Doses Of Δ9-THC Research Articles

Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability.

We aimed to assess the analgesic efficacy, pharmacokinetics, tolerability and safety of a single dose of Δ9-THC in patients with chronic abdominal pain resulting from chronic pancreatitis (CP). This was a randomized, single dose, double-blinded, placebo-controlled, two way crossover study in patients suffering from abdominal pain as result of CP (n=24), post hoc subdivided into opioid and non-opioid users. Δ9-THC (8mg) or active placebo (5mg/10mg diazepam) was administered orally in a double dummy design. No treatment effect was shown for delta VAS pain scores after Δ9-THC compared with diazepam. Δ9-THC was well absorbed with a mean tmax of 123min. No significant differences were found between Δ9-THC vs. diazepam for alertness, mood, calmness or balance. Feeling anxious and heart rate were significantly increased after Δ9-THC compared with diazepam. The most frequently reported adverse events (AEs) after Δ9-THC administration were somnolence, dry mouth, dizziness and euphoric mood. A single dose of Δ9-THC was not efficacious in reducing chronic pain resulting from CP, but was well tolerated with only mild or moderate AEs. The PK results in CP patients showed delayed absorption and an increased variability compared with healthy volunteers.

Sex differences in the subjective effects of oral Δ9-THC in cannabis users

Previous studies suggest that there are sex differences in endocannabinoid function and the response to exogenous cannabinoids, though data from clinical studies comparing acute cannabinoid effects in men and women under controlled laboratory conditions are limited. To further explore these potential differences, data from 30 cannabis users (N=18 M, 12 F) who completed previous Δ9-tetrahydrocannabinol (Δ9-THC) discrimination studies were combined for this retrospective analysis. In each study, subjects learned to discriminate between oral Δ9-THC and placebo and then received a range of Δ9-THC doses (0, 5, 15 and a “high” dose of either 25 or 30mg). Responses on a drug-discrimination task, subjective effects questionnaire, psychomotor performance tasks, and physiological measures were assessed. Δ9-THC dose-dependently increased drug-appropriate responding, ratings on “positive” Visual Analog Scale (VAS) items (e.g., good effects, like drug, take again), and items related to intoxication (e.g., high, stoned). Δ9-THC also dose-dependently impaired performance on psychomotor tasks and elevated heart rate. Sex differences on VAS items emerged as a function of dose. Women exhibited significantly greater subjective responses to oral drug administration than men at the 5mg Δ9-THC dose, whereas men were more sensitive to the subjective effects of the 15mg dose of Δ9-THC than women. These results demonstrate dose-dependent separation in the subjective response to oral Δ9-THC administration by sex, which might contribute to the differential development of problematic cannabis use.

Persistent effects of chronic Δ9-THC exposure on motor impulsivity in rats.

In humans, long-term marijuana use is associated with impaired impulse control and attentional capacity, though it has been difficult to distinguish pre-existing cognitive deficits from possible consequences of prolonged marijuana exposure. To evaluate the effects of long-term exposure to Δ9-Tetrahydrocannabinol (Δ9-THC), the primary psychoactive constituent in marijuana, on indices of impulse control and attentional capacity using the rat 5-Choice Serial Reaction Time Task (5-CSRTT). Ten 14-day cycles of Δ9-THC dosing and 5-CSRTT testing were employed, each comprised of 5-day Δ9-THC dosing (0.3 or 3 mg/kg b.i.d.) and 5-CSRTT testing during the 9 days of drug abstinence. Subsequent 5-CSRTT testing continued during 5 weeks of protracted abstinence. Dose-dependent increases in motor impulsivity (premature responses) and behavioral disinhibition (perseverative responses) emerged following 5 cycles of Δ9-THC exposure that persisted for the remaining dosing and testing cycles. Δ9-THC-related disruptions in motor impulsivity and behavioral inhibition were most pronounced during cognitively challenging 5-CSRTT sessions incorporating varying novel inter-trial intervals (ITIs), and these disruptions persisted for at least 5 weeks of Δ9-THC abstinence. Δ9-THC-related impairments in attentional capacity (response accuracy) were also evident during variable ITI challenge tests, though these attentional disruptions abated within 3 weeks of Δ9-THC abstinence. These observations demonstrate that long-term intermittent exposure to clinically meaningful Δ9-THC doses induces persistent impairments in impulse control and attentional function. If present in humans, these disruptions may impact academic and professional performance.

Neuroprotection in Experimental Autoimmune Encephalomyelitis and Progressive Multiple Sclerosis by Cannabis-Based Cannabinoids.

Multiple sclerosis (MS) is the major immune-mediated, demyelinating, neurodegenerative disease of the central nervous system. Compounds within cannabis, notably Δ9-tetrahydrocannabinol (Δ9-THC) can limit the inappropriate neurotransmissions that cause MS-related problems and medicinal cannabis is now licenced for the treatment of MS symptoms. However, the biology indicates that the endocannabinoid system may offer thepotential to control other aspects of disease. Although there is limited evidence that the cannabinoids from cannabis are having significant immunosuppressive activities that will influence relapsing autoimmunity, we and others can experimentally demonstrate that they may limit neurodegeneration that drives progressive disability. Here we show that synthetic cannabidiol can slow down the accumulation of disability from the inflammatory penumbra during relapsing experimental autoimmune encephalomyelitis (EAE) in ABH mice, possibly via blockade of voltage-gated sodium channels. In addition, whilst non-sedating doses of Δ9-THC do not inhibit relapsing autoimmunity, they dose-dependently inhibit the accumulation of disability during EAE. They also appear to slow down clinical progression during MS in humans. Although a 3year, phase III clinical trial did not detect a beneficial effect of oral Δ9-THC in progressive MS, a planned subgroup analysis of people with less disability who progressed more rapidly, demonstrated a significant slowing of progression by oral Δ9-THC compared to placebo. Whilst this may support the experimental and biological evidence for a neuroprotective effect by the endocannabinoid system in MS, it remains to be established whether this will be formally demonstrated in further trials of Δ9-THC/cannabis in progressive MS.

Separate and combined effects of gabapentin and Δ9-THC doses in cannabis users discriminating Δ9-THC

Separate and combined effects of gabapentin and Δ9-THC doses in cannabis users discriminating Δ9-THC

In vivo effects of synthetic cannabinoids JWH-018 and JWH-073 and phytocannabinoid Δ9-THC in mice: Inhalation versus intraperitoneal injection

Human users of synthetic cannabinoids (SCBs) JWH-018 and JWH-073 typically smoke these drugs, but preclinical studies usually rely on injection for drug delivery. We used the cannabinoid tetrad and drug discrimination to compare in vivo effects of inhaled drugs with injected doses of these two SCBs, as well as with the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC). Mice inhaled various doses of Δ9-THC, JWH-018 or JWH-073, or were injected intraperitoneally (IP) with these same compounds. Rectal temperature, tail flick latency in response to radiant heat, horizontal bar catalepsy, and suppression of locomotor activity were assessed in each animal. In separate studies, mice were trained to discriminate Δ9-THC (IP) from saline, and tests were performed with inhaled or injected doses of the SCBs. Both SCBs elicited Δ9-THC-like effects across both routes of administration, and effects following inhalation were attenuated by pretreatment with the CB1 antagonist/inverse agonist rimonabant. No cataleptic effects were observed following inhalation, but all compounds induced catalepsy following injection. Injected JWH-018 and JWH-073 fully substituted for Δ9-THC, but substitution was partial (JWH-073) or required relatively higher doses (JWH-018) when drugs were inhaled. These studies demonstrate that the SCBs JWH-018 and JWH-073 elicit dose-dependent, CB1 receptor-mediated Δ9-THC-like effects in mice when delivered via inhalation or via injection. Across these routes of administration, differences in cataleptic effects and, perhaps, discriminative stimulus effects, may implicate the involvement of active metabolites of these compounds.

Blunting of the HPA-axis underlies the lack of preventive efficacy of early post-stressor single-dose Delta-9-tetrahydrocannabinol (THC)

The therapeutic value of Delta-9-tetrahydrocannabinol (Δ9-THC) in the aftermath of trauma has recently raised interest. A prospective animal model for posttraumatic stress disorder was employed to assess the behavioral effects of a single dose of Δ9-THC administered intraperitoneally following exposure to psychogenic stress.Animals were exposed to predator scent stress and treated 1h later with Δ9-THC (1, 5 and 10mg/kg) or vehicle. The outcome measures included behavior in an elevated plus-maze and acoustic startle response 1, 6 and 24h or 7days after exposure and freezing behavior upon exposure to a trauma cue on day 8. Pre-set cut-off behavioral criteria classified exposed animals as those with “extreme,” “minimal” or “intermediate” (partial) response. Circulating corticosterone levels were assessed over 2h after exposure with and without Δ9-THC. The behavioral effects of a CB1 antagonist (AM251) administered systemically 1h post exposure were evaluated.In the short term (1–6h), 5mg/kg of Δ9-THC effectively attenuated anxiety-like behaviors. In the longer-term (7days), it showed no effect in attenuating PTSD-like behavioral stress responses, or freezing response to trauma cue. Δ9-THC significantly decreased corticosterone levels. In contrast, administration of AM251 (a CB1 antagonist/inverse agonist) 1h post exposure attenuated long-term behavioral stress responses through activation of the HPA-axis.The demonstrated lack of preventive efficacy of early Δ9-THC treatment and reports of its anxiogenic effects in many individuals raises doubts not only regarding its potential clinical value, but also the advisability of clinical trials. The endocannabinoids exert complex effects on behavioral responses mediating glucocorticoid effects on memory of traumatic experiences.

Chronic administration during early adulthood does not alter the hormonally-dependent disruptive effects of delta-9-tetrahydrocannabinol (Δ9-THC) on complex behavior in female rats

This study examined whether chronic Δ9-THC during early adulthood would produce the same hormonally-dependent deficits in learning that are produced by chronic Δ9-THC during adolescence. To do this, either sham-operated (intact) or ovariectomized (OVX) female rats received daily saline or 5.6mg/kg of Δ9-THC i.p. for 40days during early adulthood. Following chronic administration, and a drug-free period to train both a learning and performance task, acute dose-effect curves for Δ9-THC (0.56–10mg/kg) were established in each of the four groups (intact/saline, intact/THC, OVX/saline and OVX/THC). The dependent measures of responding under the learning and performance tasks were the overall response rate and the percentage of errors. Although the history of OVX and chronic Δ9-THC in early adulthood did not significantly affect non-drug or baseline behavior under the tasks, acute administration of Δ9-THC produced both rate-decreasing and error-increasing effects on learning and performance behavior, and these effects were dependent on their hormone condition. More specifically, both intact groups were more sensitive to the rate-decreasing and error-increasing effects of Δ9-THC than the OVX groups irrespective of chronic Δ9-THC administration, as there was no significant main effect of chronic treatment and no significant interaction between chronic treatment (saline or Δ9-THC) and the dose of Δ9-THC administered as an adult. Post mortem examination of 10 brain regions also indicated there were significant differences in agonist-stimulated GTPγS binding across brain regions, but no significant effects of chronic treatment and no significant interaction between the chronic treatment and cannabinoid signaling. Thus, acute Δ9-THC produced hormonally-dependent effects on learning and performance behavior, but a period of chronic administration during early adulthood did not alter these effects significantly, which is contrary to what we and others have shown for chronic administration during adolescence.

Biphasic effects of Δ9-tetrahydrocannabinol on brain stimulation reward and motor activity

Δ(9)-tetrahydrocannabinol (Δ(9)-THC), the main psychoactive ingredient of marijuana, has led to equivocal results when tested with the intracranial self-stimulation (ICSS) procedure or the open-field test for motor activity, two behavioural models for evaluating the reward-facilitating and locomotor stimulating effects of drugs of abuse, respectively. Therefore, in the present study, the effects of high and low doses of Δ(9)-THC were compared in the ICSS procedure and the open-field test. Moreover, the involvement of CB(1) receptors in tentative Δ(9)-THC-induced effects was investigated by pre-treating the animals with the CB(1) receptor antagonist SR141716A (rimonabant). The results obtained show that low doses of Δ(9)-THC induce opposite effects from high doses of Δ(9)-THC. Specifically, 0.1 mg/kg Δ(9)-THC decreased ICSS thresholds and produced hyperactivity, whereas 1 mg/kg increased ICSS thresholds and produced hypoactivity. Both effects were reversed by pre-treatment with SR141716A, indicating the involvement of CB(1) receptors on these actions. Altogether, our results indicate that Δ(9)-THC can produce acute activating effects in locomotion that coincide with its reward-facilitating effects in the ICSS paradigm. The present findings provide further support that Δ(9)-THC induces behaviours typical of abuse and substantiate the notion that marijuana resembles other drugs of abuse.

Additive antiemetic efficacy of low-doses of the cannabinoid CB1/2 receptor agonist Δ9-THC with ultralow-doses of the vanilloid TRPV1 receptor agonist resiniferatoxin in the least shrew (Cryptotis parva)

Previous studies have shown that cannabinoid CB1/2 and vanilloid TRPV1 agonists (delta-9-tetrahydrocannabinol (Δ9-THC) and resiniferatoxin (RTX), respectively) can attenuate the emetic effects of chemotherapeutic agents such as cisplatin. In this study we used the least shrew to demonstrate whether combinations of varying doses of Δ9-THC with resiniferatoxin can produce additive antiemetic efficacy against cisplatin-induced vomiting. RTX by itself caused vomiting in a bell-shaped dose-dependent manner with maximal vomiting at 18μg/kg when administered subcutaneously (s.c.) but not intraperitoneally (i.p.). Δ9-THC up to 10mg/kg provides only 80% protection of least shrews from cisplatin-induced emesis with an ID50 of 0.3–1.8mg/kg. Combinations of 1 or 5μg/kg RTX with varying doses of Δ9-THC completely suppressed both the frequency and the percentage of shrews vomiting with ID50 dose values 5–50 times lower than Δ9-THC doses tested alone against cisplatin. A less potent TRPV1 agonist, capsaicin, by itself did not cause emesis (i.p. or s.c.), but it did significantly reduce vomiting induced by cisplatin given after 30min but not at 2h. The TRPV1-receptor antagonist, ruthenium red, attenuated cisplatin-induced emesis at 5mg/kg; however, another TRPV1-receptor antagonist, capsazepine, did not. In summary, we present evidence that combination of CB1/2 and TRPV1 agonists have the capacity to completely abolish cisplatin-induced emesis at doses that are ineffective when used individually.

Additive antiemetic efficacy of Δ9‐THC with vanilloid TRPV1 receptor agonists in the least shrew (Cryptotis parva)

Previous studies have shown that cannabinoid CB1 and vanilloid TRPV1 agonists ( Δ9‐THC and resiniferatoxin (RTX), respectively) can attenuate the emetic effects of chemotherapeutic agents such as cisplatin. In this study we used the least shrew to demonstrate whether combination of varying doses of Δ9‐THC with resiniferatoxin can produce additive antiemetic efficacy against cisplatin‐induced vomiting. RTX by itself caused vomiting in a bell‐shaped dose‐dependent manner with maximal vomiting at 18 ug/kg when administered sc but not ip. Δ9‐THC up to 10 mg/kg can only protect least shrews from cisplatin‐induced emesis by 80% with an ID50 of 0.3 – 1.8 mg/kg. Combinations of 1 or 5 ug/kg RTX with varying doses of Δ9‐THC completely suppressed both the frequency and the percentage of shrews vomiting with ID50 dose values 5–50 times lower than Δ9‐THC doses tested alone against cisplatin. A less potent TRPV1 agonist capsaicin, by itself did not cause emesis (ip or sc), but did significantly reduce vomiting induced by cisplatin given after 30 minutes but not at 2 hours. TRPV1 antagonist ruthenium red attenuated cisplatin‐induced emesis at 5 mg/kg, however capsazepine did not. In summary, we present evidence that combinations of CB1 and TRPV1 agonists have the capacity to completely abolish cisplatin‐induced emesis at doses lower than when used individually.

The effect of cannabis use on memory function: an update

Investigating the effects of cannabis use on memory function appears challenging. While early observational investigations aimed to elucidate the longer-term effects of cannabis use on memory function in humans, findings remained equivocal and pointed to a pattern of interacting factors impacting on the relationship between cannabis use and memory function, rather than a simple direct effect of cannabis. Only recently, a clearer picture of the chronic and acute effects of cannabis use on memory function has emerged once studies have controlled for potential confounding factors and started to investigate the acute effects of delta-9-tetrahydrocannabinol (Δ9-THC) and cannabidiol (CBD), the main ingredients in the extract of the cannabis plant in pharmacological challenge experiments. Relatively consistent findings have been reported regarding the acute impairments induced by a single dose of Δ9-THC on verbal and working memory. It is unclear whether they may persist beyond the intoxication state. In the long-term, these impairments seem particularly likely to manifest and may also persist following abstinence if regular and heavy use of cannabis strains high in Δ9-THC is started at an early age. Although still at an early stage, studies that employed advanced neuroimaging techniques have started to model the neural underpinnings of the effects of cannabis use and implicate a network of functional and morphological alterations that may moderate the effects of cannabis on memory function. Future experimental and epidemiological studies that take into consideration individual differences, particularly previous cannabis history and demographic characteristics, but also the precise mixture of the ingredients of the consumed cannabis are necessary to clarify the magnitude and the mechanisms by which cannabis-induced memory impairments occur and to elucidate underlying neurobiological mechanisms.

Ovarian hormones and chronic administration during adolescence modify the discriminative stimulus effects of delta-9-tetrahydrocannabinol (Δ9-THC) in adult female rats

Marijuana abuse during adolescence may alter its abuse liability during adulthood by modifying the interoceptive (discriminative) stimuli produced, especially in females due to an interaction with ovarian hormones. To examine this possibility, either gonadally intact or ovariectomized (OVX) female rats received 40 intraperitoneal injections of saline or 5.6mg/kg of Δ9-THC daily during adolescence, yielding 4 experimental groups (intact/saline, intact/Δ9-THC, OVX/saline, and OVX/Δ9-THC). These groups were then trained to discriminate Δ9-THC (0.32–3.2mg/kg) from saline under a fixed-ratio (FR) 20 schedule of food presentation. After a training dose was established for the subjects in each group, varying doses of Δ9-THC were substituted for the training dose to obtain dose–effect (generalization) curves for drug-lever responding and response rate. The results showed that: 1) the OVX/saline group had a substantially higher mean response rate under control conditions than the other three groups, 2) both OVX groups had higher percentages of THC-lever responding than the intact groups at doses of Δ9-THC lower than the training dose, and 3) the OVX/Δ9-THC group was significantly less sensitive to the rate-decreasing effects of Δ9-THC compared to other groups. Furthermore, at sacrifice, western blot analyses indicated that chronic Δ9-THC in OVX and intact females decreased cannabinoid type-1 receptor (CB1R) levels in the striatum, and decreased phosphorylation of cyclic adenosine monophosphate response element binding protein (p-CREB) in the hippocampus. In contrast to the hippocampus, chronic Δ9-THC selectively increased p-CREB in the OVX/saline group in the striatum. Extracellular signal-regulated kinase (ERK) was not significantly affected by either hormone status or chronic Δ9-THC. In summary, these data in female rats suggest that cannabinoid abuse by adolescent human females could alter their subsequent responsiveness to cannabinoids as adults and have serious consequences for brain development.

Δ9-THC and WIN55,212-2 affect brain tissue levels of excitatory amino acids in a phenotype-, compound-, dose-, and region-specific manner

Endocannabinoids are involved in excitatory neurotransmission initiated by glutamate and aspartate. The aim of the present study was to investigate the effects of the cannabinoid agonists, Δ9-THC and WIN55,212-2, on tissue (prefrontal cortex, dorsal striatum, nucleus accumbens, hippocampus, amygdala and hypothalamus) levels of glutamate and aspartate in two rat phenotypes, high responders (HR) and low responders (LR), differentiated according to their response to a novel environment. HR displayed increased motor activity but no difference in basal levels of glutamate and aspartate as compared to LR. Both cannabinoids increased ambulatory activity at the low doses, this effect was observed only in HR following Δ9-THC, but in both HR and LR following WIN55,212-2. The cannabinoids primarily increased glutamate levels in the prefrontal cortex, dorsal striatum, nucleus accumbens and hippocampus, while the high dose of WIN55,212-2 decreased glutamate levels in the amygdala and both doses in the hypothalamus; these effects appeared overall more pronounced in HR. In contrast, the cannabinoids primarily decreased aspartate levels in all brain regions, except in the dorsal striatum, where an increase was seen after both doses of Δ9-THC and WIN55,212-2 as well as in the nucleus accumbens after the low dose of Δ9-THC in HR; these effects also appeared overall more pronounced in HR. Present results show that exogenous cannabinoids affect tissue levels of glutamate and aspartate in a phenotype-, compound-, dose-, and brain region-dependent manner.

Separate and combined effects of the cannabinoid agonists nabilone and Δ9-THC in humans discriminating Δ9-THC

BackgroundAgonist replacement treatment is a promising strategy to manage cannabis-use disorders. The aim of this study was to assess the combined effects of the synthetic cannabinoid agonist nabilone and Δ9-tetrahydrocannabinol (Δ9-THC) using drug-discrimination procedures, which are sensitive to drug interactions. Testing the concurrent administration of nabilone and Δ9-THC was also conducted to provide initial safety and tolerability data, which is important because cannabis users will likely lapse during treatment. MethodsSix cannabis users learned to discriminate 30mg oral Δ9-THC from placebo and then received nabilone (0, 1 and 3mg) and Δ9-THC (0, 5, 15 and 30mg), alone and in combination. Subjects completed the multiple-choice procedure to assess drug reinforcement, and self-report, task performance and physiological measures were collected. ResultsΔ9-THC and nabilone alone shared discriminative-stimulus effects with the training dose of Δ9-THC, increased crossover point on the multiple-choice procedure, produced overlapping subject ratings and decreased skin temperature. Nabilone alone also elevated heart rate. In combination, nabilone shifted the discriminative-stimulus effects of Δ9-THC leftward/upward and enhanced Δ9-THC effects on the other outcome measures. ConclusionsThese results replicate a previous study demonstrating that nabilone shares agonist effects with the active constituent of cannabis in cannabis users, and contribute further by indicating that nabilone would likely be safe and well tolerated when combined with cannabis. These data support the conduct of future studies to determine if nabilone treatment would produce cross-tolerance to the abuse-related effects of cannabis and reduce cannabis use.

The cannabinoid receptor agonist delta-9-tetrahydrocannabinol does not affect visceral sensitivity to rectal distension in healthy volunteers and IBS patients

Visceral hypersensitivity to distension is thought to play an important role in the pathophysiology of the irritable bowel syndrome (IBS). Cannabinoids are known to decrease somatic pain perception, but their effect on visceral sensitivity in IBS remains unclear. Therefore, we evaluated the effect of the mixed CB(1) /CB(2) receptor agonist delta-9-tetrahydrocannabinol (Δ(9) -THC, dronabinol) on rectal sensitivity. Ten IBS patients and 12 healthy volunteers (HV) underwent a barostat study to assess rectal sensitivity using an intermittent pressure-controlled distension protocol before and after sigmoid stimulation. Repetitive sigmoid stimulation is a validated method to increase visceral perception in IBS patients, consisting of a 10-min period of 30 s stimuli (60 mmHg), separated by 30 s of rest (5 mmHg). The effect of placebo and Δ(9) -THC (5 and 10 mg in healthy volunteers and 10 mg in IBS patients) on rectal sensitivity was evaluated on respectively three and two separate days in a double blind, randomized, crossover fashion. All participants (HV and IBS) reported central side effects during the highest dose of Δ(9) -THC, most frequently increased awareness of the surrounding, light-headedness and sleepiness, whereas no side effects where reported during placebo. Although blood pressure was not affected, heart rate increased in both HV and IBS, but was most pronounced in IBS patients. The cannabinoid agonist Δ(9) -THC did not alter baseline rectal perception to distension compared to placebo in HV or IBS patients. Similarly, after sigmoid stimulation there were no significant differences between placebo and Δ(9) -THC in sensory thresholds of discomfort. These findings imply that Δ(9) -THC does not modify visceral perception to rectal distension and argue against (centrally acting) CB agonists as tool to decrease visceral hypersensitivity in IBS patients.

Effects of Δ9-tetrahydrocannabinol on reward and anxiety in rats exposed to chronic unpredictable stress

Although cannabis derivatives produce clear subjective motivational responses in humans leading to drug-seeking behaviour, the reinforcing attributes of these subjective effects are difficult to define in experimental animals. The aim of this study was to examine how exposure to chronic unpredictable stress (CUS) will affect reward function and anxiety after acute administration of Delta(9)-tetrahydrocannabinol (Delta(9)-THC) in rats. Male rats were exposed to either 10 days of CUS or no stressor. Alterations in brain reward function were assessed with the intracranial self-stimulation (ICSS) paradigm, and anxiety responses were measured with the elevated plus maze. CUS did not affect baseline brain stimulation reward thresholds. Delta(9)-THC did not exhibit reinforcing actions in the ICSS paradigm neither in nonstressed nor in stressed animals. More importantly, in nonstressed animals, both the low and the high dose of Delta(9)-THC exerted anxiolytic-like effects. In stressed animals, however, only the high dose of THC induced an anxiolytic-like response, whereas the low dose induced anxiogenic effects. The present results provide clear evidence for an anxiolytic effect of Delta(9)-THC both in stressed and in nonstressed animals, and indicate that environmental conditions, such as stressful experiences, do not alter the behavioural effects of Delta( 9)-THC in the ICSS paradigm.

Substitution profile of Δ9-tetrahydrocannabinol, triazolam, hydromorphone, and methylphenidate in humans discriminating Δ9-tetrahydrocannabinol

Preclinical evidence suggests that non-cannabinoid neurotransmitter systems are involved in the behavioral and physiological effects of cannabinoids, but relatively little research has been conducted in humans. The aims of this study were to assess whether oral Delta(9)-tetrahydrocannabinol (Delta(9)-THC) would function as a discriminative stimulus in humans and to examine the substitution profile of drugs acting at opioid, GABA, and dopamine systems. Healthy subjects who reported moderate cannabis use were enrolled. Subjects learned to identify when they received oral 25 mg Delta(9)-THC or placebo under double-blind conditions. Once subjects acquired the discrimination (i.e., > or =80% drug-appropriate responding for four consecutive sessions), multiple doses of Delta(9)-THC, the GABA(A) positive modulator triazolam, the micro-opioid agonist hydromorphone and the dopamine reuptake inhibitor methylphenidate were tested to determine if they shared discriminative-stimulus effects with the training dose of Delta(9)-THC. Eight subjects (N = 8) accurately discriminated Delta(9)-THC and completed the study. The training dose of Delta(9)-THC functioned as a discriminative stimulus and produced prototypical subject-rated drug effects. All of the drugs tested produced significant effects on the self-report questionnaires, but only Delta(9)-THC substituted for the training dose. These results suggest that the discriminative-stimulus effects of Delta(9)-THC in humans are not directly mediated through central neurotransmitter systems acted upon by the drugs tested in this study.

De la prise en charge du diabète à la prévention des événements cardiovasculaires

Previous studies have shown that cannabinoid CB1/2 and vanilloid TRPV1 agonists (delta-9-tetrahydrocannabinol (Δ9-THC) and resiniferatoxin (RTX), respectively) can attenuate the emetic effects of chemotherapeutic agents such as cisplatin. In this study we used the least shrew to demonstrate whether combinations of varying doses of Δ9-THC with resiniferatoxin can produce additive antiemetic efficacy against cisplatin-induced vomiting. RTX by itself caused vomiting in a bell-shaped dose-dependent manner with maximal vomiting at 18 μg/kg when administered subcutaneously (s.c.) but not intraperitoneally (i.p.). Δ9-THC up to 10 mg/kg provides only 80% protection of least shrews from cisplatin-induced emesis with an ID50 of 0.3–1.8 mg/kg. Combinations of 1 or 5 μg/kg RTX with varying doses of Δ9-THC completely suppressed both the frequency and the percentage of shrews vomiting with ID50 dose values 5–50 times lower than Δ9-THC doses tested alone against cisplatin. A less potent TRPV1 agonist, capsaicin, by itself did not cause emesis (i.p. or s.c.), but it did significantly reduce vomiting induced by cisplatin given after 30 min but not at 2 h. The TRPV1-receptor antagonist, ruthenium red, attenuated cisplatin-induced emesis at 5 mg/kg; however, another TRPV1-receptor antagonist, capsazepine, did not. In summary, we present evidence that combination of CB1/2 and TRPV1 agonists have the capacity to completely abolish cisplatin-induced emesis at doses that are ineffective when used individually.

Cannabinoid Modulation of Kaposi's Sarcoma–Associated Herpesvirus Infection and Transformation

Kaposi's sarcoma-associated herpesvirus (KSHV; also named human herpesvirus 8) is necessary but not sufficient for the development of Kaposi's sarcoma. A variety of factors may contribute to the pathogenesis of Kaposi's sarcoma in addition to KSHV. Marijuana is a widely used recreational agent, and Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major active component of marijuana, is prescribed for medicinal use. To evaluate how cannabinoids may affect the pathogenesis of Kaposi's sarcoma, we studied primary human dermal microvascular endothelial cells (HMVEC) exposed to KSHV. There was an increased efficiency of KSHV infection in the presence of low doses of Delta(9)-THC. We also found that Delta(9)-THC increased the viral load in KSHV-infected HMVEC through activation of the KSHV lytic switch gene, the open reading frame 50. Furthermore, we observed that Delta(9)-THC stimulated expression of the KSHV-encoded viral G protein-coupled receptor and Kaposi's sarcoma cell proliferation. Our results indicate that Delta(9)-THC can enhance KSHV infection and replication and foster KSHV-mediated endothelial transformation. Thus, use of cannabinoids may place individuals at greater risk for the development and progression of Kaposi's sarcoma.