Tag: Cannabinoids

Very low doses of Δ8-THC increase food consumption and alter neurotransmitter levels following weight loss.

Avraham, Y., Ben-Shushan, D., Breuer, A., Zolotarev, O., Okon, A., Fink, N., … Berry, E. M. (2004)

Pharmacology Biochemistry and Behavior, 77(4), 675–684.

doi: 10.1016/j.pbb.2004.01.015

We have investigated the effect of 0.001 mg/kg D8 -tetrahydrocannabinol (THC) on food consumption, cognitive function, and neurotransmitters in mice. Sabra mice were treated with vehicle, THC, or THC+CB1 antagonist (SR141716A). The mice were fed for 2.5 h a day for 9 or 50 days. In the 9-day schedule, THC-treated mice showed a 16% increase in food intake compared with controls ( P<001) was recorded. During the course of the 9- and 50-day experimental protocol, all mice lost about 20% and 10% of their original weight, respectively, to reach approximately the same weights, which were not significantly different between the different treatment groups. In addition, THC caused an increase in activity ( P<05) Cognitive function showed a tendency to improve (P<06) in the THC-treated mice, which was reversed by the antagonist for Days 4 and 5 of the maze (P<01 and P<05, ) , respectively). Significant decreases in dopamine and serotonin (5-HT) levels were found both in the hypothalamus (P<01) and the hippocampus (P<01, P<05) ), respectively, while norepinephrine (NE) levels showed tendency to increase in both the hypothalamus and hippocampus. D8 -THC increased food intake significantly more (P<05) than did D9 -THC, while performance and activity were similar. Thus, D8 -THC (0.001 mg/kg) caused increased food consumption and tendency to improve cognitive function, without cannabimimetic side effects. Hence, a low dose of THC might be a potential therapeutic agent in the treatment of weight disorders.
Abstract

Treatment of Tourette Syndrome with Delta-9- Tetrahydrocannabinol (D9 -THC): No Influence on Neuropsychological Performance

Kirsten R Muller-Vahl, Heidrun Prevedel, Karen Theloe, Hans Kolbe, Hinderk M Emrich, and Udo Schneider

Neuropsychopharmacology (2003) 28, 384–388

DOI: 10.1038/sj.npp.1300047

Previous studies provide evidence that marijuana (Cannabis sativa) and delta-9-tetrahydrocannabinol (D9 -THC), the major psychoactive ingredient of marijuana, respectively, are effective in the treatment of tics and behavioral problems in Tourette syndrome (TS). It, therefore, has been speculated that the central cannabinoid receptor system might be involved in TS pathology. However, in healthy marijuana users there is an ongoing debate as to whether the use of cannabis causes acute and/or long-term cognitive deficits. In this randomized double-blind placebo-controlled study, we investigated the effect of a treatment with up to 10 mg D9 -THC over a 6-week period on neuropsychological performance in 24 patients suffering from TS. During medication and immediately as well as 5–6 weeks after withdrawal of D9 -THC treatment, no detrimental effect was seen on learning curve, interference, recall and recognition of word lists, immediate visual memory span, and divided attention. Measuring immediate verbal memory span, we even found a trend towards a significant improvement during and after treatment. Results from this study corroborate previous data suggesting that in patients suffering from TS, treatment with D9 -THC causes neither acute nor long-term cognitive deficits. Larger and longer-duration controlled studies are recommended to provide more information on the adverse effect profile of THC in patients suffering from TS.
Abstract

The therapeutic potential of cannabis.

Baker D, Pryce G, Giovannoni G, Thompson AJ.

Lancet Neurol. 2003 May;2(5):291-8

DOI: 10.1016/S1474-4422(03)00381-8

Research of the cannabinoid system has many similarities with that of the opioid system. In both instances, studies into drug-producing plants led to the discovery of an endogenous control system with a central role in neurobiology. Few compounds have had as much positive press from patients as those of the cannabinoid system. While these claims are investigated in disorders such as multiple sclerosis spasticity and pain, basic research is discovering interesting members of this family of compounds that have previously unknown qualities, the most notable of which is the capacity for neuroprotection. Large randomised clinical trials of the better known compounds are in progress. Even if the results of these studies are not as positive as many expect them to be, that we are only just beginning to appreciate the huge therapeutic potential of this family of compounds is clear.
Abstract

The psychoactive plant cannabinoid, Δ9-tetrahydrocannabinol, is antagonized by Δ8- and Δ9-tetrahydrocannabivarin in mice in vivo.

RG Pertwee, A Thomas, LA Stevenson, RA Ross, SA Varvel, AH Lichtman, BR Martin and RK Razdan

British Journal of Pharmacology, 150(5), 586–594. (2009)

doi: 10.1038/sj.bjp.0707124

To follow up in vitro evidence that D9-tetrahydrocannabivarin extracted from cannabis (D9-THCV) is a CB1 receptor antagonist by establishing whether synthetic D9-tetrahydrocannabivarin (O-4394) and D8-tetrahydrocannabivarin (O-4395) behave as CB1 antagonists in vivo.
O-4394 and O-4395 were compared with eD9 -THCV as displacers of [3H]-CP55940 from specific CB1 binding sites on mouse brain membranes and as antagonists of CP55940 in [35S]GTPgS binding assays performed with mouse brain membranes and of R-( þ )-WIN55212 in mouse isolated vasa deferentia. Their ability to antagonize in vivo effects of 3 or 10 mg kg1 (i.v.) D9-tetrahydrocannabinol in mice was then investigated.
Background & Purpose, Experimental Approach

The phytocannabinoid Δ9-tetrahydrocannabivarin modulates inhibitory neurotransmission in the cerebellum.

Y-L Ma, SE Weston, BJ Whalley and GJ Stephens

British Journal of Pharmacology, 154(1), 204–215. (2008)

doi: 10.1038/bjp.2008.57

The phytocannabinoid D9-tetrahydrocannabivarin (D9-THCV) has been reported to exhibit a diverse pharmacology; here, we investigate functional effects of D9-THCV, extracted from Cannabis sativa, using electrophysiological techniques to define its mechanism of action in the CNS.
Effects of D9-THCV and synthetic cannabinoid agents on inhibitory neurotransmission at interneurone-Purkinje cell (IN-PC) synapses were correlated with effects on spontaneous PC output using single-cell and multi-electrode array (MEA) electrophysiological recordings respectively, in mouse cerebellar brain slices in vitro.
Background & Purpose, Experimental Approach

The phytocannabinoid, Δ9-tetrahydrocannabivarin, can act through 5-HT1A receptors to produce anti-psychotic effects

Maria grazia Cascio, Erica Zamberletti, Pietro Marini, Roger G Pertwee

November 2014 British Journal of Pharmacology 172(5)

DOI: 10.1111/bph.13000

To address the questions of whether Δ9-tetrahydrocannabivarin (THCV) can (a) enhance activation of 5-HT1A receptors in vitro and (b) induce any apparent 5-HT1A receptor-mediated anti-psychotic effects in vivo.
In vitro studies investigated the effect of THCV on targeting by 8-hydroxy-2 (di-npropylamino)tetralin (8-OH-DPAT) of 5-HT1A receptors in membranes obtained from rat brainstem or human 5-HT1A CHO cells, using [35S]GTPγS and 8-[3H]-OH-DPAT binding assays. In vivo studies investigated whether THCV induces signs of 5-HT1A receptor-mediated antipsychotic effects in rats
Background & Purpose, Experimental Approach

The hexanoyl-CoA precursor for cannabinoid biosynthesis is formed by an acylactivating enzyme in Cannabis sativa trichomes

Jake M Stout, Zakia Boubakir, Stephen J Ambrose, Jonathan E Page

February 2012 The Plant Journal 71(3):353-65 

DOI: 10.1111/j.1365-313X.2012.04949.x

The psychoactive and analgesic cannabinoids (e.g. Δ(9) -tetrahydrocannabinol (THC)) in Cannabis sativa are formed from the short-chain fatty acyl-coenzyme A (CoA) precursor hexanoyl-CoA. Cannabinoids are synthesized in glandular trichomes present mainly on female flowers. We quantified hexanoyl-CoA using LC-MS/MS and found levels of 15.5 pmol g(-1) fresh weight in female hemp flowers with lower amounts in leaves, stems and roots. This pattern parallels the accumulation of the end-product cannabinoid, cannabidiolic acid (CBDA). To search for the acyl-activating enzyme (AAE) that synthesizes hexanoyl-CoA from hexanoate, we analyzed the transcriptome of isolated glandular trichomes. We identified 11 unigenes that encoded putative AAEs including CsAAE1, which shows high transcript abundance in glandular trichomes. In vitro assays showed that recombinant CsAAE1 activates hexanoate and other short- and medium-chained fatty acids. This activity and the trichome-specific expression of CsAAE1 suggest that it is the hexanoyl-CoA synthetase that supplies the cannabinoid pathway. CsAAE3 encodes a peroxisomal enzyme that activates a variety of fatty acid substrates including hexanoate. Although phylogenetic analysis showed that CsAAE1 groups with peroxisomal AAEs, it lacked a peroxisome targeting sequence 1 (PTS1) and localized to the cytoplasm. We suggest that CsAAE1 may have been recruited to the cannabinoid pathway through the loss of its PTS1, thereby redirecting it to the cytoplasm. To probe the origin of hexanoate, we analyzed the trichome expressed sequence tag (EST) dataset for enzymes of fatty acid metabolism. The high abundance of transcripts that encode desaturases and a lipoxygenase suggests that hexanoate may be formed through a pathway that involves the oxygenation and breakdown of unsaturated fatty acids.
Abstract

The Endogenous Cannabinoid System Regulates Seizure Frequency and Duration in a Model of Temporal Lobe Epilepsy

Melisa J. Wallace, Robert E. Blair, Katherine W. Falenski, Billy R. Martin and Robert J. DeLorenzo

Journal of Pharmacology and Experimental Therapeutics October 2003, 307 (1) 129-137;

DOI: 10.1124/jpet.103.051920

Several lines of evidence suggest that cannabinoid compounds are anticonvulsant. However, the anticonvulsant potential of cannabinoids and, moreover, the role of the endogenous cannabinoid system in regulating seizure activity has not been tested in an in vivo model of epilepsy that is characterized by spontaneous, recurrent seizures. Here, using the rat pilocarpine model of epilepsy, we show that the marijuana extract Δ9-tetrahydrocannabinol (10 mg/kg) as well as the cannabimimetic, 4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one [R(+)WIN55,212 (5 mg/kg)], completely abolished spontaneous epileptic seizures. Conversely, application of the cannabinoid CB1 receptor (CB1) antagonist, N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A), significantly increased both seizure duration and frequency. In some animals, CB1 receptor antagonism resulted in seizure durations that were protracted to a level consistent with the clinical condition status epilepticus. Furthermore, we determined that during an short-term pilocarpine-induced seizure, levels of the endogenous CB1ligand 2-arachidonylglycerol increased significantly within the hippocampal brain region. These data indicate not only anticonvulsant activity of exogenously applied cannabinoids but also suggest that endogenous cannabinoid tone modulates seizure termination and duration through activation of the CB1 receptor. Furthermore, Western blot and immunohistochemical analyses revealed that CB1 receptor protein expression was significantly increased throughout the CA regions of epileptic hippocampi. By demonstrating a role for the endogenous cannabinoid system in regulating seizure activity, these studies define a role for the endogenous cannabinoid system in modulating neuroexcitation and suggest that plasticity of the CB1 receptor occurs with epilepsy.
Abstract

The Effect of Light Spectrum on the Morphology and Cannabinoid Content of Cannabis sativa L.

Gianmaria Magagninia, Gianpaolo Grassia, Stiina Kotirantab 

Med Cannabis Cannabinoids 2018;1:19–27

DOI: 10.1159/000489030

Cannabis sativa L. flowers are the main source of Δ-9 tetrahydrocannabinol (THC) used in medicine. One of the most important growth factors in cannabis cultivation is light; light quality, light intensity, and photoperiod play a big role in a successful growth protocol. The aim of the present study was to examine the effect of 3 different light sources on morphology and cannabinoid production. Cannabis clones were grown under 3 different light spectra, namely high-pressure sodium (HPS), AP673L (LED), and NS1 (LED). Light intensity was set to ∼450 µmol/m2/s measured from the canopy top. AThe photoperiod was 18L:6D/21 days during the vegetative phase and 12L:12D/46 days during the generative phase, respectively. At the end of the experiment, plant dry weight partition, plant height, and cannabinoid content (THC, cannabidiol [CBD], tetrahydrocannabivarin [THCV], cannabigerol [CBG]) were measured under different light treatments. The experiment was repeated twice. The 3 light treatments (HPS, NS1, AP673L) resulted in differences in cannabis plant morphology and in cannabinoid content, but not in total yield of cannabinoids. Plants under HPS treatment were taller and had more flower dry weight than those under treatments AP673L and NS1. Treatment NS1 had the highest CBG content. Treatments NS1 and AP673L had higher CBD and THC concentrations than the HPS treatment. Results were similar between experiments 1 and 2. Our results show that the plant morphology can be manipulated with the light spectrum. Furthermore, it is possible to affect the accumulation of different cannabinoids to increase the potential of medicinal grade cannabis. In conclusion, an optimized light spectrum improves the value and quality of cannabis. Current LED technology showed significant differences in growth habit and cannabinoid profile compared to the traditional HPS light source. Finally, no difference of flowering time was observed under different R:FR (i.e., the ratio between red and far-red light).
Abstract

The effect of five day dosing with THCV on THC-induced cognitive, psychological and physiological effects in healthy male human volunteers: A placebo-controlled, double-blind, crossover pilot trial.

Amir Englund, Zerrin Atakan, Aleksandra Kralj, Nigel Tunstall, Robin Murray and Paul Morrison

Journal of Psychopharmacology
2016, Vol. 30(2) 140–151 2015

DOI: 10.1177/0269881115615104

Cannabis is mostly grown under illegal and unregulated circumstances, which seems to favour a product increasingly high in its main
cannabinoid ∆-9-tetrahydrocannabinol (THC). ∆-9-tetrahydrocannabivarin (THCV) is a relatively untested cannabinoid which is said to be a cannabinoid receptor neutral antagonist, and may inhibit the effects of THC. To explore the safety and tolerability of repeated THCV administration and its effects on symptoms normally induced by THC in a sample of healthy volunteers.
Rationale and Objective