CBD oromucosal spray in combination with the existing treatment regime, in the relief of central europathic pain in patients with multiple sclerosis J Neurol 2013260984 77 10.1007/s00415-012-6739-423180178Open DOISearch in Google Scholar

García-Merino A. Endocannabinoid system modulator use in everyday clinical practice in the UK and Spain. Expert Rev Neurother 2013;13(3 Suppl 1):9–13. doi: 10.1586/ern.13.4 García-Merino A. Endocannabinoid system modulator use in everyday clinical practice in the UK and Spain Expert Rev Neurother 2013133 Suppl 19 13 10.1586/ern.13.423369054Open DOISearch in Google Scholar

Rekand T. THC:CBD spray and MS spasticity symptoms: data from latest studies. Eur Neurol 2014;71(Suppl 1):4–9. doi: 10.1159/000357742 Rekand T THC:CBD spray and MS spasticity symptoms: data from latest studies Eur Neurol 201471Suppl 14 9 10.1159/00035774224457846Open DOISearch in Google Scholar

Aragona M, Onesti E, Tomassini V, Conte A, Gupta S, Gilio F, Pantano P, Pozzilli C. Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double-blind, placebo controlled, crossover study. Clin Neuropharm 2009;32:41–7. doi: 10.1097/WNF.0B013 E3181633497 Aragona M Onesti E Tomassini V Conte A Gupta S Gilio F Pantano P Pozzilli C Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double-blind, placebo controlled, crossover study Clin Neuropharm 20093241 7 10.1097/WNF.0B013E318163349718978501Open DOISearch in Google Scholar

Robson P. Abuse potential and psychoactive effects of Δ9-tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine. Expert Opin Drug Saf 2011;10:675–85. doi: 10.1517/14740338.2011.575778 Robson P Abuse potential and psychoactive effects of Δ9-tetrahydrocannabinol and cannabidiol oromucosal spray (Sativex), a new cannabinoid medicine Expert Opin Drug Saf 201110675 85 10.1517/14740338.2011.57577821542664Open DOISearch in Google Scholar

Recommended articles from Trend MD

Plan your remote conference with Sciendo