That Delta-9-tetrahydrocannabinol Research Articles

Perinatal Tetrahydrocannabinol Compromises Maternal Care and Increases Litter Attrition in the Long-Evans Rat.

The marijuana legalization trend in the U.S. will likely lead to increased use by younger adults during gestation and postpartum. The current study examined the hypothesis that delta-9-tetrahydrocannabinol (THC) would disrupt voluntary maternal care behaviors and negatively impact offspring development. Rat dams were gavaged with 0, 2, 5, or 10 mg/kg THC from the 1st day of gestation through the 21st postnatal day. Somatic growth and developmental milestones were measured in the offspring, and maternal pup retrieval tests were conducted on postnatal days 1, 3, and 5. THC did not affect body growth but produced transient delays in the righting reflex and eye opening in offspring. However, there was significant pup mortality due to impaired maternal care. Dams in all THC groups took significantly longer to retrieve their pups to the nest and often failed to retrieve any pups. Serum levels of THC and metabolites measured at this time were comparable to those in breastfeeding women who are chronic users. Benchmark doses associated with a 10% reduction of pup retrieval or increased pup mortality were 0.383 (BMDL 0.228) and 0.794 (BMDL 0.442) mg/kg THC, respectively. The current findings indicate that maternal care is an important and heretofore overlooked index of THC behavioral toxicity and should be included in future assessments of THC's health risks.

Chronic administration of delta9-tetrahydrocannabinol protects hyperinsulinemic gastric tissue in rats.

Hyperinsulinemia (HI) can result from some reasons such as an increase in basal/fasting circulating insulin and/or potentiation of postprandial insulin production. Diabetes mellitus (DM) is indirectly related to HI since it both causes and results from insulin resistance. Understanding the causes of HI and treating this is crucial for preventing DM. Previous research has shown that delta9-tetrahydrocannabinol (THC) has medicinal benefits. In light of this, the relationship between THC and oxidative stress, DNA repair mechanism, apoptosis, and its regulatory impact on appetite hormones in the gastric tissue of hyperinsulinemic rats has been investigated for the first time. Male rats (Spraque-Dawley, total = 32) were used, and they were randomly divided into the following groups (n = 8 in each group): control (CTRL), HI, THC administered control (THC, 1.5 mg/kg/day, during 4 weeks), and THC administered HI (HI + THC) groups. The number of poly (ADP-ribose) polymerase-1 and proliferating cell nuclear antigen (PCNA) and caspase-3 immunopositive cells in the HI group was significantly reduced compared to the CTRL group. The number of PCNA and caspase-9 immunopositive cells was significantly increased in the HI + THC group compared to the HI group. Obestatin immunopositive cell numbers in the HI + THC group were higher than in the HI and CTRL groups. The results show that THC administration may affect the regulation of appetite hormones and regeneration in the fundus of rats with HI. Glutathione (GSH) levels were higher in the HI + THC group than in the HI group. Both immunohistochemical and biochemical analyses revealed that THC promotes regeneration and regulates appetite hormones in hyperinsulinemic gastric tissues.

Experimenter administered Δ9-THC decreases nicotine self-administration in a rat model

BackgroundThe co-use of nicotine and cannabis has been steadily rising in the United States. Rodent studies suggest that delta-9-tetrahydrocannabinol (THC) could increase addictive qualities of nicotine, but whether repeated THC exposure alters self-administration of nicotine has not been tested. We hypothesized that THC would increase the reinforcing effects of nicotine and alter nicotine intake. MethodsAdult male and female Sprague-Dawley rats were treated with THC (0, 3, 30 mg/kg) daily for 14 days prior to and during training for intravenous self-administration of nicotine. Rats were allowed to self-administer nicotine for several weeks, then tested for sensitivity to nicotine dose through multiple determinations of a nicotine dose-effect curve with or without THC pretreatment. A separate set of rats were trained on fixed ratio responding for sucrose and assessed for THC effects on behavior. ResultsPost-session THC decreased nicotine self-administration in male and female rats throughout acquisition and maintenance and increased the latency to stable rates of nicotine intake during acquisition. Post-session THC shifted nicotine dose-effect curves downward, and pre-session THC suppressed responding at higher nicotine doses. Unlike nicotine, responding for sucrose was not affected by post-session THC. Pre-session THC decreased responding for sucrose, particularly for THC-naïve rats. ConclusionsRepeated post-session THC decreased nicotine-taking behaviors but did not alter sucrose responding. Thus, post-session THC may alter sensitivity to nicotine. Pre-session THC treatment decreased lever pressing in both sucrose and nicotine studies, indicating this effect was nonspecific. These studies show that THC modulates patterns of nicotine intake in rat models.

Inhibiting Human and Leishmania Arginases Using Cannabis sativa as a Potential Therapy for Cutaneous Leishmaniasis: A Molecular Docking Study.

Cutaneous leishmaniasis (CL), a vector-borne parasitic disease caused by the Leishmania protozoan, is a serious public health problem in Morocco. The treatment of this disease is still based on pentavalent antimonials as the primary therapy, but these have associated side effects. Thus, the development of effective, risk-free alternative therapeutics based on natural compounds against leishmaniasis is urgent. Arginase, the key enzyme in the polyamine biosynthetic pathway, plays a critical role in leishmaniasis outcome and has emerged as a potential therapeutic target. The objective of this study was to test Cannabis sativa's phytochemical components (cannabinoids and terpenoids) through molecular docking against Leishmania and human arginase enzymes. Our results showed that delta-9-tetrahydrocannabinol (THC) possessed the best binding energies of -6.02 and -6.35 kcal/mol with active sites of Leishmania and human arginases, respectively. Delta-9-THC interacted with Leishmania arginase through various amino acids including His139 and His 154 and linked to human arginase via His 126. In addition to delta-9-THC, caryophyllene oxide and cannabidiol (CBD) also showed a good inhibition of Leishmania and human arginases, respectively. Overall, the studied components were found to inhibit both arginases active sites via hydrogen bonds and hydrophobic interactions. These components may serve as therapeutic agents or in co-administrated therapy for leishmaniasis.

Anti-inflammatory potential of delta-9-tetrahydrocannabinol in hyperinsulinemia: an experimental study.

Hyperinsulinemia (HI) means that the amount of insulin in the blood is higher than normal and is often associated with type 2 diabetes. It is known that delta-9-tetrahydrocannabinol (THC) obtained from a medicinal plant, Cannabis sativa, has therapeutic effects on many diseases. This study aimed to investigate the effects of THC on inflammatory and oxidant status in rat pancreas with HI. Rats were divided into groups; Control, HI, THC and HI + THC. Each group consists of 8 animals. HI and HI + THC groups were given 10% fructose in the drinking waterfor 12weeks. In the last four weeks of the experiment, 1.5mgkg-1 THC was injected intraperitoneally daily into THC and HI + THC groups. The expression of tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), and nuclear factor-kappa B (NF-κB) were detected. JNK/SAPK and Grap2/p38 levels, total antioxidant and oxidant capacities (TAC and TOC) were analyzed in the pancreas. Levels of IL-6, NF-κβ, and TNF-α mRNA expression were higher in the pancreas with HI than in the control (p < 0.001 for all). THC treatment reduced the expression of IL-6, NF-κβ, and TNF-α mRNAs in the HI + THC group compared to the HI group (p < 0.001 for all). TOC increased in the HI group compared to the control group (p < 0.001). However, THC treatment reduced TOC levels in the HI + THC group compared to the HI group (p < 0.001). According to the results, the THC treatment may regulate inflammation and TOC in rats with hyperinsulinemia. Thus, we can say that THC may have anti-inflammatory and antioxidant potential in metabolic disorders.

Oxidative Stress Status in Testis of Type-2 Diabetic Rats Treated with Delta-9-Tetrahydrocannabinol

Objective: Type-2 diabetes (T2D) is a multifactorial disease that occurs as a result of impaired insulin secretion and increased glucose. Researchers emphasize that oxidative stress prevention and improvement strategies are important in the general treatment of T2D. It is reported that delta-9-tetrahydrocannabinol (THC), a component of the cannabis plant, has positive effects against oxidative stress and inflammation. Therefore, this study explored the inhibitory effects of THC on oxidative damage of testis in type-2 diabetic rats. Materials and Methods: Adult Spraque-Dawley rats were separated into 4 groups. In the control group, physiological saline was given intraperitoneally. In the T2D model group (T2DM), streptozotocin (STZ) + nicotinamide (NAD) was administered intraperitoneally. Three mg/kg/day THC was given to the THC and T2DM+THC groups for 7 days, intraperitoneally. Glutathione (GSH), malondialdehyde (MDA), and protein carbonyl levels (PCO), and superoxide dismutase (SOD) activity were measured spectrophotometrically in testicular tissue. Total oxidant and antioxidant status were determined by ELISA. Results: Testicular GSH level and SOD activity were significantly decreased in T2D, while MDA and PCO levels increased. In contrast to this effect, the THC treatment increased GSH levels and SOD activity in diabetics, but decreased MDA and PCO levels. Conclusion: According to the study results, THC may have an oxidative stress inhibitory effect on diabetic rat testis.

Activation of Cannabinoid Receptor 2 Prevents Colitis-Associated Colon Cancer through Myeloid Cell De-activation Upstream of IL-22 Production.

SummaryIntestinal disequilibrium leads to inflammatory bowel disease (IBD), and chronic inflammation predisposes to oncogenesis. Antigen-presenting dendritic cells (DCs) and macrophages can tip the equilibrium toward tolerance or pathology. Here we show that delta-9-tetrahydrocannabinol (THC) attenuates colitis-associated colon cancer and colitis induced by anti-CD40. Working through cannabinoid receptor 2 (CB2), THC increases CD103 expression on DCs and macrophages and upregulates TGF-β1 to increase T regulatory cells (Tregs). THC-induced Tregs are necessary to remedy systemic IFNγ and TNFα caused by anti-CD40, but CB2-mediated suppression of APCs by THC quenches pathogenic release of IL-22 and IL-17A in the colon. By examining tissues from multiple sites, we confirmed that THC affects DCs, especially in mucosal barrier sites in the colon and lungs, to reduce DC CD86. Using models of colitis and systemic inflammation we show that THC, through CB2, is a potent suppressor of aberrant immune responses by provoking coordination between APCs and Tregs.

Preclinical studies on the reinforcing effects of cannabinoids. A tribute to the scientific research of Dr. Steve Goldberg.

The reinforcing effects of most abused drugs have been consistently demonstrated and studied in animal models, although those of marijuana were not, until the demonstration 15years ago that delta-9-tetrahydrocannabinol (THC) could serve as a reinforcer in self-administration (SA) procedures in squirrel monkeys. Until then, those effects were inferred using indirect assessments. The aim of this manuscript is to review the primary preclinical procedures used to indirectly and directly infer reinforcing effects of cannabinoid drugs. Results will be reviewed from studies of cannabinoid discrimination, intracranial self-stimulation (ICSS), conditioned place preference (CPP), as well as change in levels of dopamine assessed in brain areas related to reinforcement, and finally from self-administration procedures. For each procedure, an evaluation will be made of the predictive validity in detecting the potential abuse liability of cannabinoids based on seminal papers, with the addition of selected reports from more recent years especially those from Dr. Goldberg's research group. ICSS and CPP do not provide consistent results for the assessment of potential for abuse of cannabinoids. However, drug discrimination and neurochemistry procedures appear to detect potential for abuse of cannabinoids, as well as several novel "designer cannabinoid drugs." Though after 15years transfer of the self-administration model of marijuana abuse from squirrel monkeys to other species remains somewhat problematic, studies with the former species have substantially advanced the field, and several reports have been published with consistent self-administration of cannabinoid agonists in rodents.

Cannabis-based medicine reduces multiple pathological processes in AβPP/PS1 mice.

Several recent findings suggest that targeting the endogenous cannabinoid system can be considered as a potential therapeutic approach to treat Alzheimer's disease (AD). The present study supports this hypothesis demonstrating that delta-9-tetrahydrocannabinol (THC) or cannabidiol (CBD) botanical extracts, as well as the combination of both natural cannabinoids, which are the components of an already approved cannabis-based medicine, preserved memory in AβPP/PS1 transgenic mice when chronically administered during the early symptomatic stage. Moreover, THC + CBD reduced learning impairment in AβPP/PS1 mice. A significant decrease in soluble Aβ42 peptide levels and a change in plaques composition were also observed in THC + CBD-treated AβPP/PS1 mice, suggesting a cannabinoid-induced reduction in the harmful effect of the most toxic form of the Aβ peptide. Among the mechanisms related with these positive cognitive effects, the anti-inflammatory properties of cannabinoids may also play a relevant role. Here we observed reduced astrogliosis, microgliosis, and inflammatory-related molecules in treated AβPP/PS1 mice, which were more marked after treatment with THC + CBD than with either THC or CBD. Moreover, other cannabinoid-induced effects were uncovered by a genome-wide gene expression study. Thus, we have identified the redox protein thioredoxin 2 and the signaling protein Wnt16 as significant substrates for the THC + CBD-induced effects in our AD model. In summary, the present findings show that the combination of THC and CBD exhibits a better therapeutic profile than each cannabis component alone and support the consideration of a cannabis-based medicine as potential therapy against AD.

Cannabinoids, Working Memory, and Schizophrenia

S I n this issue, Bossong et al. (1) report that delta-9-tetrahydrocannabinol (THC), the primary psychoactive constituent in cannabis, can induce both abnormal working memory (WM) perforance and altered brain activity. Based on these findings, they uggest a role for endocannabinoids in both prefrontal cortical unction and the pathophysiology of schizophrenia. Deficits in neurocognition, particularly processes related to WM, ave been known to be core features of schizophrenia for nearly 2 ecades (2). Existing antipsychotic drugs, all of which block dopaine (DA) D2 receptors, have limited efficacy against neurocogniive deficits. Treatments based on alternate hypotheses involving he neurotransmitters gamma-aminobutyric acid (GABA) and gluamate (GLU) are of considerable interest. Of note, in numerous rain regions relevant to working memory processes, both GABA nd GLU release are modulated by the activation of central cannainoid receptors (CB1Rs), which are among the most abundant G rotein-coupled receptors in the nervous system (3), and the prinipal target of THC.

Δ9-Tetrahydrocannabinol Induces Dopamine Release in the Human Striatum

The influence of cannabis on mental health receives growing scientific and political attention. An increasing demand for treatment of cannabis dependence has refueled the discussion about the addictive potential of cannabis. A key feature of all addictive drugs is the ability to increase synaptic dopamine levels in the striatum, a mechanism involved in their rewarding and motivating effects. However, it is currently unknown if cannabis can stimulate striatal dopamine neurotransmission in humans. Here we show that Delta 9-tetrahydrocannabinol (THC), the main psychoactive component in cannabis, induces dopamine release in the human striatum. Using the dopamine D(2)/D(3) receptor tracer [(11)C]raclopride and positron emission tomography in seven healthy subjects, we demonstrate that THC inhalation reduces [(11)C]raclopride binding in the ventral striatum and the precommissural dorsal putamen but not in other striatal subregions. This is consistent with an increase in dopamine levels in these regions. These results suggest that THC shares a potentially addictive property with other drugs of abuse. Further, it implies that the endogenous cannabinoid system is involved in regulating striatal dopamine release. This allows new directions in research on the effects of THC in neuropsychiatric disorders, such as schizophrenia.

The in Vitro and in Vivo Cardiovascular Effects of Δ9-Tetrahydrocannabinol in Rats Made Hypertensive by Chronic Inhibition of Nitric-Oxide Synthase

Evidence suggests that Delta9-tetrahydrocannabinol (THC) may have antihypertensive effects and that the vasodilator effect of endocannabinoids is enhanced in rats made hypertensive by chronic NO synthase inhibition. Therefore, the aims of the present study were to investigate whether the in vitro and in vivo cardiovascular responses to THC are altered by Nomega-nitro-L-arginine methyl ester (L-NAME) treatment. The vasorelaxant effects of THC were enhanced in small mesenteric arteries from L-NAME-treated rats. This enhanced response was not inhibited by cannabinoid CB1 receptor antagonism [1 microM N-(piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide; AM251]. Pretreating vessels with the transient receptor potential vanilloid receptor receptor agonist capsaicin at 10 microM for 1 h reduced vasorelaxation to THC to a greater extent in L-NAME-treated than control rats. Inhibition of cyclooxygenase with 10 microM indomethacin inhibited THC responses in arteries from L-NAME-treated rats but not from control rats. In conscious, chronically instrumented rats, 1 mg kg-1 i.v. THC caused a pressor effect, with vasoconstriction of the renal and mesenteric vascular beds, and hindquarters vasodilatation. Pretreatment with 3 mg kg-1 i.v. AM251 reduced the pressor and vasoconstrictor effects of THC, abolished the hindquarters vasodilatation, and revealed a bradycardic response. L-NAME-treated rats showed similar pressor and vasoconstrictor responses to THC, but with bradycardia, and reduced hindquarter vasodilatation. These data show that, in vitro, isolated arteries of L-NAME-treated rats show enhanced vasorelaxant responses to THC through an increased sensory nerve component and stimulation of prostanoids. However, in vivo, THC causes a CB1 receptor-mediated pressor effect with hindquarters vasodilatation. There was no evidence of enhanced vasodilator effects of THC in L-NAME-treated animals in vivo.

The analgesic effect of oral delta-9-tetrahydrocannabinol (THC), morphine, and a THC-morphine combination in healthy subjects under experimental pain conditions

From folk medicine and anecdotal reports it is known that Cannabis may reduce pain. In animal studies it has been shown that delta-9-tetrahydrocannabinol (THC) has antinociceptive effects or potentiates the antinociceptive effect of morphine. The aim of this study was to measure the analgesic effect of THC, morphine, and a THC-morphine combination (THC-morphine) in humans using experimental pain models. THC (20 mg), morphine (30 mg), THC-morphine (20 mg THC+30 mg morphine), or placebo were given orally and as single doses. Twelve healthy volunteers were included in the randomized, placebo-controlled, double-blinded, crossover study. The experimental pain tests (order randomized) were heat, cold, pressure, single and repeated transcutaneous electrical stimulation. Additionally, reaction time, side-effects (visual analog scales), and vital functions were monitored. For the pharmacokinetic profiling, blood samples were collected. THC did not significantly reduce pain. In the cold and heat tests it even produced hyperalgesia, which was completely neutralized by THC-morphine. A slight additive analgesic effect could be observed for THC-morphine in the electrical stimulation test. No analgesic effect resulted in the pressure and heat test, neither with THC nor THC-morphine. Psychotropic and somatic side-effects (sleepiness, euphoria, anxiety, confusion, nausea, dizziness, etc.) were common, but usually mild.

Delta-9-tetrahydrocannabinol interferes with the establishment and the expression of conditioned rejection reactions produced by cyclophosphamide: a rat model of nausea.

Reliable animal models of nausea are necessary to better understand the neurobiology of nausea and to assess treatment effectiveness. We present such a model based on conditioned rejection reactions in rats. Our results demonstrate that delta-9-tetrahydrocannabinol (THC), a treatment reported to reduce chemotherapy-induced nausea in humans, also reduces conditioned rejection reactions in rats. Rats were administered THC or vehicle prior to a pairing of saccharin solution with cyclophosphamide or saline during conditioning and/or prior to test. THC interfered with the establishment of cyclophosphamide-induced conditioned rejection during conditioning and with the expression of conditioned rejection during testing. Our results confirm that the conditioned rejection reaction in the rat is a useful animal model of nausea.

Delta-9-tetrahydrocannabinol suppresses tumor necrosis factor α maturation and secretion but not its transcription in mouse macrophages

Various in vitro studies have shown that delta-9-tetrahydrocannabinol (THC), the major psychoactive component of marijuana, has a variety of inhibitory effects on immune functions including effects on macrophages. The present studies have examined the mechanism of THC's effects on tumor necrosis factor α (TNF-α), a major macrophage-produced cytokine and an important mediator involved in cytokine networks and in host defense mechanisms. Exposure of macrophages to medium containing THC has resulted in low levels of soluble TNF-α protein and reduced TNF-α bioactivity in the culture supernatant. However, THC did not inhibit the levels of LPS-induced TNF-α mRNA and intracellular TNF-α precursor protein, had only a weak effect on expression of membrane-bound TNF-α, but suppressed TNF-α maturation/secretion by macrophages. The higher the THC concentration in the medium during TNF-α induction, the greater the amount of intracellular TNF-α precursors that accumulated in the activated macrophages and the less mature TNF-α was released from the cells. Data suggest that TNF-α production by macrophages was altered greatly by exposure to THC at the levels of TNF-α precursor maturation and secretion.

Δ9-tetrahydrocannabinol suppresses concanavalin a induced increase in cytoplasmic free calcium in mouse thymocytes

It has been shown that delta-9-tetrahydrocannabinol (THC) suppresses thymocyte, lymph node, and splenic lymphocyte proliferation in response to a mitogenic stimulus. It has also been reported that increases occur in the cytosolic free calcium concentration (Ca 2+) in mitogen treated lymphocytes. In an attempt to understand a portion of the molecular basis of the THC induced suppression of lymphocyte proliferation, we have examined the effects of THC on the Concanavalin A (Con A) induced cytosolic free Ca 2+ mobilization in mouse thymocytes measured by fluorescent Ca 2+ probes and spectrofluorometry. The results show that a 10 minute pretreatment with THC suppresses the normal rise in intracellular free Ca 2+ in response to Con A. A THC concentration of 4μg/ml (13μM) was suppressive and the drug vehicle, DMSO, had no effect. In addition, we found that THC pretreatment did not inhibit the binding of FITC labeled Con A to the thymocytes suggesting that the drug did not interfere with lectin binding to the cell surface. To further define the nature of the Ca 2+ response affected by THC, mouse thymocytes containing fura-2 were exposed to Con A either in the presence or absence of Ca 2+-containing medium. It was observed that THC abrogated both intracellular release (measured in Ca 2+-free medium) as well as extracellular Ca 2+ influx. These results suggest that a portion of the proliferation defect in THC treated lymphocytes may be related to a drug induced inhibition of Ca 2+ mobilization that normally occurs following mitogen treatment.

Marijuana components suppress induction and cytolytic function of murine cytotoxic T cells in vitro and in vivo

Killer lymphocytes play a major role in host defense against tumors and infectious diseases. Previously, we reported that delta-9-tetrahydrocannabinol (THC) and II-hydroxy-delta-9-tetrahydrocannabinol (II-hydroxy-THC) suppressed the cytolytic activity of cultured natural killer (NK) cells. Also, we showed that the drugs appeared to be affecting a stage in the killing process subsequent to the binding of the killer cell to the target cell. In the present report, we have extended these studies to an examination of the effect of cannabinoids on the activity of cytotoxic T lymphocytes (CTLs). The cytolytic activity of CTLs generated by cocultivation with either allospecific stimulators or TNP-modified-self stimulators were suppressed by both THC and II-hydroxy-THC treatment. Allospecific CTLs generated in vivo were also inhibited by an in vitro exposure to either THC or II-hydroxy-THC, and the sensitivity of these cells to drug effects appeared to be greater than the sensitivity of the in vitro generated CTLs. Suppression of cytolytic function by THC and II-hydroxy-THC was maximal after a 4-h drug treatment, suggesting that the drug effects were inducible and therefore required a finite period of time to develop maximally. As seen in previous studies involving NK cells, drug treatment of mature CTLs appears to have little effect on the binding capacity of these cells for the target. However, the maximal killing capacity of the cells and the frequency of CTLs were significantly reduced by drug treatment. In addition to suppressing the cytolytic activity of mature effector CTLs, we also show that drug treatment inhibits both the proliferation of lymphocytes responding to an allogeneic stimulus and the maturation of these lymphocytes to mature CTLs. Similarly, CTL activity developing in vivo could be inhibited by THC injection. These results suggest that CTLs are inhibited by cannabinoids by at least two mechanisms. First, the cytolytic activity of mature killers is suppressed at some point beyond the binding to the target cell. Second, the cannabinoids appear to suppress the normal development of these mature effector cells from less mature precursor cells.

In vitro effect of delta 9-tetrahydrocannabinol to stimulate somatostatin release and block that of luteinizing hormone-releasing hormone by suppression of the release of prostaglandin E2.

Previous in vivo studies have shown that delta 9-tetrahydrocannabinol (THC), the principal active ingredient in marijuana, can suppress both luteinizing hormone (LH) and growth hormone (GH) secretion after its injection into the third ventricle of conscious male rats. The present studies were designed to determine the mechanism of these effects. Various doses of THC were incubated with either stalk median eminence fragments (MEs) or mediobasal hypothalamic (MBH) fragments in vitro. Although THC (10 nM) did not alter basal release of LH-releasing hormone (LHRH) from MEs in vitro, it completely blocked the stimulatory action of dopamine or norepinephrine on LHRH release. The effective doses to block LHRH release were associated with a blockade of synthesis and release of prostaglandin E2 (PGE2) from MBH in vitro. In contrast to the suppressive effect of THC on LHRH release, somatostatin release from MEs was enhanced in a dose-related manner with a minimal effective dose of 1 nM. Since PGE2 suppresses somatostatin release, this enhancement may also be related to the suppressive effect of THC on PGE2 synthesis and release. We speculate that these actions are mediated by the recently discovered THC receptors in the tissue. The results indicate that the suppressive effect of THC on LH release is mediated by a blockade of LHRH release, whereas the suppressive effect of the compound on growth hormone release is mediated, at least in part, by a stimulation of somatostatin release.

The effect of delta-9-tetrahydrocannabinol and 11-hydroxy-delta-9-tetrahydrocannabinol on T-lymphocyte and B-lymphocyte mitogen responses.

Previous studies have shown that delta-9-tetrahydrocannabinol (THC) suppresses T-lymphocyte proliferation when added to human cell cultures. We report that THC when added to mouse splenocyte cultures suppressed T-lymphocyte (Con A, PHA) and B-lymphocyte (LPS) mitogen-induced proliferation. Although the ED50 concentrations (5 micrograms/ml; 1.6 X 10(-5)M) of THC were similar for suppressing all three mitogen responses, higher threshold concentrations of drug were required to effect suppression of the T-lymphocyte mitogen responses. Complete suppression of T- and B-lymphocyte responses was achieved with THC concentrations (8 micrograms/ml or 2.6 X 10(-5)M) which were not directly toxic as judged by vital dye exclusion. The hydroxylated metabolite of THC, 11-hydroxy-THC, was observed to be much less potent in the inhibition of lymphocyte proliferation. However, as with the parent compound, B-lymphocyte responses appeared to be the most affected by the drug. Additional studies demonstrated that both T- and B-lymphocyte proliferation is rapidly suppressed following THC treatment, not affected by a 24 hr. pretreatment with THC, and not as readily suppressed by THC in cultures containing 20% serum. Thus, THC appears to inhibit both T- and B-lymphocyte proliferation with B-lymphocyte responses displaying greater inhibition at lower drug concentration. The 11-hydroxy metabolite is much less suppressive in this system than the parent compound.

Clinical experience with levonantradol hydrochloride in the prevention of cancer chemotherapy-induced nausea and vomiting.

Reports suggesting that delta 9-tetrahydrocannabinol (THC) had a potent antiemetic effect in patients treated with cancer chemotherapeutic agents led to the synthesis of other cannabinol derivatives with possibly less side effects. We report here our initial observations with the antiemetic levonantradol in 12 patients with advanced solid tumors receiving cytotoxic polychemotherapy. All patients had a history of vomiting and nausea without successful treatment with standard antiemetic drugs in previous, identical chemotherapy cycles. No other antiemetic or psychoactive drugs were given. Patients received 1 mg levonantradol i.m. 2 hours before as well as 2 and 6 hours after cytotoxic treatment. When compared to the last course of chemotherapy with alternate antiemetic drugs, we found that 11/12 patients had less nausea and vomiting when treated with levonantradol. 8/12 Patients considered the antiemetic treatment with levonantradol better than the one given before. The following side effects were observed: 4 patients complained of pain and local irritation after injection. 2 patients showed a fall in blood pressure, especially orthostatic hypotension. 8 patients complained of sedation and drowsiness. 7 patients experienced psychic side effects, such as decrease of vigilance and reaction, altered sense of timing, body image distortions and even depersonalization. Levonantradol is a potent antiemetic drug but its applicability, especially in outpatients, may be complicated by a high incidence of side effects.