The Effects Of Delta-9-tetrahydrocannabinol Research Articles

Risk of Motor Vehicle Collisions and Culpability among Older Drivers Using Cannabis: A Meta-Analysis.

Limited studies have investigated the effects of cannabis use on driving among older adults, who represent the fastest growing segment of drivers globally. We conducted a systematic review and meta-analysis to evaluate the effects of delta-9-tetrahydrocannabinol (THC) exposure on risks of (1) motor vehicle collisions (MVC) and (2) culpability for MVCs among adults 50 years and older. Three reviewers screened 7022 studies identified through MEDLINE, EMBASE, CENTRAL, and PsycINFO. Odds Ratios (OR) were calculated using the Mantel-Haenszel method in Review Manager 5.4.1. Heterogeneity was assessed using I2. The National Heart, Lung, and Blood Institute tool was used to assess the quality of each study. Seven cross-sectional studies were included. Three studies evaluated culpability while four evaluated MVC. The pooled risk of MVC was not significantly different between THC-positive and THC-negative older drivers (OR, 95% CI 1.15 [0.40, 3.31]; I2 = 72%). In culpability studies, THC exposure was not significantly associated with an increased risk of being culpable for MVC among adults over the age of 50 (OR, 95% CI 1.24 [0.95, 1.61]; I2 = 0%). Inspection of funnel plots did not indicate publication bias. Our review found that THC exposure was not associated with MVC involvement nor with culpability for MVCs.

Maternal Delta-9-Tetrahydrocannabinol Exposure Induces Abnormalities of the Developing Heart in Mice.

Introduction: Cannabis is increasingly being consumed by pregnant women for recreational purposes as well as for its antiemetic and anxiolytic effects despite limited studies on its safety during pregnancy. Importantly, phytocannabinoids found in cannabis can pass through the placenta and enter the fetal circulation. Recent reports suggest gestational cannabis use is associated with negative fetal outcomes, including fetal growth restriction and perinatal intensive care, however, the effects of delta-9-tetrahydrocannabinol (THC) on fetal heart development remains to be elucidated. Materials and Methods: We aimed to determine the outcomes of maternal THC exposure on fetal heart development in mice by administering 0, 5, or 10 mg/kg/day of THC orally to C57BL/6 dams starting at embryonic day (E)3.5. Offspring were collected at E12.5 for molecular analysis, at E17.5 to analyze cardiac morphology or at postnatal day (PND)21 to assess heart function. Results: Maternal THC exposure in E17.5 fetuses resulted in an array of cardiac abnormalities with an incidence of 44% and 55% in the 5 and 10 mg/kg treatment groups, respectively. Maternal THC exposure in offspring resulted in ventricular septal defect, higher semilunar valve volume relative to orifice ratio, and higher myocardial wall thickness. Notably, cell proliferation within the ventricular myocardium was increased, and expression of multiple cardiac transcription factors was downregulated in THC-exposed E12.5 fetuses. Furthermore, heart function was compromised with lower left ventricular ejection fraction, fractional shortening, and cardiac output in PND21 pups exposed to THC compared to controls. Discussion: The results show that maternal THC exposure during gestation induces myocardial hyperplasia and semilunar valve thickening in the fetal heart and postnatal cardiac dysfunction. Our study suggests that maternal cannabis consumption may induce abnormalities in the developing heart and cardiac dysfunction in postnatal life.

Delta-9-tetrahydrocannabinol increases vascular endothelial growth factor (VEGF) secretion through a cyclooxygenase-dependent mechanism in rat granulosa cells

While the effects of delta-9-tetrahydrocannabinol (THC), the psychoactive component of cannabis, have been studied extensively in the central nervous system, there is limited knowledge about its effects on the female reproductive system. The aim of this study was to assess the effect of THC on the expression and secretion of the angiogenic factor vascular endothelial growth factor (VEGF) in the ovary, and to determine if these effects were mediated by prostaglandins. Spontaneously immortalized rat granulosa cells (SIGCs) were exposed to THC for 24 h. Gene expression, proliferation and TNFα-induced apoptosis were evaluated in the cells and concentrations of VEGF and prostaglandin E2 (PGE2), a known regulator of VEGF production, were determined in the media. To evaluate the role of the prostanoid pathway, cells were pre-treated with cyclooxygenase (COX) inhibitors prior to THC exposure. THC-exposed SIGCs had a significant increase in VEGF and PGE2 secretion, along with an increase in proliferation and cell survival when challenged with an apoptosis-inducing factor. Pre-treatment with COX inhibitors reversed the THC-induced increase in both PGE2 and VEGF secretion. Alterations in granulosa cell function, such as the ones observed after THC exposure, may impact essential ovarian processes including folliculogenesis and ovulation, which could in turn affect female reproductive health and fertility. With the ongoing increase in cannabis use and potency, further study on the impact of cannabis and its constituents on female reproductive health is required.

Highs and lows of cannabinoid-dopamine interactions: effects of genetic variability and pharmacological modulation of catechol-O-methyl transferase on the acute response to delta-9-tetrahydrocannabinol in humans.

The catechol-O-methyl transferase (COMT) enzyme has been implicated in determining dopaminergic tone and the effects of delta-9-tetrahydrocannabinol (THC) in the human brain. This study was designed to evaluate the effect of (1) a functional polymorphism and (2) acute pharmacological inhibition of COMT on the acute response to THC in humans. Sub-study I: The effect of intravenous (IV) THC (0.05mg/kg) was investigated in 74 healthy subjects genotyped for the COMT rs4680 (Val/Met) polymorphism in a 2-test-day double-blind, randomized, placebo-controlled study. Sub-study II: COMT rs4680 homozygous subjects (Val/Val and Met/Met) from sub-study I received the COMT enzyme inhibitor tolcapone (200mg) followed by IV THC or placebo on two additional test days. Subjective, behavioral, and cognitive data were obtained periodically on each test day. Sub-study I: Val/Val individuals were most sensitive to THC-induced attention and working memory deficits. In contrast, the psychotomimetic and subjective effects of THC were not influenced by COMT genotype. Sub-study II: Tolcapone reduced THC-induced working memory deficits, but not THC's psychotomimetic effects. Tolcapone and COMT genotype (met/met) were associated with an increased report of feeling "mellow." The interaction between COMT rs4680 polymorphisms and tolcapone on the cognitive, but not on the psychotomimetic and overall subjective effects of THC, suggests that modulation of dopaminergic signaling may selectively influence specific cannabinoid effects in healthy individuals. The role of dopaminergic signaling in the cognitive effects of cannabinoids should be considered in drug development efforts targeting these effects. CLINICALTRIALS.GOV REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00678730?term=NCT00678730&rank=1 ClinicalTrials.gov Identifier: NCT00678730.

Persistent and Long-Term Neuropsychiatric Implications of Cannabis Use in Adolescents

Persistent and Long-Term Neuropsychiatric Implications of Cannabis Use in Adolescents

Amygdala activity contributes to the dissociative effect of cannabis on pain perception

Cannabis is reported to be remarkably effective for the relief of otherwise intractable pain. However, the bases for pain relief afforded by this psychotropic agent are debatable. Nonetheless, the frontal-limbic distribution of cannabinoid receptors in the brain suggests that cannabis may target preferentially the affective qualities of pain. This central mechanism of action may be relevant to cannabinoid analgesia in humans, but has yet to be demonstrated. Here, we employed functional magnetic resonance imaging to investigate the effects of delta-9-tetrahydrocannabinol (THC), a naturally occurring cannabinoid, on brain activity related to cutaneous ongoing pain and hyperalgesia that were temporarily induced by capsaicin in healthy volunteers. On average, THC reduced the reported unpleasantness, but not the intensity of ongoing pain and hyperalgesia: the specific analgesic effect on hyperalgesia was substantiated by diminished activity in the anterior mid cingulate cortex. In individuals, the drug-induced reduction in the unpleasantness of hyperalgesia was positively correlated with right amygdala activity. THC also reduced functional connectivity between the amygdala and primary sensorimotor areas during the ongoing-pain state. Critically, the reduction in sensory-limbic functional connectivity was positively correlated with the difference in drug effects on the unpleasantness and the intensity of ongoing pain. Peripheral mechanisms alone cannot account for the dissociative effects of THC on the pain that was observed. Instead, the data reveal that amygdala activity contributes to interindividual response to cannabinoid analgesia, and suggest that dissociative effects of THC in the brain are relevant to pain relief in humans.

Effect of cannabinoid receptor activation on spreading depression.

The objective of this study was to evaluate the effect of cannabinoid on cortical spreading depression (CSD) in rat brain. Cannabis has been used for centuries for both symptomatic and prophylactic treatment of different types of headaches including migraine. CSD is believed to be a putative neuronal mechanism underlying migraine aura and subsequent pain. The effects of Delta9-tetrahydrocannabinol (THC), as well as, cannabinoid CB1 and CB2 receptor agonists on CSD in rat neocortical slices were investigated. Furthermore, the effect of cannabinoid CB1 agonist was tested on field excitatory postsynaptic potentials (fEPSP) and long-term potentiation (LTP). HC (1-20 microM) dose dependently suppressed CSD amplitude, duration, and propagation velocity. Cannabinoid CB1 agonist, WIN 55,212-2 mesylate (1-10 microM), also significantly suppressed all characteristic features of CSD. However, cannabinoid CB2 agonist, JWH-133 (1-20 microM), did not affect CSD. FEPSP and induction of LTP were suppressed by application of WIN55212-2. Suppression of CSD by activation of CB1 receptors points to the potential therapeutic effects of cannabinoids in migraine with aura. More research is needed before we know whether cannabinoids may be helpful in treating migraine pain.

Cannabinoid facilitation of behavioral and biochemical hedonic taste responses

Cannabinoid receptor agonists are known to stimulate feeding in humans and animals and this effect is thought to be related to an increase in food palatability. On the other hand, highly palatable food stimulates dopamine (DA) transmission in the shell of the nucleus accumbens (NAc) and this effect undergoes one trial habituation. In order to investigate the relationship between the affective properties of tastes and the response of NAc shell DA we studied the effect of delta-9-tetrahydrocannabinol (THC) on behavioral taste reactivity to intraoral infusion of appetitive (sucrose solutions) and aversive (quinine and saturated NaCl solutions) tastes and on the response of in vivo DA transmission in the NAc shell to intraoral sucrose. Rats were implanted with intraoral cannulae and the effect of systemic administration of THC on the behavioral reactions to intraoral infusion of sucrose and of quinine or saturated NaCl solutions were scored. THC increased the hedonic reactions to sucrose but did not affect the aversive reactions to quinine and NaCl. The effects of THC were completely blocked by the CB1 receptor inverse agonist/antagonist rimonabant given at doses that do not affect taste reactivity to sucrose. In rats implanted with microdialysis probes and with intraoral cannulae, THC, made sucrose effective in raising dialysate DA in the shell of the NAc. As in the case of highly palatable food (Fonzies, sweet chocolate), the stimulatory effect of sucrose on shell DA under THC underwent one trial habituation. Altogether, these findings demonstrate that stimulation of CB1 receptors specifically increases the palatability of hedonic taste without affecting that of aversive tastes. Consistent with the ability of THC to increase sucrose palatability is the observation that under THC pretreatment sucrose acquires the ability to induce a release of DA in the shell of the NAc and this property undergoes adaptation after repeated exposure to the taste (habituation).This article is part of a Special Issue entitled ‘Central Control of Food Intake’.

P.1.e.007 The effects of delta9-tetrahydrocannabinol (THC) on human brain function involved in emotional processing: a pharmacological fMRI study

P.1.e.007 The effects of delta9-tetrahydrocannabinol (THC) on human brain function involved in emotional processing: a pharmacological fMRI study

Modulation of Auditory and Visual Processing by Delta-9-Tetrahydrocannabinol and Cannabidiol: an fMRI Study

Although the effects of cannabis on perception are well documented, little is known about their neural basis or how these may contribute to the formation of psychotic symptoms. We used functional magnetic resonance imaging (fMRI) to assess the effects of Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) during visual and auditory processing in healthy volunteers. In total, 14 healthy volunteers were scanned on three occasions. Identical 10 mg THC, 600 mg CBD, and placebo capsules were allocated in a balanced double-blinded pseudo-randomized crossover design. Plasma levels of each substance, physiological parameters, and measures of psychopathology were taken at baseline and at regular intervals following ingestion of substances. Volunteers listened passively to words read and viewed a radial visual checkerboard in alternating blocks during fMRI scanning. Administration of THC was associated with increases in anxiety, intoxication, and positive psychotic symptoms, whereas CBD had no significant symptomatic effects. THC decreased activation relative to placebo in bilateral temporal cortices during auditory processing, and increased and decreased activation in different visual areas during visual processing. CBD was associated with activation in right temporal cortex during auditory processing, and when contrasted, THC and CBD had opposite effects in the right posterior superior temporal gyrus, the right-sided homolog to Wernicke's area. Moreover, the attenuation of activation in this area (maximum 61, -15, -2) by THC during auditory processing was correlated with its acute effect on psychotic symptoms. Single doses of THC and CBD differently modulate brain function in areas that process auditory and visual stimuli and relate to induced psychotic symptoms.

S39-03 Neurofunctional effects of cannabis on response inhibition

Background:This study examined the effect of Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on brain activation during a motor inhibition task.Methods:Functional magnetic resonance imaging and behavioural measures were recorded while 15 healthy volunteers performed a Go/No-Go task following administration of either THC or CBD or placebo in a double-blind, pseudo-randomized, placebo-controlled repeated measures within-subject design.Results:Relative to placebo, THC attenuated activation in the right inferior frontal and the anterior cingulate gyrus. In contrast, CBD deactivated the left temporal cortex and insula. These effects were not related to changes in anxiety, intoxication, sedation, and psychotic symptoms.Conclusions:These data suggest that THC attenuates the engagement of brain regions that mediate response inhibition. CBD modulated function in regions not usually implicated in response inhibition.

Inhibition of THC-induced effects on the central nervous system and heart rate by a novel CB1 receptor antagonist AVE1625

CB1 antagonists such as AVE1625 are potentially useful in the treatment of obesity, smoking cessation and cognitive impairment. Proof of pharmacological action of AVE1625 in the brain can be given by antagonising the effects of delta-9-tetrahydrocannabinol (THC), a CB1/CB2 agonist. Inhibition of THC-induced effects by AVE1625 was observed on Visual Analogue Scales 'alertness', 'feeling high', 'external perception', 'body sway' and 'heart rate'. Even the lowest dose of AVE1625 20 mg inhibited most of THC-induced effects. AVE1625 did not have any effect on psychological and behavioural parameters or heart rate by itself. After THC and AVE1625 administration, changes on electroencephalography were observed. This study shows a useful method for studying the effects of CB1 antagonists. AVE1625 penetrates the brain and antagonises THC-induced effects with doses at or above 20 mg.

Effect of intrapulmonary tetrahydrocannabinol administration in humans

This randomised, double-blind, placebo-controlled, cross-over study was designed to identify which pharmacodynamic parameters most accurately quantify the effects of delta-9-Tetrahydrocannabinol (THC), the predominantly psychoactive component of cannabis. In addition, we investigated the acceptability and usefulness of a novel mode of intrapulmonary THC administration using a Volcano vaporizer and pure THC instead of cannabis. Rising doses of THC (2, 4, 6 and 8 mg) or vehicle were administered with 90 minutes intervals to twelve healthy males using a Volcano vaporizer. Very low between-subject variability was observed in THC plasma concentrations, characterising the Volcano vaporizer as a suitable method for the administration of THC. Heart rate showed a sharp increase and rapid decline after each THC administration (8 mg: 19.4 bpm: 95% CI 13.2, 25.5). By contrast, dose dependent effects of body sway (8 mg: 108.5%: 95% CI 72.2%, 152.4%) and different subjective parameters did not return to baseline between doses (Visual Analogue Scales of 'alertness' (8 mg: -33.6 mm: 95% CI -41.6, -25.7), 'feeling high' (8 mg: 1.09 U: 95% CI 0.85, 1.33), 'external perception' (8 mg: 0.62 U: 95% CI 0.37, 0.86)). PK/PD-modeling of heart rate displayed a relatively short equilibration half-life of 7.68 min. CNS parameters showed equilibration half-lives ranging between 39.4 - 84.2 min. Some EEG-frequency bands, and pupil size showed small changes following the highest dose of THC. No changes were seen in saccadic eye movements, smooth pursuit and adaptive tracking performance. These results may be applicable in the development of novel cannabinoid agonists and antagonists, and in studies of the pharmacology and physiology of cannabinoid systems in humans.

Neural Basis of Δ-9-Tetrahydrocannabinol and Cannabidiol: Effects During Response Inhibition

This study examined the effect of Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) on brain activation during a motor inhibition task. Functional magnetic resonance imaging and behavioural measures were recorded while 15 healthy volunteers performed a Go/No-Go task following administration of either THC or CBD or placebo in a double-blind, pseudo-randomized, placebo-controlled repeated measures within-subject design. Relative to placebo, THC attenuated activation in the right inferior frontal and the anterior cingulate gyrus. In contrast, CBD deactivated the left temporal cortex and insula. These effects were not related to changes in anxiety, intoxication, sedation, and psychotic symptoms. These data suggest that THC attenuates the engagement of brain regions that mediate response inhibition. CBD modulated function in regions not usually implicated in response inhibition.

Sex differences in the effects of Δ9-tetrahydrocannabinol on spatial learning in adolescent and adult rats

Like other recreational drugs, cannabinoids may produce different effects in men and women. In this study we measured the effects of delta9-tetrahydrocannabinol (THC) on spatial learning in two groups that are underrepresented in drug research--females and adolescents. In the first experiment, adolescent (postnatal day 30) and adult (postnatal day 70) rats of both sexes were treated subchronically with 5.0 mg/kg THC or vehicle for five consecutive days. Thirty minutes after each daily injection, they were tested on the spatial version of the Morris water maze task. In the second experiment, a separate group of adolescent and adult rats of both sexes was treated with 5.0 mg/kg THC or vehicle daily for 21 days and tested, 4 weeks later, on the spatial version of the water maze. Subchronic THC impaired spatial learning, and this effect was dependent upon both the age and sex of the animals tested. Prior exposure to chronic THC, however, did not cause any long-lasting spatial learning deficits. On the basis of our previous studies in male rats the third experiment assessed the dose-response relationship for the effects of THC on spatial learning and memory in female animals. We found that subchronic THC treatment (2.5, 5.0, or 10.0 mg/kg, intraperitoneally) disrupted learning in both adolescents and adults, but with greater effects at higher doses in adolescents compared with adults. The developmental sensitivity to subchronic THC confirms previous work carried out in our laboratory, and the sex-dependent effects highlight the importance of including females in drug abuse and addiction research.

Differential effects of delta 9-THC on learning in adolescent and adult rats

Marijuana use remains strikingly high among young users in the U.S., and yet few studies have assessed the effects of delta 9-tetrahydrocannabinol (THC) in adolescents compared to adults. This study measured the effects of THC on male adolescent and adult rats in the Morris water maze. In Experiment 1, adolescent (PD = 30–32) and adult (PD = 65–70) rats were treated acutely with 5.0 mg/kg THC or vehicle while trained on the spatial version of the water maze on five consecutive days. In Experiment 2, adolescent and adult rats were treated acutely with 2.5 or 10.0 mg/kg THC or vehicle while trained on either the spatial and non-spatial versions of the water maze. In Experiment 3, adolescent and adult rats were treated with 5.0 mg/kg THC or vehicle daily for 21 days, and were trained on the spatial and then the non-spatial versions of the water maze task four weeks later in the absence of THC. THC impaired both spatial and nonspatial learning more in adolescents than in adults at all doses tested. However, there were no long-lasting significant effects on either spatial or non-spatial learning in rats that had been previously exposed to THC for 21 days. This developmental sensitivity is analogous to the effects of ethanol, another commonly used recreational drug.

Highs and Lows

Highs and Lows

Self-administration of delta9-tetrahydrocannabinol (THC) by drug naive squirrel monkeys.

Interest in therapeutic activities of cannabinoids has been restrained by the fact that they are most often mediated through activation of cannabinoid CB1 receptors, the same receptors that mediate the effects of delta9-tetrahydrocannabinol (THC) and are responsible for the abuse liability of marijuana. Persistent intravenous self-administration of THC by animals was first demonstrated in squirrel monkeys and shown to be mediated by CB1 receptors, but monkeys in the study had a history of cocaine self-administration, raising the possibility that persistent neurobiological adaptations might subsequently predispose animals to self-administer THC. To demonstrate persistent intravenous self-administration of THC in drug-naive squirrel monkeys. Monkeys with no history of exposure to other drugs learned to press a lever for intravenous injections (0.2 ml in 0.2 s) of THC under a 10-response, fixed-ratio schedule with a 60-s time-out after each injection. Acquisition of THC self-administration was rapid and the final schedule was reached in 11-34 sessions. Dose of THC was then varied from 1 to 16 microg/kg per injection with vehicle extinction following each dose of THC. THC maintained significantly higher numbers of self-administered injections per session and higher rates of responding than vehicle at doses of 2, 4 and 8 microg/kg per injection, with maximal rates of responding at 4 microg/kg per injection. Response rates, injections per session and total THC intake per session were two- to three-fold greater in monkeys with no history of exposure to other drugs compared to previous findings in monkeys with a history of cocaine self-administration. THC can act as an effective reinforcer of drug-taking behavior in monkeys with no history of exposure to other drugs, suggesting that self-administration of THC by monkeys provides a reliable animal model of human marijuana abuse.

Delta 9-tetrahydrocannabinol-induced alterations in limbic system glucose use in the rat.

The effects of Delta9-tetrahydrocannabinol (THC) on neural activity in the rat were investigated using [14C]2-deoxyglucose autoradiography to measure local cerebral glucose use. Overall, THC reduced glucose use at 5 mg/kg and slightly increased it at 1 mg/kg. Significant reductions were seen at the higher dose in regions of the hippocampus and limbic system, and in structures associated with sensory and sensorimotor process ing, consistent with the effects of THC on memory, sensory perception and motor control. Glucose use was increased in the shell of the nucleus accumbens at 1 mg/kg but not reduced at 5 mg/kg. This may reflect increases in activity in mesolimbic reward pathways which at the higher dose are mitigated by reduced glutamatergic outflow from the hippocampus.

Cerebellar activity and disturbed time sense after THC

Because marijuana continues to be the most commonly used illicit drug, its effects on the brain function are of major interest. We utilized positron emission tomography (PET) and magnetic resonance imaging (MRI) to study the effects of delta-9-tetrahydrocannabinol (THC) infusion on brain blood flow and its behavioral correlates in 46 volunteers. Consistent with previous reports, there was a significant increase in cortical and cerebellar blood flow following THC, but not all subjects showed this effect. Those who showed a decrease in cerebellar CBF also had a significant alteration in time sense. The relationship between decreased cerebellar flow and impaired time sense is of interest because the cerebellum has been linked to an internal timing system.