Does intravenous Δ9-tetrahydrocannabinol increase dopamine release? A SPET study

Barkus, Emma; Morrison, Paul; Vuletic, Daniella; Dickson, John; Ell, Peter J.; Pilowsky, Lyn S.; Brenneisen, Rudolf; Holt, David W.; Powell, John; Kapur, Shitij; Murray, Robin M.

doi:10.1177/0269881110382465

Cited by 92 publications

(79 citation statements)

References 39 publications

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“…THC iv injection solutions originally developed and validated in our lab have already been used successfully in several clinical studies [5,[10][11][12][13][14]. No technical problems and adverse effects (VAS) were observed following the stan- Table 1.…”

Section: Resultsmentioning

confidence: 99%

Human Pharmacokinetics and Adverse Effects of Pulmonary and Intravenous THC-CBD Formulations

Meyer

Langos

Brenneisen³

2018

Med Cannabis Cannabinoids

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Background: Due to variable absorption and extensive first-pass metabolism, the bioavailability of oral delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) is low, and, therefore, alternative application forms are necessary. Methods: In an open-label, 2-period phase-1 study on 11 healthy volunteers, a combination of THC and CBD was compared by pulmonary (inh) and intravenous (iv) application. The liquid aerosol was produced by an in vitro validated pressurized metered-dose inhaler (pMDI) device, releasing 41–44% of the cannabinoid dose, enabling a dosage of 81 µg THC and 87 µg CBD per actuation. Three subjects (pilot trial, low-dose session) received 324 and 348 μg THC and CBD, respectively, and 8 subjects (main trial, high-dose session) received 648 and 696 µg THC and CBD, respectively. The addition of the local anesthetic lidocaine to the inh preparation should prevent airways irritation and coughing. The pharmacokinetic evaluation was based on plasma profiles acquired by gas chromatography-mass spectrometry. Adverse effects were monitored by visual analog scales and measuring vital functions. Results: After low inh doses, THC and CBD were not measurable in plasma longer than 20 and 40 min after administration, respectively. Therefore, only plasma levels resulting after high doses were further evaluated. After inh and iv administration, THC plasma peaks were observed 5 min post-drug, with THC peak concentrations ranging from 3 to 22 and from 13 to 40 ng/mL, respectively. CBD peaks were also measured 5 min after inh and iv administration, with concentrations ranging from 2 to 17 and from 14 to 26 ng/mL, respectively. The elimination half-lives were 7 and 11 min after inh and 22 and 24 min after iv administration for THC and CBD, respectively. The mean inh bioavailability (calculated vs. iv) was 55 ± 37 and 59 ± 47% for THC and CBD, respectively. Conjugated 11-carboxy-THC was the main THC metabolite. The nebulized aerosol was generally well tolerated with little or no coughing and only slight psychological adverse effects. These were more distinct after iv administration, especially irritations and hallucinations. Besides moderate tachycardia, the vital functions stayed unchanged. Conclusions: We conclude that a THC-CBD inh aerosol shows favorable pharmacokinetic properties, which are similar to those of an iv preparation. Adding a local anesthetic is recommended to prevent coughing, which decreases absorption. The negligible psychoactivity may be due to an antipsychotic effect of CBD, the low THC dosage, and/or the decreased formation of the psychoactive metabolite 11- hydroxy-THC. Therefore, the inhalation via a pMDI is a viable, safe, and well-tolerated alternative to the oral administration.

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Section: Resultsmentioning

confidence: 99%

Human Pharmacokinetics and Adverse Effects of Pulmonary and Intravenous THC-CBD Formulations

Meyer

Langos

Brenneisen³

2018

Med Cannabis Cannabinoids

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“…CHDR trials 0508 and 0916 were performed with 28 and 24 healthy male subjects, respectively. The 0508 trial used a multiple pulmonary dose of 2, 4, and 6 mg, with a 1.5-h interval, and the 0916 used a [30][31][32][33] from the King's College London performing an IV infusion with a duration of 5 min in two groups of healthy male volunteers were combined into one dataset. The first group of 23 subjects received 2.5 mg of THC, and the second group of 13 subjects received 1.25 mg of THC.…”

Section: Datasets For External Validationmentioning

confidence: 99%

Population Pharmacokinetic Model of THC Integrates Oral, Intravenous, and Pulmonary Dosing and Characterizes Short- and Long-term Pharmacokinetics

et al. 2014

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Δ(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple-dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials.

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“…Indeed, in humans, imaging studies have shown that drugs of abuse increase DA release in striatum (including the nucleus accumbens), and these increases have been associated with the subjective experience of reward (7)(8)(9). However, for marijuana, the results have been inconsistent: One study reported striatal DA increases during intoxication (10); two studies showed no effects (11,12); and one study reported DA increases in individuals with a psychotic disorder and in their relatives, but not in controls (13). Imaging studies of the brain DA system in marijuana abusers have also shown different findings from those reported for other types of substance abusers.…”

mentioning

confidence: 96%

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

Volkow

Wang

Telang

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

195

147

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Moves to legalize marijuana highlight the urgency to investigate effects of chronic marijuana in the human brain. Here, we challenged 48 participants (24 controls and 24 marijuana abusers) with methylphenidate (MP), a drug that elevates extracellular dopamine (DA) as a surrogate for probing the reactivity of the brain to DA stimulation. We compared the subjective, cardiovascular, and brain DA responses (measured with PET and [ 11 C]raclopride) to MP between controls and marijuana abusers. Although baseline (placebo) measures of striatal DA D2 receptor availability did not differ between groups, the marijuana abusers showed markedly blunted responses when challenged with MP. Specifically, compared with controls, marijuana abusers had significantly attenuated behavioral ("self-reports" for high, drug effects, anxiety, and restlessness), cardiovascular (pulse rate and diastolic blood pressure), and brain DA [reduced decreases in distribution volumes (DVs) of [ 11 C]raclopride, although normal reductions in striatal nondisplaceable binding potential (BP ND )] responses to MP. In ventral striatum (key brain reward region), MP-induced reductions in DVs and BP ND (reflecting DA increases) were inversely correlated with scores of negative emotionality, which were significantly higher for marijuana abusers than controls. In marijuana abusers, DA responses in ventral striatum were also inversely correlated with addiction severity and craving. The attenuated responses to MP, including reduced decreases in striatal DVs, are consistent with decreased brain reactivity to the DA stimulation in marijuana abusers that might contribute to their negative emotionality (increased stress reactivity and irritability) and addictive behaviors.nucleus accumbens | amotivation | cannabinoid 1 receptors | brain imaging | midbrain D espite the high prevalence of marijuana consumption, the effects of marijuana abuse in the human brain are not well understood. Marijuana, like other drugs of abuse, stimulates brain dopamine (DA) signaling in the nucleus accumbens (1, 2), which is a mechanism believed to underlie the rewarding effects of drugs (3-5) and to trigger the neuroadaptations that result in addiction (reviewed in ref. 6). Indeed, in humans, imaging studies have shown that drugs of abuse increase DA release in striatum (including the nucleus accumbens), and these increases have been associated with the subjective experience of reward (7-9). However, for marijuana, the results have been inconsistent: One study reported striatal DA increases during intoxication (10); two studies showed no effects (11, 12); and one study reported DA increases in individuals with a psychotic disorder and in their relatives, but not in controls (13). Imaging studies of the brain DA system in marijuana abusers have also shown different findings from those reported for other types of substance abusers. Specifically, substance abusers (cocaine, methamphetamine, alcohol, heroin, and nicotine), but not marijuana abusers (14-16), show reduced baseline availability ...

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Does intravenous Δ9-tetrahydrocannabinol increase dopamine release? A SPET study

Cited by 92 publications

References 39 publications

Human Pharmacokinetics and Adverse Effects of Pulmonary and Intravenous THC-CBD Formulations

Human Pharmacokinetics and Adverse Effects of Pulmonary and Intravenous THC-CBD Formulations

Population Pharmacokinetic Model of THC Integrates Oral, Intravenous, and Pulmonary Dosing and Characterizes Short- and Long-term Pharmacokinetics

Decreased dopamine brain reactivity in marijuana abusers is associated with negative emotionality and addiction severity

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