Medicine › Pharmacology

Cannabis and Cannabinoid Research

Works Count: 67532

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Description

This cluster of papers explores the endocannabinoid system, including the role of cannabinoid receptors, the effects of cannabis use on health, and the potential therapeutic applications of cannabinoids in neurological and psychiatric disorders. It covers topics such as synaptic transmission, neuroprotection, metabolic disorders, and the use of medical marijuana.

Keywords

Endocannabinoid System; Cannabinoid Receptors; Cannabis Use; Neurological Disorders; Psychiatric Effects; Metabolic Disorders; CB1 and CB2 Receptors; Medical Marijuana; Synaptic Transmission; Neuroprotection

Vanilloid receptors on sensory nerves mediate the vasodilator action of anandamide

1999-07-01

Peter M. Zygmunt , Jesper Petersson , David A. Andersson +5 more

A second endogenous cannabinoid that modulates long-term potentiation

1997-08-21

Nephi Stella , Paul Schweitzer , Daniele Piomelli

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Presynaptically Located CB1 Cannabinoid Receptors Regulate GABA Release from Axon Terminals of Specific Hippocampal Interneurons

1999-06-01

István Katona , Beáta Sperlágh , Attila Sı́k +4 more

To understand the functional significance and mechanisms of action in the CNS of endogenous and exogenous cannabinoids, it is crucial to identify the neural elements that serve as the structural … To understand the functional significance and mechanisms of action in the CNS of endogenous and exogenous cannabinoids, it is crucial to identify the neural elements that serve as the structural substrate of these actions. We used a recently developed antibody against the CB1 cannabinoid receptor to study this question in hippocampal networks. Interneurons with features typical of basket cells showed a selective, intense staining for CB1 in all hippocampal subfields and layers. Most of them (85.6%) contained cholecystokinin (CCK), which corresponded to 96.9% of all CCK-positive interneurons, whereas only 4.6% of the parvalbumin (PV)-containing basket cells expressed CB1. Accordingly, electron microscopy revealed that CB1-immunoreactive axon terminals of CCK-containing basket cells surrounded the somata and proximal dendrites of pyramidal neurons, whereas PV-positive basket cell terminals in similar locations were negative for CB1. The synthetic cannabinoid agonist WIN 55,212-2 (0.01–3 μ m ) reduced dose-dependently the electrical field stimulation-induced [ 3 H]GABA release from superfused hippocampal slices, with an EC 50 value of 0.041 μ m . Inhibition of GABA release by WIN 55,212-2 was not mediated by inhibition of glutamatergic transmission because the WIN 55,212-2 effect was not reduced by the glutamate blockers AP5 and CNQX. In contrast, the CB1 cannabinoid receptor antagonist SR 141716A (1 μ m ) prevented this effect, whereas by itself it did not change the outflow of [ 3 H]GABA. These results suggest that cannabinoid-mediated modulation of hippocampal interneuron networks operate largely via presynaptic receptors on CCK-immunoreactive basket cell terminals. Reduction of GABA release from these terminals is the likely mechanism by which both endogenous and exogenous CB1 ligands interfere with hippocampal network oscillations and associated cognitive functions.

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Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses

2001-03-29

Rachel I. Wilson , Roger A. Nicoll

The orphan receptor GPR55 is a novel cannabinoid receptor

2007-09-17

Erik Ryberg , Niklas Larsson , S. Sjögren +7 more

The endocannabinoid system functions through two well characterized receptor systems, the CB1 and CB2 receptors. Work by a number of groups in recent years has provided evidence that the system … The endocannabinoid system functions through two well characterized receptor systems, the CB1 and CB2 receptors. Work by a number of groups in recent years has provided evidence that the system is more complicated and additional receptor types should exist to explain ligand activity in a number of physiological processes.Cells transfected with the human cDNA for GPR55 were tested for their ability to bind and to mediate GTPgammaS binding by cannabinoid ligands. Using an antibody and peptide blocking approach, the nature of the G-protein coupling was determined and further demonstrated by measuring activity of downstream signalling pathways.We demonstrate that GPR55 binds to and is activated by the cannabinoid ligand CP55940. In addition endocannabinoids including anandamide and virodhamine activate GTPgammaS binding via GPR55 with nM potencies. Ligands such as cannabidiol and abnormal cannabidiol which exhibit no CB1 or CB2 activity and are believed to function at a novel cannabinoid receptor, also showed activity at GPR55. GPR55 couples to Galpha13 and can mediate activation of rhoA, cdc42 and rac1.These data suggest that GPR55 is a novel cannabinoid receptor, and its ligand profile with respect to CB1 and CB2 described here will permit delineation of its physiological function(s).

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Determination and characterization of a cannabinoid receptor in rat brain.

1988-11-01

William A. Devane , F A Dysarz , M R Johnson +2 more

The determination and characterization of a cannabinoid receptor from brain are reported. A biologically active bicyclic cannabinoid analgetic CP-55,940 was tritium-labeled to high specific activity. Conditions for binding to rat … The determination and characterization of a cannabinoid receptor from brain are reported. A biologically active bicyclic cannabinoid analgetic CP-55,940 was tritium-labeled to high specific activity. Conditions for binding to rat brain P2 membranes and synaptosomes were established. The pH optimum was between 7 and 8, and specific binding could be eliminated by heating the membranes to 60 degrees. Binding to the P2 membranes was linear within the range of 10 to 50 micrograms of protein/ml. Specific binding (defined as total binding displaced by 1 microM delta 9-tetrahydrocannabinol (delta 9-THC) or 100 nM desacetyllevonantradol) was saturable. The Kd determined from Scatchard analysis was 133 pM, and the Bmax for rat cortical P2 membranes was 1.85 pmol/mg of protein. The Hill coefficient for [3H]CP-55,940 approximated 1, indicating that, under the conditions of assay, a single class of binding sites was determined that did not exhibit cooperativity. The binding was rapid (kon approximately 2.6 x 10(-4) pM-1 min-1) and reversible (Koff approximately 0.016 min-1) and (koff' greater than 0.06 min-1). The two Kd values estimated from the kinetic constants approximately 55 pM and exceeded 200 pM, respectively. The binding of the agonist ligand [3H]CP-55,940 was decreased by the nonhydrolyzable GTP analog guanylylimidodiphosphate. The guanine nucleotide induced a more rapid dissociation of the ligand from the binding site, consistent with an allosteric regulation of the putative receptor by a G protein. The binding was also sensitive to MgCl2 and CaCl2. Binding of [3H]CP-55,940 was displaced by cannabinoid drugs in the following order of potency: CP-55,940 greater than or equal to desacetyllevonantradol greater than 11-OH-delta 9-THC = delta 9-THC greater than cannabinol. Cannabidiol and cannabigerol displaced [3H]CP-55,940 by less than 50% at 1 microM concentrations. The (-)-isomer of CP-55,940 displaced with 50-fold greater potency than the (+)-isomer. This pharmacology is comparable to both the inhibition of adenylate cyclase in vitro and the analgetic activity of these compounds in vivo. The criteria for a high affinity, stereoselective, pharmacologically distinct cannabinoid receptor in brain tissue have been fulfilled.

Characterization and localization of cannabinoid receptors in rat brain: a quantitative in vitro autoradiographic study

1991-02-01

Miles Herkenham , A B Lynn , MR Johnson +3 more

A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide- mounted sections of rat brain and pituitary. Assay conditions for 3H- CP55,940 binding … A potent, synthetic cannabinoid was radiolabeled and used to characterize and precisely localize cannabinoid receptors in slide- mounted sections of rat brain and pituitary. Assay conditions for 3H- CP55,940 binding in Tris-HCl buffer with 5% BSA were optimized, association and dissociation rate constants determined, and the equilibrium dissociation constant (Kd) calculated (21 nM by liquid scintillation counting, 5.2 nM by quantitative autoradiography). The results of competition studies, using several synthetic cannabinoids, add to prior data showing enantioselectivity of binding and correlation of in vitro potencies with potencies in biological assays of cannabinoid actions. Inhibition of binding by guanine nucleotides was selective and profound: Nonhydrolyzable analogs of GTP and GDP inhibited binding by greater than 90%, and GMP and the nonhydrolyzable ATP analog showed no inhibition. Autoradiography showed great heterogeneity of binding in patterns of labeling that closely conform to cytoarchitectural and functional domains. Very dense 3H-CP55,940 binding is localized to the basal ganglia (lateral caudate-putamen, globus pallidus, entopeduncular nucleus, substantia nigra pars reticulata), cerebellar molecular layer, innermost layers of the olfactory bulb, and portions of the hippocampal formation (CA3 and dentate gyrus molecular layer). Moderately dense binding is found throughout the remaining forebrain. Sparse binding characterizes the brain stem and spinal cord. Densitometry confirmed the quantitative heterogeneity of cannabinoid receptors (10 nM 3H-CP55,940 binding ranged in density from 6.3 pmol/mg protein in the substantia nigra pars reticulata to 0.15 pmol/mg protein in the anterior lobe of the pituitary). The results suggest that the presently characterized cannabinoid receptor mediates physiological and behavioral effects of natural and synthetic cannabinoids, because it is strongly coupled to guanine nucleotide regulatory proteins and is discretely localized to cortical, basal ganglia, and cerebellar structures involved with cognition and movement.

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Molecular characterization of an enzyme that degrades neuromodulatory fatty-acid amides

1996-11-01

Benjamin F. Cravatt , Dan K. Giang , Stephen P. Mayfield +3 more

Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study

2005-04-01

Luc F. Van Gaal , Aila Rissanen , André Scheen +2 more

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Expression of Central and Peripheral Cannabinoid Receptors in Human Immune Tissues and Leukocyte Subpopulations

1995-08-01

Sylvaine Galiègue , Sophie Mary , Jean Marchand +7 more

Two proteins with seven transmembrane-spanning domains typical of guanosine-nucleotide-binding-protein-coupled receptors have been identified as cannabinoid receptors; the central cannabinoid receptor, CB1, and the peripheral cannabinoid receptor, CB2, initially described in … Two proteins with seven transmembrane-spanning domains typical of guanosine-nucleotide-binding-protein-coupled receptors have been identified as cannabinoid receptors; the central cannabinoid receptor, CB1, and the peripheral cannabinoid receptor, CB2, initially described in rat brain and spleen, respectively. Here, we report the distribution patterns for both CB1 and CB2 transcripts in human immune cells and in several human tissues, as analysed using a highly sensitive and quantitative PCR-based method. CB1 was mainly expressed in the central nervous system and, to a lower extent, in several peripheral tissues such as adrenal gland, heart, lung, prostate, uterus, ovary, testis, bone marrow, thymus and tonsils. In contrast, the CB2 gene, which is not expressed in the brain, was particularly abundant in immune tissues, with an expression level 10-100-fold higher than that of CB1. Although CB2 mRNA was also detected in some other peripheral tissues, its level remained very low. In spleen and tonsils, the CB2 mRNA content was equivalent to that of CB1 mRNA in the central nervous system. Among the main human blood cell subpopulations, the distribution pattern of the CB2 mRNA displayed important variations. The rank order of CB2 mRNA levels in these cells was B-cells > natural killer cells >> monocytes > polymorphonuclear neutrophil cells > T8 cells > T4 cells. The same rank order was also established in human cell lines belonging to the myeloid, monocytic and lymphoid lineages. The prevailing expression of the CB2 gene in immune tissues was confirmed by Northern-blot analysis. In addition, the expression of the CB2 protein was demonstrated by an immunohistological analysis performed on tonsil sections using specific anti-(human CB2) IgG; this experiment showed that CB2 expression was restricted to B-lymphocyte-enriched areas of the mantle of secondary lymphoid follicles. These results suggest that (a) CB1 and CB2 can be considered as tissue-selective antigens of the central nervous system and immune system, respectively, and (b) cannabinoids may exert specific receptor-mediated actions on the immune system through the CB2 receptor.

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Metabolic activation of benzo(a)pyrene proceeds by a diol-epoxide

1974-11-01

Peter Sims , P.L. Grover , Alan Swaisland +2 more

The endogenous cannabinoid system controls extinction of aversive memories

2002-08-01

Giovanni Marsicano , Carsten T. Wotjak , Shahnaz Christina Azad +7 more

Isolation and Structure of a Brain Constituent That Binds to the Cannabinoid Receptor

1992-12-18

William A. Devane , L Hanŭs , Aviva Breuer +7 more

Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," … Arachidonylethanolamide, an arachidonic acid derivative in porcine brain, was identified in a screen for endogenous ligands for the cannabinoid receptor. The structure of this compound, which has been named "anandamide," was determined by mass spectrometry and nuclear magnetic resonance spectroscopy and was confirmed by synthesis. Anandamide inhibited the specific binding of a radiolabeled cannabinoid probe to synaptosomal membranes in a manner typical of competitive ligands and produced a concentration-dependent inhibition of the electrically evoked twitch response to the mouse vas deferens, a characteristic effect of psychotropic cannabinoids. These properties suggest that anandamide may function as a natural ligand for the cannabinoid receptor.

Effect of Rimonabant, a Cannabinoid-1 Receptor Blocker, on Weight and Cardiometabolic Risk Factors in Overweight or Obese Patients

2006-02-14

F. Xavier Pi‐Sunyer , Louis J. Aronne , Hassan M. Heshmati +3 more

Rimonabant, a selective cannabinoid-1 receptor blocker, may reduce body weight and improve cardiometabolic risk factors in patients who are overweight or obese.To compare the efficacy and safety of rimonabant with … Rimonabant, a selective cannabinoid-1 receptor blocker, may reduce body weight and improve cardiometabolic risk factors in patients who are overweight or obese.To compare the efficacy and safety of rimonabant with placebo each in conjunction with diet and exercise for sustained changes in weight and cardiometabolic risk factors over 2 years.Randomized, double-blind, placebo-controlled trial of 3045 obese (body mass index > or =30) or overweight (body mass index >27 and treated or untreated hypertension or dyslipidemia) adult patients at 64 US and 8 Canadian clinical research centers from August 2001 to April 2004.After a 4-week single-blind placebo plus diet (600 kcal/d deficit) run-in period, patients were randomized to receive placebo, 5 mg/d of rimonabant, or 20 mg/d of rimonabant for 1 year. Rimonabant-treated patients were rerandomized to receive placebo or continued to receive the same rimonabant dose while the placebo group continued to receive placebo during year 2.Body weight change over year 1 and prevention of weight regain during year 2. Additional efficacy measures included changes in waist circumference, plasma lipid levels, and other cardiometabolic risk factors.At year 1, the completion rate was 309 (51%) patients in the placebo group, 620 (51%) patients in the 5 mg of rimonabant group, and 673 (55%) patients in the 20 mg of rimonabant group. Compared with the placebo group, the 20 mg of rimonabant group produced greater mean (SEM) reductions in weight (-6.3 [0.2] kg vs -1.6 [0.2] kg; P<.001), waist circumference (-6.1 [0.2] cm vs -2.5 [0.3] cm; P<.001), and level of triglycerides (percentage change, -5.3 [1.2] vs 7.9 [2.0]; P<.001) and a greater increase in level of high-density lipoprotein cholesterol (percentage change, 12.6 [0.5] vs 5.4 [0.7]; P<.001). Patients who were switched from the 20 mg of rimonabant group to the placebo group during year 2 experienced weight regain while those who continued to receive 20 mg of rimonabant maintained their weight loss and favorable changes in cardiometabolic risk factors. Use of different imputation methods to account for the high rate of dropouts in all 3 groups yielded similar results. Rimonabant was generally well tolerated; the most common drug-related adverse event was nausea (11.2% for the 20 mg of rimonabant group vs 5.8% for the placebo group).In this multicenter trial, treatment with 20 mg/d of rimonabant plus diet for 2 years promoted modest but sustained reductions in weight and waist circumference and favorable changes in cardiometabolic risk factors. However, the trial was limited by a high drop-out rate and longer-term effects of the drug require further study. Clinical Trials Registration ClinicalTrials.gov Identifier: NCT00029861.

Pharmacology of cannabinoid CB1 and CB2 receptors

1997-01-01

Roger G. Pertwee

Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors

1995-06-01

Raphael Mechoulam , Shimon Ben‐Shabat , L Hanŭs +7 more

Molecular targets for cannabidiol and its synthetic analogues: effect on vanilloid VR1 receptors and on the cellular uptake and enzymatic hydrolysis of anandamide

2001-10-01

Tiziana Bisogno , L Hanŭs , Luciano De Petrocellis +7 more

(−)‐Cannabidiol (CBD) is a non‐psychotropic component of Cannabis with possible therapeutic use as an anti‐inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether … (−)‐Cannabidiol (CBD) is a non‐psychotropic component of Cannabis with possible therapeutic use as an anti‐inflammatory drug. Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 (VR1), the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide (AEA). CBD and its enantiomer, (+)‐CBD, together with seven analogues, obtained by exchanging the C‐7 methyl group of CBD with a hydroxy‐methyl or a carboxyl function and/or the C‐5′ pentyl group with a di‐methyl‐heptyl (DMH) group, were tested on: (a) VR1‐mediated increase in cytosolic Ca 2+ concentrations in cells over‐expressing human VR1; (b) [ 14 C]‐AEA uptake by RBL‐2H3 cells, which is facilitated by a selective membrane transporter; and (c) [ 14 C]‐AEA hydrolysis by rat brain membranes, which is catalysed by the fatty acid amide hydrolase. Both CBD and (+)‐CBD, but not the other analogues, stimulated VR1 with EC 50 =3.2 – 3.5 μ M , and with a maximal effect similar in efficacy to that of capsaicin, i.e. 67 – 70% of the effect obtained with ionomycin (4 μ M ). CBD (10 μ M ) desensitized VR1 to the action of capsaicin. The effects of maximal doses of the two compounds were not additive. (+)‐5′‐DMH‐CBD and (+)‐7‐hydroxy‐5′‐DMH‐CBD inhibited [ 14 C]‐AEA uptake (IC 50 =10.0 and 7.0 μ M ); the (−)‐enantiomers were slightly less active (IC 50 =14.0 and 12.5 μ M ). CBD and (+)‐CBD were also active (IC 50 =22.0 and 17.0 μ M ). CBD (IC 50 =27.5 μ M ), (+)‐CBD (IC 50 =63.5 μ M ) and (−)‐7‐hydroxy‐CBD (IC 50 =34 μ M ), but not the other analogues (IC 50 >100 μ M ), weakly inhibited [ 14 C]‐AEA hydrolysis. Only the (+)‐isomers exhibited high affinity for CB 1 and/or CB 2 cannabinoid receptors. These findings suggest that VR1 receptors, or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield synthesis, and the weak affinity for CB 1 and CB 2 receptors, (−)‐5′‐DMH‐CBD represents a valuable candidate for further investigation as inhibitor of AEA uptake and a possible new therapeutic agent. British Journal of Pharmacology (2001) 134 , 845–852; doi: 10.1038/sj.bjp.0704327

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Supersensitivity to anandamide and enhanced endogenous cannabinoid signaling in mice lacking fatty acid amide hydrolase

2001-07-24

Benjamin F. Cravatt , Kristin Demarest , Matthew P. Patricelli +4 more

The medicinal properties of marijuana have been recognized for centuries, but clinical and societal acceptance of this drug of abuse as a potential therapeutic agent remains fiercely debated. An attractive … The medicinal properties of marijuana have been recognized for centuries, but clinical and societal acceptance of this drug of abuse as a potential therapeutic agent remains fiercely debated. An attractive alternative to marijuana-based therapeutics would be to target the molecular pathways that mediate the effects of this drug. To date, these neural signaling pathways have been shown to comprise a cannabinoid receptor (CB 1 ) that binds the active constituent of marijuana, tetrahydrocannabinol (THC), and a postulated endogenous CB 1 ligand anandamide. Although anandamide binds and activates the CB 1 receptor in vitro , this compound induces only weak and transient cannabinoid behavioral effects in vivo , possibly a result of its rapid catabolism. Here we show that mice lacking the enzyme fatty acid amide hydrolase (FAAH −/− ) are severely impaired in their ability to degrade anandamide and when treated with this compound, exhibit an array of intense CB 1 -dependent behavioral responses, including hypomotility, analgesia, catalepsy, and hypothermia. FAAH −/− -mice possess 15-fold augmented endogenous brain levels of anandamide and display reduced pain sensation that is reversed by the CB 1 antagonist SR141716A. Collectively, these results indicate that FAAH is a key regulator of anandamide signaling in vivo , setting an endogenous cannabinoid tone that modulates pain perception. FAAH may therefore represent an attractive pharmaceutical target for the treatment of pain and neuropsychiatric disorders.

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Molecular characterization of a peripheral receptor for cannabinoids

1993-09-01

Sean Munro , Kerrie L. Thomas , Muna Abu-Shaar

SR141716A, a potent and selective antagonist of the brain cannabinoid receptor

1994-08-22

Murielle Rinaldi‐Carmona , Francis Barth , Michel Héaulme +7 more

SR141716A is the first selective and orally active antagonist of the brain cannabinoid receptor. This compound displays nanomolar affinity for the central cannabinoid receptor but is not active on the … SR141716A is the first selective and orally active antagonist of the brain cannabinoid receptor. This compound displays nanomolar affinity for the central cannabinoid receptor but is not active on the peripheral cannabinoid receptor. In vitro, SR141716A antagonises the inhibitory effects of cannabinoid receptor agonists on both mouse vas deferens contractions and adenylyl cyclase activity in rat brain membranes. After intraperitoneal or oral administration SR141716A antagonises classical pharmacological and behavioural effects of cannabinoid receptor agonists. This compound should prove to be a powerful tool for investigating the in vivo functions of the anandamide/cannabinoid system.

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Immunohistochemical distribution of cannabinoid CB1 receptors in the rat central nervous system

1998-01-01

K Tsou , Sean M. Brown , M.Clara Sañudo-Peña +2 more

Structure of a cannabinoid receptor and functional expression of the cloned cDNA

1990-08-09

Lisa A. Matsuda , Stephen J. Lolait , Michael Brownstein +2 more

The molecular logic of endocannabinoid signalling

2003-11-01

Daniele Piomelli

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Formation and inactivation of endogenous cannabinoid anandamide in central neurons

1994-12-01

Vincenzo Di Marzo , Angelo Fontana , Hugues Cadas +4 more

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2-Arachidonoylgylcerol: A Possible Endogenous Cannabinoid Receptor Ligand in Brain

1995-10-01

Takayuki Sugiura , Shigeru Kondo , Akihiro Sukagawa +5 more

Effects of Rimonabant on Metabolic Risk Factors in Overweight Patients with Dyslipidemia

2005-11-16

Jean‐Pierre Després , Alain Golay , Lars Sjöström

Rimonabant, a selective cannabinoid-1 receptor (CB1) blocker, has been shown to reduce body weight and improve cardiovascular risk factors in obese patients. The Rimonabant in Obesity-Lipids (RIO-Lipids) study examined the … Rimonabant, a selective cannabinoid-1 receptor (CB1) blocker, has been shown to reduce body weight and improve cardiovascular risk factors in obese patients. The Rimonabant in Obesity-Lipids (RIO-Lipids) study examined the effects of rimonabant on metabolic risk factors, including adiponectin levels, in high-risk patients who are overweight or obese and have dyslipidemia.We randomly assigned 1036 overweight or obese patients (body-mass index [the weight in kilograms divided by the square of the height in meters], 27 to 40) with untreated dyslipidemia (triglyceride levels >1.69 to 7.90 mmol per liter, or a ratio of cholesterol to high-density lipoprotein [HDL] cholesterol of >4.5 among women and >5 among men) to double-blinded therapy with either placebo or rimonabant at a dose of 5 mg or 20 mg daily for 12 months in addition to a hypocaloric diet.The rates of completion of the study were 62.6 percent, 60.3 percent, and 63.9 percent in the placebo group, the group receiving 5 mg of rimonabant, and the group receiving 20 mg of rimonabant, respectively. The most frequent adverse events resulting in discontinuation of the drug were depression, anxiety, and nausea. As compared with placebo, rimonabant at a dose of 20 mg was associated with a significant (P<0.001) mean weight loss (repeated-measures method, -6.7+/-0.5 kg, and last-observation-carried-forward analyses, -5.4+/-0.4 kg), reduction in waist circumference (repeated-measures method, -5.8+/-0.5 cm, and last-observation-carried-forward analyses, -4.7+/-0.5 cm), increase in HDL cholesterol (repeated-measures method, +10.0+/-1.6 percent, and last-observation-carried-forward analyses, +8.1+/-1.5 percent), and reduction in triglycerides (repeated-measures method, -13.0+/-3.5 percent, and last-observation-carried-forward analyses, -12.4+/-3.2 percent). Rimonabant at a dose of 20 mg also resulted in an increase in plasma adiponectin levels (repeated-measures method, 57.7 percent, and last-observation-carried-forward analyses, 46.2 percent; P<0.001), for a change that was partly independent of weight loss alone.Selective CB1-receptor blockade with rimonabant significantly reduces body weight and waist circumference and improves the profile of several metabolic risk factors in high-risk patients who are overweight or obese and have an atherogenic dyslipidemia.

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Moderation of the Effect of Adolescent-Onset Cannabis Use on Adult Psychosis by a Functional Polymorphism in the Catechol-O-Methyltransferase Gene: Longitudinal Evidence of a Gene X Environment Interaction

2005-03-19

Avshalom Caspi , Terrie E. Moffitt , Mary Cannon +7 more

International Union of Basic and Clinical Pharmacology. LXXIX. Cannabinoid Receptors and Their Ligands: Beyond CB<sub>1</sub>and CB<sub>2</sub>

2010-11-15

Roger G. Pertwee , Allyn C. Howlett , Mary E. Abood +7 more

There are at least two types of cannabinoid receptors (CB<sub>1</sub> and CB<sub>2</sub>). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ<sup>9</sup>-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known … There are at least two types of cannabinoid receptors (CB<sub>1</sub> and CB<sub>2</sub>). Ligands activating these G protein-coupled receptors (GPCRs) include the phytocannabinoid Δ<sup>9</sup>-tetrahydrocannabinol, numerous synthetic compounds, and endogenous compounds known as endocannabinoids. Cannabinoid receptor antagonists have also been developed. Some of these ligands activate or block one type of cannabinoid receptor more potently than the other type. This review summarizes current data indicating the extent to which cannabinoid receptor ligands undergo orthosteric or allosteric interactions with non-CB<sub>1</sub>, non-CB<sub>2</sub> established GPCRs, deorphanized receptors such as GPR55, ligand-gated ion channels, transient receptor potential (TRP) channels, and other ion channels or peroxisome proliferator-activated nuclear receptors. From these data, it is clear that some ligands that interact similarly with CB<sub>1</sub> and/or CB<sub>2</sub> receptors are likely to display significantly different pharmacological profiles. The review also lists some criteria that any novel “CB<sub>3</sub>” cannabinoid receptor or channel should fulfil and concludes that these criteria are not currently met by any non-CB<sub>1</sub>, non-CB<sub>2</sub> pharmacological receptor or channel. However, it does identify certain pharmacological targets that should be investigated further as potential CB<sub>3</sub> receptors or channels. These include TRP vanilloid 1, which possibly functions as an ionotropic cannabinoid receptor under physiological and/or pathological conditions, and some deorphanized GPCRs. Also discussed are 1) the ability of CB<sub>1</sub> receptors to form heteromeric complexes with certain other GPCRs, 2) phylogenetic relationships that exist between CB<sub>1</sub>/CB<sub>2</sub> receptors and other GPCRs, 3) evidence for the existence of several as-yet-uncharacterized non-CB<sub>1</sub>, non-CB<sub>2</sub> cannabinoid receptors; and 4) current cannabinoid receptor nomenclature.

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International Union of Pharmacology. XXVII. Classification of Cannabinoid Receptors

2002-06-01

Allyn C. Howlett

Two types of cannabinoid receptor have been discovered so far, CB<sub>1</sub> (2.1: CBD:1:CB1:), cloned in 1990, and CB<sub>2</sub>(2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in … Two types of cannabinoid receptor have been discovered so far, CB<sub>1</sub> (2.1: CBD:1:CB1:), cloned in 1990, and CB<sub>2</sub>(2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB<sub>1</sub> and CB<sub>2</sub> exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB<sub>1</sub> receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB<sub>1</sub> agonists probably serve as retrograde synaptic messengers. CB<sub>2</sub> receptors are present mainly on immune cells. Such cells also express CB<sub>1</sub>receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.

Endocannabinoid-Mediated Control of Synaptic Transmission

2009-01-01

Masanobu Kano , Takako Ohno‐Shosaku , Yuki Hashimotodani +2 more

The discovery of cannabinoid receptors and subsequent identification of their endogenous ligands (endocannabinoids) in early 1990s have greatly accelerated research on cannabinoid actions in the brain. Then, the discovery in … The discovery of cannabinoid receptors and subsequent identification of their endogenous ligands (endocannabinoids) in early 1990s have greatly accelerated research on cannabinoid actions in the brain. Then, the discovery in 2001 that endocannabinoids mediate retrograde synaptic signaling has opened up a new era for cannabinoid research and also established a new concept how diffusible messengers modulate synaptic efficacy and neural activity. The last 7 years have witnessed remarkable advances in our understanding of the endocannabinoid system. It is now well accepted that endocannabinoids are released from postsynaptic neurons, activate presynaptic cannabinoid CB(1) receptors, and cause transient and long-lasting reduction of neurotransmitter release. In this review, we aim to integrate our current understanding of functions of the endocannabinoid system, especially focusing on the control of synaptic transmission in the brain. We summarize recent electrophysiological studies carried out on synapses of various brain regions and discuss how synaptic transmission is regulated by endocannabinoid signaling. Then we refer to recent anatomical studies on subcellular distribution of the molecules involved in endocannabinoid signaling and discuss how these signaling molecules are arranged around synapses. In addition, we make a brief overview of studies on cannabinoid receptors and their intracellular signaling, biochemical studies on endocannabinoid metabolism, and behavioral studies on the roles of the endocannabinoid system in various aspects of neural functions.

The Endocannabinoid System as an Emerging Target of Pharmacotherapy

2006-09-01

Pál Pacher , Sándor Bátkai , George Kunos

The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. … The recent identification of cannabinoid receptors and their endogenous lipid ligands has triggered an exponential growth of studies exploring the endocannabinoid system and its regulatory functions in health and disease. Such studies have been greatly facilitated by the introduction of selective cannabinoid receptor antagonists and inhibitors of endocannabinoid metabolism and transport, as well as mice deficient in cannabinoid receptors or the endocannabinoid-degrading enzyme fatty acid amidohydrolase. In the past decade, the endocannabinoid system has been implicated in a growing number of physiological functions, both in the central and peripheral nervous systems and in peripheral organs. More importantly, modulating the activity of the endocannabinoid system turned out to hold therapeutic promise in a wide range of disparate diseases and pathological conditions, ranging from mood and anxiety disorders, movement disorders such as Parkinson9s and Huntington9s disease, neuropathic pain, multiple sclerosis and spinal cord injury, to cancer, atherosclerosis, myocardial infarction, stroke, hypertension, glaucoma, obesity/metabolic syndrome, and osteoporosis, to name just a few. An impediment to the development of cannabinoid medications has been the socially unacceptable psychoactive properties of plant-derived or synthetic agonists, mediated by CB<sub>1</sub> receptors. However, this problem does not arise when the therapeutic aim is achieved by treatment with a CB<sub>1</sub> receptor antagonist, such as in obesity, and may also be absent when the action of endocannabinoids is enhanced indirectly through blocking their metabolism or transport. The use of selective CB<sub>2</sub> receptor agonists, which lack psychoactive properties, could represent another promising avenue for certain conditions. The abuse potential of plant-derived cannabinoids may also be limited through the use of preparations with controlled composition and the careful selection of dose and route of administration. The growing number of preclinical studies and clinical trials with compounds that modulate the endocannabinoid system will probably result in novel therapeutic approaches in a number of diseases for which current treatments do not fully address the patients9 need. Here, we provide a comprehensive overview on the current state of knowledge of the endocannabinoid system as a target of pharmacotherapy.

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Cannabinoids for Medical Use

2015-06-23

Penny Whiting , Robert Wolff , Sohan Deshpande +7 more

<h3>Importance</h3> Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. <h3>Objective</h3> To conduct a systematic review of … <h3>Importance</h3> Cannabis and cannabinoid drugs are widely used to treat disease or alleviate symptoms, but their efficacy for specific indications is not clear. <h3>Objective</h3> To conduct a systematic review of the benefits and adverse events (AEs) of cannabinoids. <h3>Data Sources</h3> Twenty-eight databases from inception to April 2015. <h3>Study Selection</h3> Randomized clinical trials of cannabinoids for the following indications: nausea and vomiting due to chemotherapy, appetite stimulation in HIV/AIDS, chronic pain, spasticity due to multiple sclerosis or paraplegia, depression, anxiety disorder, sleep disorder, psychosis, glaucoma, or Tourette syndrome. <h3>Data Extraction and Synthesis</h3> Study quality was assessed using the Cochrane risk of bias tool. All review stages were conducted independently by 2 reviewers. Where possible, data were pooled using random-effects meta-analysis. <h3>Main Outcomes and Measures</h3> Patient-relevant/disease-specific outcomes, activities of daily living, quality of life, global impression of change, and AEs. <h3>Results</h3> A total of 79 trials (6462 participants) were included; 4 were judged at low risk of bias. Most trials showed improvement in symptoms associated with cannabinoids but these associations did not reach statistical significance in all trials. Compared with placebo, cannabinoids were associated with a greater average number of patients showing a complete nausea and vomiting response (47% vs 20%; odds ratio [OR], 3.82 [95% CI, 1.55-9.42]; 3 trials), reduction in pain (37% vs 31%; OR, 1.41 [95% CI, 0.99-2.00]; 8 trials), a greater average reduction in numerical rating scale pain assessment (on a 0-10-point scale; weighted mean difference [WMD], −0.46 [95% CI, −0.80 to −0.11]; 6 trials), and average reduction in the Ashworth spasticity scale (WMD, −0.12 [95% CI, −0.24 to 0.01]; 5 trials). There was an increased risk of short-term AEs with cannabinoids, including serious AEs. Common AEs included dizziness, dry mouth, nausea, fatigue, somnolence, euphoria, vomiting, disorientation, drowsiness, confusion, loss of balance, and hallucination. <h3>Conclusions and Relevance</h3> There was moderate-quality evidence to support the use of cannabinoids for the treatment of chronic pain and spasticity. There was low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy, weight gain in HIV infection, sleep disorders, and Tourette syndrome. Cannabinoids were associated with an increased risk of short-term AEs.

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Identification and Functional Characterization of Brainstem Cannabinoid CB <sub>2</sub> Receptors

2005-10-13

Marja D. Van Sickle , Marnie Duncan , Philip J. Kingsley +7 more

The presence and function of CB 2 receptors in central nervous system (CNS) neurons are controversial. We report the expression of CB 2 receptor messenger RNA and protein localization on … The presence and function of CB 2 receptors in central nervous system (CNS) neurons are controversial. We report the expression of CB 2 receptor messenger RNA and protein localization on brainstem neurons. These functional CB 2 receptors in the brainstem were activated by a CB 2 receptor agonist, 2-arachidonoylglycerol, and by elevated endogenous levels of endocannabinoids, which also act at CB 1 receptors. CB 2 receptors represent an alternative site of action of endocannabinoids that opens the possibility of nonpsychotropic therapeutic interventions using enhanced endocannabinoid levels in localized brain areas.

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Role of Endogenous Cannabinoids in Synaptic Signaling

2003-07-01

Tamás F. Freund , István Katona , Daniele Piomelli

Freund, Tamás F., István Katona, and Daniele Piomelli. Role of Endogenous Cannabinoids in Synaptic Signaling. Physiol Rev 83: 1017–1066, 2003; 10.1152/physrev.00004.2003.—Research of cannabinoid actions was boosted in the 1990s by … Freund, Tamás F., István Katona, and Daniele Piomelli. Role of Endogenous Cannabinoids in Synaptic Signaling. Physiol Rev 83: 1017–1066, 2003; 10.1152/physrev.00004.2003.—Research of cannabinoid actions was boosted in the 1990s by remarkable discoveries including identification of endogenous compounds with cannabimimetic activity (endocannabinoids) and the cloning of their molecular targets, the CB 1 and CB 2 receptors. Although the existence of an endogenous cannabinoid signaling system has been established for a decade, its physiological roles have just begun to unfold. In addition, the behavioral effects of exogenous cannabinoids such as delta-9-tetrahydrocannabinol, the major active compound of hashish and marijuana, await explanation at the cellular and network levels. Recent physiological, pharmacological, and high-resolution anatomical studies provided evidence that the major physiological effect of cannabinoids is the regulation of neurotransmitter release via activation of presynaptic CB 1 receptors located on distinct types of axon terminals throughout the brain. Subsequent discoveries shed light on the functional consequences of this localization by demonstrating the involvement of endocannabinoids in retrograde signaling at GABAergic and glutamatergic synapses. In this review, we aim to synthesize recent progress in our understanding of the physiological roles of endocannabinoids in the brain. First, the synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation. The fine-grain anatomical distribution of the neuronal cannabinoid receptor CB 1 is described in most brain areas, emphasizing its general presynaptic localization and role in controlling neurotransmitter release. Finally, the possible functions of endocannabinoids as retrograde synaptic signal molecules are discussed in relation to synaptic plasticity and network activity patterns.

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Endocannabinoid Signaling in the Brain

2002-04-26

Rachel I. Wilson , Roger A. Nicoll

The primary psychoactive ingredient in cannabis, Delta9-tetrahydrocannabinol (Delta9-THC), affects the brain mainly by activating a specific receptor (CB1). CB1 is expressed at high levels in many brain regions, and several … The primary psychoactive ingredient in cannabis, Delta9-tetrahydrocannabinol (Delta9-THC), affects the brain mainly by activating a specific receptor (CB1). CB1 is expressed at high levels in many brain regions, and several endogenous brain lipids have been identified as CB1 ligands. In contrast to classical neurotransmitters, endogenous cannabinoids can function as retrograde synaptic messengers: They are released from postsynaptic neurons and travel backward across synapses, activating CB1 on presynaptic axons and suppressing neurotransmitter release. Cannabinoids may affect memory, cognition, and pain perception by means of this cellular mechanism.

CB1 Cannabinoid Receptors and On-Demand Defense Against Excitotoxicity

2003-10-02

Giovanni Marsicano , Sharon Goodenough , Krisztina Monory +7 more

Abnormally high spiking activity can damage neurons. Signaling systems to protect neurons from the consequences of abnormal discharge activity have been postulated. We generated conditional mutant mice that lack expression … Abnormally high spiking activity can damage neurons. Signaling systems to protect neurons from the consequences of abnormal discharge activity have been postulated. We generated conditional mutant mice that lack expression of the cannabinoid receptor type 1 in principal forebrain neurons but not in adjacent inhibitory interneurons. In mutant mice,the excitotoxin kainic acid (KA) induced excessive seizures in vivo. The threshold to KA-induced neuronal excitation in vitro was severely reduced in hippocampal pyramidal neurons of mutants. KA administration rapidly raised hippocampal levels of anandamide and induced protective mechanisms in wild-type principal hippocampal neurons. These protective mechanisms could not be triggered in mutant mice. The endogenous cannabinoid system thus provides on-demand protection against acute excitotoxicity in central nervous system neurons.

Adverse Health Effects of Marijuana Use

2014-06-04

Nora D. Volkow , Rubén Baler , Wilson M. Compton +1 more

As marijuana use becomes legal in some states, the dominant public opinion is that marijuana is a harmless source of mood alteration. Although the harms associated with marijuana use have … As marijuana use becomes legal in some states, the dominant public opinion is that marijuana is a harmless source of mood alteration. Although the harms associated with marijuana use have not been well studied, enough information is available to cause concern.

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Brain monoglyceride lipase participating in endocannabinoid inactivation

2002-07-22

T. P. Dinh , D. L. Carpenter , F.M. Leslie +5 more

The endogenous cannabinoids (endocannabinoids) are lipid molecules that may mediate retrograde signaling at central synapses and other forms of short-range neuronal communication. The monoglyceride 2-arachidonoylglycerol (2-AG) meets several criteria of … The endogenous cannabinoids (endocannabinoids) are lipid molecules that may mediate retrograde signaling at central synapses and other forms of short-range neuronal communication. The monoglyceride 2-arachidonoylglycerol (2-AG) meets several criteria of an endocannabinoid substance: ( i ) it activates cannabinoid receptors; ( ii ) it is produced by neurons in an activity-dependent manner; and ( iii ) it is rapidly eliminated. 2-AG inactivation is only partially understood, but it may occur by transport into cells and enzymatic hydrolysis. Here we tested the hypothesis that monoglyceride lipase (MGL), a serine hydrolase that converts monoglycerides to fatty acid and glycerol, participates in 2-AG inactivation. We cloned MGL by homology from a rat brain cDNA library. Its cDNA sequence encoded for a 303-aa protein with a calculated molecular weight of 33,367 daltons. Northern blot and in situ hybridization analyses revealed that MGL mRNA is heterogeneously expressed in the rat brain, with highest levels in regions where CB 1 cannabinoid receptors are also present (hippocampus, cortex, anterior thalamus, and cerebellum). Immunohistochemical studies in the hippocampus showed that MGL distribution has striking laminar specificity, suggesting a presynaptic localization of the enzyme. Adenovirus-mediated transfer of MGL cDNA into rat cortical neurons increased MGL expression and attenuated N -methyl-D-aspartate/carbachol-induced 2-AG accumulation in these cells. No such effect was observed on the accumulation of anandamide, another endocannabinoid lipid. The results suggest that hydrolysis by means of MGL is a primary mechanism for 2-AG inactivation in intact neurons.

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Taming THC: potential cannabis synergy and phytocannabinoid‐terpenoid entourage effects

2011-07-12

Ethan B. Russo

Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and … Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α‐pinene, linalool, β‐caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL −1 . They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis‐based medicinal extracts. Particular focus will be placed on phytocannabinoid‐terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin‐resistant Staphylococcus aureus ). Scientific evidence is presented for non‐cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid‐terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant. LINKED ARTICLES This article is part of a themed issue on Cannabinoids in Biology and Medicine. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.163.issue‐7

Persistent cannabis users show neuropsychological decline from childhood to midlife

2012-08-27

Madeline H. Meier , Avshalom Caspi , Antony Ambler +7 more

Recent reports show that fewer adolescents believe that regular cannabis use is harmful to health. Concomitantly, adolescents are initiating cannabis use at younger ages, and more adolescents are using cannabis … Recent reports show that fewer adolescents believe that regular cannabis use is harmful to health. Concomitantly, adolescents are initiating cannabis use at younger ages, and more adolescents are using cannabis on a daily basis. The purpose of the present study was to test the association between persistent cannabis use and neuropsychological decline and determine whether decline is concentrated among adolescent-onset cannabis users. Participants were members of the Dunedin Study, a prospective study of a birth cohort of 1,037 individuals followed from birth (1972/1973) to age 38 y. Cannabis use was ascertained in interviews at ages 18, 21, 26, 32, and 38 y. Neuropsychological testing was conducted at age 13 y, before initiation of cannabis use, and again at age 38 y, after a pattern of persistent cannabis use had developed. Persistent cannabis use was associated with neuropsychological decline broadly across domains of functioning, even after controlling for years of education. Informants also reported noticing more cognitive problems for persistent cannabis users. Impairment was concentrated among adolescent-onset cannabis users, with more persistent use associated with greater decline. Further, cessation of cannabis use did not fully restore neuropsychological functioning among adolescent-onset cannabis users. Findings are suggestive of a neurotoxic effect of cannabis on the adolescent brain and highlight the importance of prevention and policy efforts targeting adolescents.

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Pharmacokinetics and Pharmacodynamics of Cannabinoids

2003-01-01

Franjo Grotenhermen

Extent of illicit drug use and dependence, and their contribution to the global burden of disease

2012-01-01

Louisa Degenhardt , Wayne Hall

The diverse CB<sub>1</sub> and CB<sub>2</sub> receptor pharmacology of three plant cannabinoids: Δ<sup>9</sup>‐tetrahydrocannabinol, cannabidiol and Δ<sup>9</sup>‐tetrahydrocannabivarin

2007-09-10

Roger G. Pertwee

Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, … Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, (-)-trans-delta9-tetrahydrocannabinol (delta9-THC), (-)-cannabidiol (CBD) and (-)-trans-delta9-tetrahydrocannabivarin (delta9-THCV), interact with cannabinoid CB1 and CB2 receptors. Delta9-THC, the main psychotropic constituent of cannabis, is a CB1 and CB2 receptor partial agonist and in line with classical pharmacology, the responses it elicits appear to be strongly influenced both by the expression level and signalling efficiency of cannabinoid receptors and by ongoing endogenous cannabinoid release. CBD displays unexpectedly high potency as an antagonist of CB1/CB2 receptor agonists in CB1- and CB2-expressing cells or tissues, the manner with which it interacts with CB2 receptors providing a possible explanation for its ability to inhibit evoked immune cell migration. Delta9-THCV behaves as a potent CB2 receptor partial agonist in vitro. In contrast, it antagonizes cannabinoid receptor agonists in CB1-expressing tissues. This it does with relatively high potency and in a manner that is both tissue and ligand dependent. Delta9-THCV also interacts with CB1 receptors when administered in vivo, behaving either as a CB1 antagonist or, at higher doses, as a CB1 receptor agonist. Brief mention is also made in this review, first of the production by delta9-THC of pharmacodynamic tolerance, second of current knowledge about the extent to which delta9-THC, CBD and delta9-THCV interact with pharmacological targets other than CB1 or CB2 receptors, and third of actual and potential therapeutic applications for each of these cannabinoids.

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Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review

2007-07-01

Theresa HM Moore , Stanley Zammit , Anne Lingford‐Hughes +4 more

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Unresponsiveness to Cannabinoids and Reduced Addictive Effects of Opiates in CB <sub>1</sub> Receptor Knockout Mice

1999-01-15

Catherine Ledent , Olga Valverde , G Cossu +7 more

The function of the central cannabinoid receptor (CB 1 ) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive role of the … The function of the central cannabinoid receptor (CB 1 ) was investigated by invalidating its gene. Mutant mice did not respond to cannabinoid drugs, demonstrating the exclusive role of the CB 1 receptor in mediating analgesia, reinforcement, hypothermia, hypolocomotion, and hypotension. The acute effects of opiates were unaffected, but the reinforcing properties of morphine and the severity of the withdrawal syndrome were strongly reduced. These observations suggest that the CB 1 receptor is involved in the motivational properties of opiates and in the development of physical dependence and extend the concept of an interconnected role of CB 1 and opiate receptors in the brain areas mediating addictive behavior.

Cannabis sativa: The Plant of the Thousand and One Molecules

2016-02-04

Christelle M. André , Jean-François Hausman , Gea Guerriero

Cannabis sativa L. is an important herbaceous species originating from Central Asia, which has been used in folk medicine and as a source of textile fibre since the dawn of … Cannabis sativa L. is an important herbaceous species originating from Central Asia, which has been used in folk medicine and as a source of textile fibre since the dawn of times. This fast-growing plant has recently seen a resurgence of interest because of its multi-purpose applications: it is indeed a treasure trove of phytochemicals and a rich source of both cellulosic and woody fibres. Equally highly interested in this plant are the pharmaceutical and construction sectors, since its metabolites show potent bioactivities on human health and its outer and inner stem tissues can be used to make bioplastics and concrete-like material, respectively. In this review, the rich spectrum of hemp phytochemicals is discussed by putting a special emphasis on molecules of industrial interest, including cannabinoids, terpenoids and phenolic compounds, and their biosynthetic routes. Cannabinoids represent the most studied group of compounds, mainly due to their wide range of pharmaceutical effects in humans, including psychotropic activities. The therapeutic and commercial interests of some terpenoids and phenolic compounds, and in particular stilbenoids and lignans, are also highlighted in view of the most recent literature data. Biotechnological avenues to enhance the production and bioactivity of hemp secondary metabolites are proposed by discussing the power of plant genetic engineering and tissue culture. In particular two systems are reviewed, i.e. cell suspension and hairy root cultures. Additionally, an entire section is devoted to hemp trichomes, in the light of their importance as phytochemical factories. Ultimately, prospects on the benefits linked to the use of the -omics technologies, such as metabolomics and transcriptomics to speed up the identification and the large-scale production of lead agents from bioengineered Cannabis cell culture, are presented.

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A Comparison of Sustained-Release Bupropion and Placebo for Smoking Cessation

1997-10-23

R. Douglas Hurt , David P.L. Sachs , Elbert D. Glover +7 more

Trials of antidepressant medications for smoking cessation have had mixed results. We conducted a double-blind, placebo-controlled trial of a sustained-release form of bupropion for smoking cessation. We excluded smokers with … Trials of antidepressant medications for smoking cessation have had mixed results. We conducted a double-blind, placebo-controlled trial of a sustained-release form of bupropion for smoking cessation. We excluded smokers with current depression, but not those with a history of major depression. The 615 subjects were randomly assigned to receive placebo or bupropion at a dose of 100, 150, or 300 mg per day for seven weeks. The target quitting date (or "target quit date") was one week after the beginning of treatment. Brief counseling was provided at base line, weekly during treatment, and at 8, 12, 26, and 52 weeks. Self-reported abstinence was confirmed by a carbon monoxide concentration in expired air of 10 ppm or less.At the end of seven weeks of treatment, the rates of smoking cessation as confirmed by carbon monoxide measurements were 19.0 percent in the placebo group, 28.8 percent in the 100-mg group, 38.6 percent in the 150-mg group, and 44.2 percent in the 300-mg group (P<0.001). At one year the respective rates were 12.4 percent, 19.6 percent, 22.9 percent, and 23.1 percent. The rates for the 150-mg group (P=0.02) and the 300-mg group (P=0.01) -- but not the 100-mg group (P=0.09) -- were significantly better than those for the placebo group. Among the subjects who were continuously abstinent through the end of treatment, the mean absolute weight gain was inversely associated with the dose (a gain of 2.9 kg in the placebo group, 2.3 kg in 100-mg and 150-mg groups, and 1.5 kg in the 300-mg group; P= 0.02). No effects of treatment were observed on depression scores as measured serially by the Beck Depression Inventory. Thirty-seven subjects stopped treatment prematurely because of adverse events; the frequency was similar among all groups.A sustained-release form of bupropion was effective for smoking cessation and was accompanied by reduced weight gain and minimal side effects. Many participants in all groups were smoking at one year.

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Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome

2017-05-24

Orrin Devinsky , J. Helen Cross , Linda Laux +6 more

The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in … The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome.In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period.The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, -22.8 percentage points; 95% confidence interval [CI], -41.1 to -5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient's overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375 .).

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Cannabinoid Receptors and the Endocannabinoid System: Signaling and Function in the Central Nervous System

2018-03-13

Shenglong Zou , Ujendra Kumar

The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana) are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 … The biological effects of cannabinoids, the major constituents of the ancient medicinal plant Cannabis sativa (marijuana) are mediated by two members of the G-protein coupled receptor family, cannabinoid receptors 1 (CB1R) and 2. The CB1R is the prominent subtype in the central nervous system (CNS) and has drawn great attention as a potential therapeutic avenue in several pathological conditions, including neuropsychological disorders and neurodegenerative diseases. Furthermore, cannabinoids also modulate signal transduction pathways and exert profound effects at peripheral sites. Although cannabinoids have therapeutic potential, their psychoactive effects have largely limited their use in clinical practice. In this review, we briefly summarized our knowledge of cannabinoids and the endocannabinoid system, focusing on the CB1R and the CNS, with emphasis on recent breakthroughs in the field. We aim to define several potential roles of cannabinoid receptors in the modulation of signaling pathways and in association with several pathophysiological conditions. We believe that the therapeutic significance of cannabinoids is masked by the adverse effects and here alternative strategies are discussed to take therapeutic advantage of cannabinoids.

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Modulation of anxiety through blockade of anandamide hydrolysis

2002-12-02

Satish Kathuria , Silvana Gaetani , Darren Fegley +7 more

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Cannabis-Associated Emergencies in the Emergency Department.

2025-07-11

David Eichhorn , Andreas Schaper , Stefanie Iwersen‐Bergmann +3 more

Now that the Cannabis Act legalizing the use of cannabis has come into effect in Germany, the frequency of cannabis use in Germany may rise, and with it the number … Now that the Cannabis Act legalizing the use of cannabis has come into effect in Germany, the frequency of cannabis use in Germany may rise, and with it the number of cannabis-related visits to emergency departments. In this narrative review, we identify and evaluate the observed trends in case numbers after cannabis legalization in other countries, the common reasons for emergency department visits, and the options for treatment. Data on trends in cannabis-related emergency contacts in Germany were provided by the Poison Control Center North and are evaluated descriptively. The prevalence of cannabis use in Europe is estimated at 8%. In Canada, after legalization, cannabis use among the total population aged 15 years and over rose from 15% in 2017 to 25% in 2021, and hospital admissions doubled from 15/100 000 in 2017 to 32/100 000 in 2022. Acute intoxication is the most common reason for hospital admission and is often accompanied by acute anxiety and panic attacks. The risk of developing psychosis increases with THC content and frequency of use. Cannabinoid hyperemesis syndrome manifests itself with abdominal pain and severe, cyclical vomiting. The most important acute measure is to replace the often massive fluid loss. Benzodiazepines and antipsychotic drugs can be given as symptomatic treatment. The legalization of cannabis use can be expected to lead to an increase in cannabis-related emergencies in Germany as well. As the clinical manifestations are often nonspecific, the targeted investigation of possible cannabis use is indicated so that the affected patients can be given appropriate treatment and assistance.

How to ESCAPE from Pain? An Observational Study on Improving Pain and Quality of Life with the Cannamedical® Hybrid Cannabis Extract

2025-06-25

Yvonne Wagner , Ines Samel , Kristina Probst +3 more | Advances in Therapy

Chronic pain remains a challenge, with standard therapies often providing inadequate pain relief and causing undesirable side effects. Medicinal cannabis has emerged as promising alternative. This study assessed the impact … Chronic pain remains a challenge, with standard therapies often providing inadequate pain relief and causing undesirable side effects. Medicinal cannabis has emerged as promising alternative. This study assessed the impact of a cannabis hybrid extract on pain intensity and quality of life in daily clinical use. ESCAPE was an observational study and included patients aged ≥ 18 years with chronic pain in Germany. The primary objective was to evaluate the effectiveness of the Cannamedical® Hybrid Cannabis Extract THC25:CBD25 on pain during four visits (V1-V4) in clinical practice, and key secondary objectives were pain interference and quality of life. Pain intensity was measured using the Numeric Rating Scale (NRS) of the Brief Pain Inventory (BPI) questionnaire. Pain interference was evaluated with the BPI pain interference subscore, and quality of life-particularly physical and mental health-was assessed with the Short Form-12 (SF-12) questionnaire. Additionally, patient and physician satisfaction with the extract was assessed. The study included 64 patients (50% female) with chronic pain (intention-to treat population; ITT). Cannabis-naïve patients of the ITT were defined as a subgroup and analyzed separately (N = 35). Mean (± SD) NRS-assessed pain intensity decreased during the study, in both the ITT (5.46 ± 1.73 at V1 vs. 3.37 ± 2.43 at V4) and in the cannabis-naïve subgroup (5.92 ± 1.34 at V1 vs. 2.37 ± 1.69 at V4). Mean pain interference subscore decreased between V1 and V4 for the ITT (5.39 ± 1.92 vs. 3.38 ± 2.46) and the cannabis-naïve group (5.68 ± 1.46 vs. 2.54 ± 1.99). Physical and mental health improved in both groups and high satisfaction with the hybrid cannabis extract was reported by patients and physicians. Treatment with the Cannamedical® Hybrid Cannabis Extract THC25:CBD25 in daily clinical practice showed positive effects on patients' pain and quality of life. German Clinical Trials Registry identifier DRKS00026906.

Cannabis Use in Women and Sexual Dysfunction

2025-06-25

Becky Lynn , Julia López , Morgan E. Link +1 more | Sexes

The purpose of this study is to evaluate the differences in sexual functioning in women who used cannabis before sex and those who used cannabis but not before sex, among … The purpose of this study is to evaluate the differences in sexual functioning in women who used cannabis before sex and those who used cannabis but not before sex, among those with sexual dysfunction. The cross-sectional study, conducted from August 2019 to January 2020 at an academic sexual dysfunction clinic in the Midwest region of the United States, included 187 participants. Patients completed an anonymous questionnaire during their visit, which included the Female Sexual Function Index (FSFI), cannabis use, and sociodemographic factors. The primary objective of this study was to assess the relationship between cannabis use and female sexual dysfunction (FSD). The secondary objective was to examine the FSFI domains of sexual function with cannabis use over the past four weeks. Among the participants, 90% (n = 168) had sexual dysfunction based on the FSFI scores among those with FSD. Women with FSD who used cannabis before sex reported significantly higher lubrication scores and trends toward higher arousal and total FSFI scores than those who used cannabis but not before sex. However, no significant differences were observed in sexual desire, satisfaction, or pain. Quality of life was statistically significant across cannabis groups, with those who never used cannabis indicating “very good to excellent” health more often than those who used cannabis before sex. In addition, women with FSD who had never smoked cigarettes had a significantly higher proportion of never having used cannabis compared to those who used cannabis not before sex and those who used it before sex. These findings suggest that women with sexual dysfunction who use cannabis before sex may experience improvements in lubrication, arousal, and overall sexual function, highlighting the potential benefits of cannabis use in enhancing specific aspects of sexual health in this population.

Modulation of Neurexins Alternative Splicing by Cannabinoid Receptors 1 (CB1) Signaling

2025-06-25

Elisa Innocenzi , Giuseppe Sciamanna , Alice Zucchi +6 more | Cells

Synaptic plasticity is the key mechanism underlying learning and memory. Neurexins are pre-synaptic molecules that play a pivotal role in synaptic plasticity, interacting with many different post-synaptic molecules in the … Synaptic plasticity is the key mechanism underlying learning and memory. Neurexins are pre-synaptic molecules that play a pivotal role in synaptic plasticity, interacting with many different post-synaptic molecules in the formation of neural circuits. Neurexins are alternatively spliced at different splice sites, yielding thousands of isoforms with different properties of interaction with post-synaptic molecules for a quick adaptation to internal and external inputs. The endocannabinoid system also plays a central role in synaptic plasticity, regulating key retrograde signaling at both excitatory and inhibitory synapses. This study aims at elucidating the crosstalk between alternative splicing of neurexin and the endocannabinoid system in the hippocampus. By employing an ex vivo hippocampal system, we found that pharmacological activation of cannabinoid receptor 1 (CB1) with the specific agonist ACEA led to reduced neurotransmission, associated with increased expression of the Nrxn1–3 spliced isoforms excluding the exon at splice site 4 (SS4−). In contrast, treatment with the CB1 antagonist AM251 increased glutamatergic activity and promoted the expression of the Nrxn variants including the exon (SS4+) Knockout of the involved splicing factor SLM2 determined the suppression of the exon splicing at SS4 and the expression only of the SS4+ variants of Nrxns1–3 transcripts. Interestingly, in SLM2 ko hippocampus, modulation of neurotransmission by AM251 or ACEA was abolished. These findings suggest a direct crosstalk between CB1-dependent signaling, neurotransmission and expression of specific Nrxns splice variants in the hippocampus. We propose that the fine-tuned regulation of Nrxn1–3 genes alternative splicing may play an important role in the feedback control of neurotransmission by the endocannabinoid system.

Unveiling the Antioxidant Role of Hemp Oils in Cancer Prevention and Treatment

2025-06-25

Marios C. Christodoulou , Panagiotis Rodosthenous , Christiana M. Neophytou | Cancers

The global incidence of cancer continues to rise at an alarming rate, with annual cases projected to increase by 47% from 19.3 million in 2020 to 28.4 million by 2025. … The global incidence of cancer continues to rise at an alarming rate, with annual cases projected to increase by 47% from 19.3 million in 2020 to 28.4 million by 2025. Cannabis sativa L. was among the earliest plants investigated for potential anticancer therapies, due to its more than 100 bioactive constituents that confer notable antioxidant properties. Hemp-derived extracts, particularly those rich in cannabidiol (CBD), exhibit notable synergistic biological effects, including the inhibition of cancer cell proliferation, angiogenesis, and metastasis, alongside the promotion of apoptosis. These pharmacological attributes suggest that hemp oils may serve as promising alternatives or adjuncts to conventional chemotherapy, offering potential therapeutic benefits with a reduced risk of severe adverse effects. This review discusses the current literature on hemp oils, with emphasis on their roles in cancer prevention, therapeutic efficacy, and potential toxicity in humans. Furthermore, it explores the various extraction methods employed in hemp oil production and examines their chemical compositions, offering a comprehensive understanding of the principal antioxidant constituents responsible for their bioactivity to the readers.

Therapeutic Use of Cannabis: Perceptions of Youth and Adults in Trujillo, Peru

2025-06-25

Valeria Gómez-Amaya , Amy Casanova-Coral , Josué Campaña-Silva +4 more | F1000Research

<ns3:p>Background In Peru, the legalization of Cannabis was given in 2017 and approved in 2019; however, there are discrepancies in the knowledge of the therapeutic use of this plant, causing … <ns3:p>Background In Peru, the legalization of Cannabis was given in 2017 and approved in 2019; however, there are discrepancies in the knowledge of the therapeutic use of this plant, causing rejection in its application as an alternative medicine. Methods The research was of a basic type with a quantitative approach and a non-experimental design, with a cross-sectional and descriptive scope. Non-probabilistic sampling was used and a total of 324 people (18 – 60 years old) were estimated as the sample. The instrument used was a virtual questionnaire consisting of closed questions with a KR-20 value of 0.825. Finally, the data were treated with descriptive statistics and frequency and percentage tables were used. Results Participants have a positive perception of the benefits of medical cannabis, although their knowledge of its therapeutic application and dosage is limited. The need for its use to be restricted to prescriptions by specialized physicians and backed by scientific evidence is highlighted. Despite having superficial information on applications in chronic diseases and cancer, there is a moderate acceptance of its regular use under medical supervision. Conclusion The population of Trujillo lacks knowledge about the medical benefits and applications of cannabis highlighting the need for educational campaigns. Although regulation is supported, concerns about safety and abuse remain. More studies should be conducted to obtain more accurate data.</ns3:p>

The individual and interactive effects of alpha-pinene and delta-9-tetrahydrocannabinol (Δ9-THC) in healthy adults

2025-06-25

Lakshmi Kumar , Tory R. Spindle , C. Austin Zamarripa +4 more | Medical Cannabis and Cannabinoids

Introduction. Cannabis contains hundreds of chemical constituents beyond delta-9-tetrahydrocannabinol (Δ9-THC), which is thought to be the primary driver of most of its acute pharmacodynamic effects. The entourage effect theory asserts … Introduction. Cannabis contains hundreds of chemical constituents beyond delta-9-tetrahydrocannabinol (Δ9-THC), which is thought to be the primary driver of most of its acute pharmacodynamic effects. The entourage effect theory asserts that the pharmacological and therapeutic effects of cannabis are not solely attributable to Δ9-THC, but are influenced by other constituents, such as minor cannabinoids and terpenes, through distinct pharmacological action. However, empirical studies that have systematically evaluated this theory in humans remain limited. This study tested the hypothesis that the terpene α-pinene can attenuate the acute memory-impairing effects of inhaled Δ9-THC in humans. Methods. Participants (N = 19; last cannabis use 39 days, on average, prior to first test session [SD = 84; range = 2–365]) completed six double-blind outpatient drug administration sessions during which they inhaled, using a Mighty Medic hand-held vaporizer, α-pinene alone (15 mg), Δ9-THC alone (30 mg), Δ9-THC and α-pinene together (30 mg Δ9-THC + 0.5 mg α-pinene; 30 mg Δ9-THC + 5 mg α-pinene; 30 mg Δ9-THC + 15 mg α-pinene), or placebo (ambient air) in a randomized order. Outcomes, which were collected up to 6 hours post drug exposure, included subjective drug effects, cognitive/psychomotor performance, and vital signs. Results. Administration of 15 mg α-pinene alone produced no significant pharmacodynamic effects compared to placebo. Administration of 30 mg Δ9-THC alone elicited subjective, cognitive, and physiological effects consistent with acute Δ9-THC-dominant cannabis exposure, including impairment of cognitive performance and working memory ability compared to placebo. The co-administration of α-pinene with Δ9-THC did not mitigate Δ9-THC-induced memory impairment or significantly alter other acute subjective, cognitive, or physiological effects. Conclusions. Inhaled α-pinene, at doses at and above those naturally found in cannabis flowers, did not mitigate Δ9-THC-induced cognitive impairments as hypothesized or influence other common acute effects of Δ9-THC in this sample of healthy adults. This result is inconsistent with some cannabis industry claims and speculation by some cannabis researchers. By systematically varying both Δ9-THC and terpene exposure and assessing their interaction across multiple pharmacodynamic domains, this work provides a model for future investigations into Δ9-THC-terpene interactions. As cannabis use continues to expand for both medicinal and non-medicinal purposes, more research is needed to better understand the acute effects of lesser studied chemical constituents of the plant and how they interact with predominant phytocannabinoids like Δ9-THC. This can inform cannabinoid drug development and product policy considerations.

Starker Cannabiskonsum erhöht das Demenzrisiko

2025-06-25

| DMW - Deutsche Medizinische Wochenschrift

Factors Influencing Co‐Use of Tobacco and Cannabis Amongst Young Adults in <scp>UK</scp> Further Education Colleges: A Qualitative Study

2025-06-24

Hannah Walsh , Ann McNeill , María Duaso | Drug and Alcohol Review

ABSTRACT Introduction Tobacco and cannabis are commonly co‐used (i.e., used concurrently or co‐administered) but rarely ‘co‐addressed’ and few co‐use interventions exist. Young adulthood presents a key age for intervening in … ABSTRACT Introduction Tobacco and cannabis are commonly co‐used (i.e., used concurrently or co‐administered) but rarely ‘co‐addressed’ and few co‐use interventions exist. Young adulthood presents a key age for intervening in substance use, therefore understanding young adults' perspective is crucial, but little is known about how they understand or experience co‐use. This study aimed to explore factors influencing co‐use and changes to use within a population of young adults in the UK. Methods Participants were young adults recruited via three Further Education (vocational) colleges, who reported past 6‐month co‐use. Individual semi‐structured interviews were carried out and analysed using the Framework approach. Results Eighteen participants were interviewed. Analysis identified influential factors, comprising three categories: (i) identity and social context including the concept of co‐use; (ii) experiences; and (iii) understanding of effects. Family and peers were an important influence on use and cessation and young adults used their observation of peers' experiences to understand potential harms of each substance, as well as the complex relationship between cannabis use and mental health. Discussion and Conclusions A broad range of factors influence co‐use, and changes made to co‐use, of tobacco and cannabis in young adults. Further investigation is needed to inform the development of co‐use interventions. Credible co‐use health risk information relevant to young adults, and the role of co‐occurring mental health challenges need consideration in the development of co‐use interventions.

Development of a Validated LC-MS Method for the Determination of Cannabinoids and Evaluation of Supercritical CO2 vs. Ultrasound-Assisted Extraction in Cannabis sativa L. (Kompolti cv.)

2025-06-24

Vasileios A. Ioannidis , Varvara Sygouni , Sotirios Giannopoulos +4 more | Antioxidants

Cannabis (Cannabis sativa L.) contains numerous secondary metabolites with different bioactivities. Extraction methods differ in their efficiency in recovering metabolites from plant material, and thus cannabis extracts vary significantly in … Cannabis (Cannabis sativa L.) contains numerous secondary metabolites with different bioactivities. Extraction methods differ in their efficiency in recovering metabolites from plant material, and thus cannabis extracts vary significantly in their composition and activity. We aimed to develop a repeatable and accurate HPLC-MS method for the determination of nine common cannabinoids and compare two widely used extraction techniques: ultrasound-assisted extraction (UAE) with methanol and supercritical CO2 extraction (SFE). Inflorescences of the Kompolti cultivar were used as the plant material. On a polar C18 column, more than thirty compounds were well separated within 25 min; thirteen cannabinoids were identified and eight of them were quantified, with cannabidiol and its acidic precursor being the most abundant. Additionally, three spectrophotometric assays were employed for extract characterization: the total phenolic content, total flavonoid content, and DPPH radical scavenging capacity. The SFE extract, obtained using ethanol as a co-solvent under low pressure (<100 bar) and temperature (<45 °C), was more enriched than the UAE extract (181.62 ± 2.90 vs. 140.64 ± 13.24 mg quercetin equivalents/g of dry extract) and cannabinoids (446.29 ± 22.66 vs. 379.85 ± 17.16 mg/g of dry extract), especially cannabinoid acids. However, UAE achieved greater recovery from the plant material (cannabinoids: 83.42 ± 5.15 vs. 68.84 ± 3.49 mg/g of plant material) and showed superior antioxidant capacity (DPPH IC50: 2.50 ± 0.18 vs. 3.37 ± 0.07 mg/mL). Notwithstanding the observed partial decarboxylation, the high repeatability (RSD < 15%, n = 11) of the entire analytical workflow involving UAE extraction and LC-MS analysis renders it suitable for routine analyses. This study contributes to the ongoing efforts toward the quality control and valorization of C. sativa.

The Endocannabinoid System in Retinal Müller Glia: Lessons From Astrocyte Research

2025-06-24

Sandra Beriain , Ignacio Fernández‐Moncada , Xandra Pereiro +3 more | Neurochemical Research

Effect of Cannabidiol and Δ9-tetrahydrocannabinol on Anti-Inflammatory Lipid Mediator Synthesis in Humans

2025-06-24

Alan Morris , Raeghan L. Mueller , Cristina Sempio +4 more | Cannabis and Cannabinoid Research

Background: Eicosanoids-lipid mediators derived from polyunsaturated fatty acids such as arachidonic acid-have a notable role in inflammatory signaling. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) have been shown in preclinical studies to … Background: Eicosanoids-lipid mediators derived from polyunsaturated fatty acids such as arachidonic acid-have a notable role in inflammatory signaling. Cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) have been shown in preclinical studies to modulate inflammatory pathways the modulating the enzymes that generate eicosanoids, namely lipoxygenase (LOX), cyclooxygenase (COX), and cytochrome P450 (CYP450). Methods: This present study aimed to investigate how CBD and THC effect plasma levels of eicosanoids generated through LOX, COX, and cytochrome P450 (CYP450) pathways. Using plasma sample data from multiple clinical studies, we tested the hypothesis that high-CBD cannabis use would increase eicosanoid levels compared with high-THC cannabis. Results: Following cannabis use, high-CBD cannabis led to a rise in plasma eicosanoids, particularly lipoxins, while high-THC cannabis did not. Conclusions: CBD promoted anti-inflammatory eicosanoid production via the 15-LOX pathway, therefore supporting the potential role of CBD as a therapeutic candidate for inflammatory diseases.

From Immune Dysregulation to Cancer: The Therapeutic Potential of CBD-Rich Cannabis Extracts in Lichen Planus, GVHD, and HNSCC

2025-06-24

Kifah Blal | International Journal of Oral and Maxillofacial Surgery

The Impact of Cannabis on Acute Pain Following Oral Surgery

2025-06-24

H. El-Awour | International Journal of Oral and Maxillofacial Surgery

The Role of Cannabidiol (CBD) in Promoting Osteoblastic Differentiation and Bone Healing: A Systematic Review

2025-06-24

H. El-Awour | International Journal of Oral and Maxillofacial Surgery

Fatty acid amide hydrolase in major depressive episodes: A [11C]CURB positron emission tomography study

2025-06-23

Dorsa Rafiei , Michelle De Pol , Jeffrey H. Meyer +7 more | Neuropsychopharmacology

The role of the endocannabinoid system (ECS) in major depressive disorder (MDD) is under-investigated despite reports of increased activity and/or concentration of fatty acid amide hydrolase (FAAH), a key ECS … The role of the endocannabinoid system (ECS) in major depressive disorder (MDD) is under-investigated despite reports of increased activity and/or concentration of fatty acid amide hydrolase (FAAH), a key ECS enzyme, in fronto-limbic brain regions in some animal models of depressive behavior. We hypothesized that [11C]CURB λk3, an index of FAAH density, would be elevated in the prefrontal cortex, hippocampus, and anterior cingulate cortex in major depressive episodes of MDD compared to healthy controls. Fifteen unmedicated MDD participants and 15 age- and sex-matched healthy controls underwent [11C]CURB positron emission tomography and FAAH genotyping. Psychological tests of depressive severity, apathy, and anxiety were administered and measurements were assessed as covariates in exploratory analyses. No significant group differences in [11C]CURB λk3 were observed between MDD participants and controls (F1,27 = 0.32; p = 0.58). A mixed effects model revealed that Marin Apathy Evaluation Scale scores in the MDD group had a significant main effect on [11C]CURB λk3 binding across the collective regions of medial prefrontal cortex, orbitofrontal cortex, anterior cingulate cortex, ventral striatum, and midbrain (F1,11 = 6.75; p = 0.02). Depressive severity and anxiety did not have a significant relationship to [11C]CURB λk3 binding. The relationship of greater fronto-limbic [11C]CURB λk3 to greater apathy along with the metabolic role of FAAH in the ECS, the latter which supports maintaining feelings of interest, initiative, and motivation, has important implications for the pathophysiology of apathy in MDD.

Cannabis in Hematology Survey Study (CHESS): A Longitudinal Investigation on Uses, Attitudes, and Outcomes of Cannabis Among Hematology Patients Undergoing Hematopoietic Stem Cell Transplant

2025-06-23

Andrew McLennan , Reanne Booker , Cameron Roessner +1 more | International Journal of Environmental Research and Public Health

Cancer patients use cannabis for medicinal purposes; however, few studies have examined hematology patients’ use of cannabis and no research to our knowledge has investigated the use of cannabis amongst … Cancer patients use cannabis for medicinal purposes; however, few studies have examined hematology patients’ use of cannabis and no research to our knowledge has investigated the use of cannabis amongst hematology patients before and after hematopoietic stem cell transplant (HCT). The purpose of this longitudinal survey study was to assess aspects of cannabis use in patients who underwent HCT. Eligible patients (N = 30) completed two surveys before and 90 days following their HCT. The surveys inquired about several aspects of cannabis (e.g., rate of use, beliefs and attitudes, access to information) and physical and psychological outcomes (e.g., anxiety, comorbidities, graft-versus-host-disease). Rates of cannabis use decreased following HCT (n = 14, 46% to n = 11, 40%). Conversations on cannabis that were initiated by an oncology health care provider increased post-transplant (n = 3, 10% to n = 11, 37%). This coincided with fewer who were smoking cannabis as a primary consumption method (n = 5, 38 to n = 2, 18) and an increase in the use of pharmaceutical cannabinoid products (n = 4, 13% to n = 6, 21%) as well as oils and topicals. Of the total sample, 63% (n = 17) experienced post-treatment complications and 33% (n = 10) developed GVHD, six of whom where recent cannabis users. This study provided insight into cannabis use amongst HCT patients and warrants further research with this population, including more exploration of the relationship between GVHD and cannabis.

Absolute Risk Prediction for Cannabis Use Disorder in Adolescence and Early Adulthood Using Bayesian Machine Learning

2025-06-22

Tingfang Wang , Joseph M. Boden , Swati Biswas +1 more | Drug and Alcohol Review

ABSTRACT Introduction Substance use disorders (SUD) have emerged as a pressing public health concern in the United States, with adolescent substance use often leading to SUDs in adulthood. Effective strategies … ABSTRACT Introduction Substance use disorders (SUD) have emerged as a pressing public health concern in the United States, with adolescent substance use often leading to SUDs in adulthood. Effective strategies are needed to stem this progression. To help fulfil this need, we developed a novel absolute risk prediction model for cannabis use disorder (CUD) for adolescents or young adults who use cannabis. Methods We trained a Bayesian machine learning model that provides a personalised CUD absolute risk for adolescents or young adults who use cannabis with data from the National Longitudinal Study of Adolescent to Adult Health. Model performance was assessed using five‐fold cross‐validation (CV) with area under the curve (AUC) and ratio of the expected to observed number of cases (E/O). Independent validation of the final model was conducted using two datasets. Results The proposed model has five risk factors: biological sex, delinquency, and scores on personality traits of conscientiousness, neuroticism and openness. For predicting CUD risk within 5 years of first cannabis use, AUC values for the training dataset and two validation datasets were 0.68, 0.64 and 0.75, respectively, and E/O values were 0.95, 0.98 and 1, respectively. This indicates good discrimination and calibration performance of the model. Discussion and Conclusion The proposed model can aid clinicians in assessing the risk of developing CUD among adolescents and young adults who use cannabis, enabling clinically appropriate interventions.

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Sex and Gender Influences on Problematic Cannabis Use and Cannabis Use Disorder: A Scoping Review Protocol

2025-06-22

Justin Matheson , Catharine A. Mielnik , R. J. Knight +6 more | medRxiv (Cold Spring Harbor Laboratory)

ABSTRACT Introduction Cannabis use and cannabis use disorder (CUD) are more prevalent among men and boys than among women and girls. However, this sex/gender gap has been narrowing in recent … ABSTRACT Introduction Cannabis use and cannabis use disorder (CUD) are more prevalent among men and boys than among women and girls. However, this sex/gender gap has been narrowing in recent decades, likely due to an increase in cannabis use among women and girls, who have been historically under-represented in cannabis research. The lack of sex- and gender-based approaches within cannabis research has been highlighted in previous reviews, some of which have synthesized existing literature of associations between sex, gender, and cannabis use. What is missing is a clinically-relevant synthesis of evidence for sex and gender influences on problematic cannabis use, including treatment-related outcomes that could be used to influence care. The objective of this scoping review is to identify and synthesize published evidence about the influence of sex and gender on correlates and outcomes of treatment among people with problematic cannabis use (including CUD). Furthermore, we will examine to what extent this published literature has considered how sex and gender intersect with other social categories such as race and sexuality. Methods and Analysis This scoping review will follow the most commonly used methodology, the 2005 Arksey and O’Malley scoping study framework (including the optional consultation exercise to solicit feedback from relevant stakeholders) and the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) Extension for Scoping Reviews reporting guidelines. We will search MEDLINE, Embase, CINAHL, PsycINFO, and Web of Science for articles published between 2010 and the present. Included studies must be conducted in human participants with problematic cannabis use (e.g., diagnosis or screening for CUD) and include an analysis of sex- and/or gender-related factors. Using Covidence software, two independent reviewers will screen each record at the title/abstract and full text phases. Two independent reviewers will then use a data charting form developed by the study team to extract data. Data charting and both phases of article screening will begin with a pilot process completed by the entire team to ensure consistency. Article data will be exported into a spreadsheet to facilitate summary and basic descriptive statistics. Studies will be grouped together first by content area (e.g., treatment correlates, treatment effectiveness), then by study design, and which sex- or gender-related factors are considered in the analysis. Dissemination We will disseminate findings using two main strategies. First, we will engage in traditional knowledge translation, including publication in peer-reviewed journals and presentation at both medical and scientific conferences. Second, we will engage in knowledge translation strategies that will reach a wider audience (e.g., presentations to non-researcher audiences, dissemination of findings through social media networks, and development of brochures, infographics, and short videos to summarize our findings for a lay audience). We aim to ultimately engage relevant stakeholders (including clinicians) to determine how the identified evidence can best support care of problematic cannabis use.

Cannabis and Neurodegenerative Disorders

2025-06-20

Elie Atallah , Sahar Obeïd , Myriam El Khoury-Malhame +1 more | CRC Press eBooks

Vincamine induces cytoprotective autophagy via regulation of ampk/mtor signaling pathway in gentamicin-induced hepatotoxicity and nephrotoxicity in rats

2025-06-20

Alaa Sayed Abou-Elhamd , Nadine Shehata , Sara Mohamed Naguib Abdel Hafez +1 more | Scientific Reports

Abstract Gentamicin (GET), a widely utilized aminoglycoside antibiotic for severe bacterial infections, is associated with significant hepatorenal toxicity. These adverse effects are frequently exacerbated by GET-induced oxidative stress and inflammation. … Abstract Gentamicin (GET), a widely utilized aminoglycoside antibiotic for severe bacterial infections, is associated with significant hepatorenal toxicity. These adverse effects are frequently exacerbated by GET-induced oxidative stress and inflammation. This study aimed to evaluate the potential protective efficacy of vincamine (VIN) against GET-induced hepatic and renal damage. 4 groups of adult male rats were assigned: normal control (received CMC), GET (100 mg/kg, i.p.), VIN (40 mg/kg, p.o.), and GET/VIN (received both VIN and GET) for 7 days. Liver and kidney function tests were performed. Serum total antioxidant capacity (TAC) and tissue malondialdehyde (MDA) were quantified. To assess apoptosis, Bax and Bcl-2 mRNA levels were quantified using real-time polymerase chain reaction (RT-PCR), while cleaved caspase-3 protein levels were measured using ELISA. Histopathological alterations were also examined. The implication of autophagy was assessed by detecting AMPK, beclin-1, LC3 and mTOR proteins. Our results indicated that VIN significantly attenuated GET-induced hepatotoxicity and nephrotoxicity by mitigating oxidative stress and apoptosis. Mechanistically, VIN modulated apoptotic pathways by upregulating the anti-apoptotic Bcl-2 gene and downregulating the pro-apoptotic Bax gene. Notably, VIN potently enhanced autophagy through modulation of the AMPK/mTOR signaling pathway, evidenced by the upregulation of beclin1 and LC3 levels. Histopathological analysis further corroborated these findings, demonstrating that VIN markedly reduced the tissue damage associated with GET administration. VIN demonstrates potential as a cytoprotective agent against GET-induced hepatorenal toxicity. The protective effect of VIN may be attributed to its capacity to modulate the Bax/Bcl-2/Caspase-3-dependent apoptotic pathway and the AMPK/mTOR-mediated autophagy pathway.

In Case You Haven't Heard…

2025-06-20

| Alcoholism & Drug Abuse Weekly

Add heart attacks to the possible adverse effects of cannabis use. A recent meta‐analysis has found that acute coronary syndrome, stroke, and cardiovascular death are all linked to cannabis use. … Add heart attacks to the possible adverse effects of cannabis use. A recent meta‐analysis has found that acute coronary syndrome, stroke, and cardiovascular death are all linked to cannabis use. “These findings should encourage investigating cannabis use in all patients presenting with serious cardiovascular disorders,” concluded Emilie Jouanjus, PharmD, PhD, of University of Toulouse in France, and colleagues in their report, published in Heart last week.

Cannabinoids and Adverse Convulsive Effects: A Pharmacovigilance and Addictovigilance Analysis of Cases Reported in France

2025-06-20

Marie‐Laure Laroche , Marc Labétoulle , Émilie Jouanjus +2 more | Fundamental and Clinical Pharmacology

Seizures after the use of cannabinoids are reported, but no precise descriptions of the characteristics of subjects and factors that may trigger seizures are available. To study the characteristics and … Seizures after the use of cannabinoids are reported, but no precise descriptions of the characteristics of subjects and factors that may trigger seizures are available. To study the characteristics and circumstances associated with the occurrence of seizures in individuals using cannabinoids for medical or recreational purposes. A retrospective analysis of spontaneous reports of adverse drug effects issued by the French pharmacovigilance and addictovigilance systems, and by manufacturers, extracted data from the Eudravigilance database (01/01/1985-21/07/2023). The request used the broad MedDRA SMQ term 'convulsive', with all products containing cannabinoids (THC, CBD, cannabis or natural cannabinoids). Among 4296 notifications with cannabinoids, 130 (3%) reports of convulsive effects were analysed: 29 cases (23.3%) related to medical use (27 CBD, 1 THC and 2 combined THC/CBD preparations) and 98 (75.4%) related to recreational use. The median age was 29.0 years (min-max: 3-75), 78.7% were men and 81.1% were serious cases. Among the recreational users, 38.8% used Cannabis sativa with a history of epilepsy, and 68.4% of them were taking antiepileptics. In total, 67.7% of individuals had at least one risk factor for seizures, i.e., 31.0% among medical users and 78.6% among recreational users. The main risk factors with medical use were inefficacy of CBD (17.2%), fatigue (13.8%) and concomitant epileptogenic medications (10.3%). The main risk with recreational use was concomitant epileptogenic medications (39.8%), consumption of illicit drugs (33.7%) and alcohol (32.7%). This analysis demonstrates the importance of alerting cannabinoid users, particularly recreational cannabis users and those with a history of epilepsy, about seizure-associated risks. Moreover, educational information should be provided together with the prescription of licensed cannabinoids and medical cannabis.

The changing landscape of cannabis use: impact on maternal health and neonatal outcomes

2025-06-20

Parvathy Krishnan , Elizabeth Yen | Pediatric Research

<em>In vitro</em> Cannabis Exposures of Lung Epithelial Cells at the Air-Liquid Interface

2025-06-20

Emily T. Wilson , Laila Husna Zahratul Muna , Percival J. Graham +4 more | Journal of Visualized Experiments

Prevention of Allodynia and Hyperalgesia by Cannabidiol in a Rat Model of Chemotherapy-Induced Peripheral Neuropathy

2025-06-20

Michael Ippolito , C. Maddox , Amal Inam +2 more | Journal of Visualized Experiments

Evaluation of the causal impact of recreational marijuana legalisation on traffic safety in the US

2025-06-20

Anupriya , Emma J. McCoy , Daniel J. Graham | Accident Analysis & Prevention

Since the legalisation of recreational marijuana in certain US states, traffic fatalities involving drivers testing positive for marijuana have markedly increased, thereby prompting the need to understand how this policy … Since the legalisation of recreational marijuana in certain US states, traffic fatalities involving drivers testing positive for marijuana have markedly increased, thereby prompting the need to understand how this policy change affects road safety. While marijuana is well-known to impair driving, determining if its recreational use directly causes more traffic fatalities remains contentious due to challenges in roadside impairment testing. Additional challenges arise because (i) Simulations may not accurately replicate driver impairment and road conditions, (ii) Estimation based on observational data must adjust for (unobserved) confounding factors, requiring an innovative model to generate causal inference, and (iii) The dynamic, evolving nature of the process requires capturing temporal relationships. This paper contributes by employing a rigorous study design based on an augmented synthetic control method to assess the causal impact of recreational marijuana legalisation on traffic fatalities. It identifies a consistent but lagged pattern of increased fatality rates in several states post-legalisation, with the effect primarily linked to the drug's retail availability. These findings disprove any prevailing conjectures that dismiss the link between recreational marijuana use and fatal traffic crashes, highlighting the need for informed policy responses.

Pharmacokinetics of Cannabidiol in Rat Brain Tissue After Single-Dose Administration of Different Formulations

2025-06-20

Zuzana Binova , František Beneš , Marie Zlechovcova +5 more | Molecules

Cannabidiol (CBD), a phytocannabinoid commonly isolated from chemotype III Cannabis sativa plants, is known for its therapeutic potential. However, comprehensive information on its bioavailability is still lacking. The key objective … Cannabidiol (CBD), a phytocannabinoid commonly isolated from chemotype III Cannabis sativa plants, is known for its therapeutic potential. However, comprehensive information on its bioavailability is still lacking. The key objective of this study was to investigate the impact of specific formulations on CBD delivery to the site of action and, in particular, the brain of experimental animals. As brain tissue is an extremely complex matrix, a highly sensitive method employing liquid chromatography–tandem mass spectrometry (LC-MS/MS) had to be implemented. To make it applicable for multiple analytes, the method was validated for 17 other phytocannabinoids and selected metabolites. Using this method, a pharmacokinetic study was conducted on 200 brain samples collected from rats that had been administered various CBD formulations (carriers) via oral gavage. The peak concentration in brain occurred within 1–2 h; notably, the highest was reached with carriers containing triacylglycerols with the shortest fatty acid chains (caprylic/capric). In addition to the parent compound, 7-hydroxy-cannabidiol and 7-carboxy-cannabidiol were detected, confirming rapid post-administration metabolism. Overall, this research enhances understanding of CBD distribution in the brain and underscores the impact of specific formulations on its bioavailability, offering insights into optimizing CBD-based therapies to be both effective and ‘patient-friendly’.

Identification of Cannabigerol-Derived Dual CB<sub>2</sub> Receptor Agonists and TRPM8 Antagonists with Anti-Inflammatory and Analgesic Activities

2025-06-20

Wenjiao Yang , Haiguo Sun , Jing Ji +7 more | Journal of Medicinal Chemistry

Emerging evidence suggests that compounds possessing both CB2 receptor (CB2R) agonist and TRPM8 antagonist activities may offer effective pain relief while minimizing the severe side effects commonly associated with current … Emerging evidence suggests that compounds possessing both CB2 receptor (CB2R) agonist and TRPM8 antagonist activities may offer effective pain relief while minimizing the severe side effects commonly associated with current analgesics. In this study, we designed and synthesized a series of novel cannabigerol (CBG) derivatives with the goal of identifying potent dual ligands that act as both CB2R agonists and TRPM8 antagonists. Structure-activity relationship studies revealed that the introduction of an amide group at the C-2 position or alkylation at the C-3 position of CBG is essential for enhancing CB2R agonistic and TRPM8 antagonistic activities. CBG amides 2a and 6b exhibited dual activity as CB2R agonists and TRPM8 antagonists, displaying notable anti-inflammatory and analgesic efficacy alongside a favorable safety profile. Notably, compound 8b, a prodrug of 6b, demonstrated improved oral plasma exposure and enhanced analgesic effects in mice.

Cannabis and Liver Transplant: We Need to Chill, Man

2025-06-20

Alexandra Shingina , Seth A. Waits | Liver Transplantation

Exploring the Potential of Phytocannabinoids Against Multidrug-Resistant Bacteria

2025-06-20

Carmina Sirignano , Simona De Vita , Ernesto Gargiulo +7 more | Plants

The rapid emergence of multidrug-resistant (MDR) bacterial pathogens poses a critical threat to global health, creating an urgent need for novel antimicrobial agents. In this study, we evaluated a small … The rapid emergence of multidrug-resistant (MDR) bacterial pathogens poses a critical threat to global health, creating an urgent need for novel antimicrobial agents. In this study, we evaluated a small library of natural and semisynthetic phytocannabinoids against a broad panel of MDR Gram-positive bacterial strains, evidencing very good activity in the low µM range. We provide evidence of the antibacterial activity of the two separated enantiomers of cannabidiol, offering novel insights into the stereochemical aspects of their bioactivity. To investigate the possible molecular targets and clarify the mechanism of action, we employed Inverse Virtual Screening (IVS), a computational approach optimized for predicting potential protein–ligand interactions, on three selected MDR bacterial species. Interestingly, key targets belonging to important bacterial metabolic pathways and defense mechanisms were retrieved, and the results were used to rationalize the observed biological activities. To the best of our knowledge, this study marks the first application of IVS to microorganisms, offering a novel strategy for identifying bacterial protein targets. The results pave the way for future experimental validation, structure-based drug design, and the development of novel antibacterial agents.

Age-specific effects of synthetic cannabinoids on cognitive function and hippocampal gene expression in mice: insights from behavioral and molecular correlates

2025-06-20

Kaixi Li , Yuanyuan Chen , Y. P. Xu +7 more | Frontiers in Pharmacology

The increasing use of Synthetic cannabinoids (SCs) in adolescents and young adults poses significant medical and psychiatric risks, and previous reports have been dominated by single-age animal studies. Here, we … The increasing use of Synthetic cannabinoids (SCs) in adolescents and young adults poses significant medical and psychiatric risks, and previous reports have been dominated by single-age animal studies. Here, we first investigated the effects of a single exposure of the fourth-generation synthetic cannabinoid 4F-ABUTINACA on cognitive behaviors in adolescent (PND 28–35 days) and adult (PND 49–56 days) male mice in an animal model, followed by an age-specific systematic study by conducting a whole-gene transcriptomics study of hippocampal tissue in the brain. Behavioral results showed that 4F-ABUTINACA impaired recognition memory, fear memory extraction, and spatial navigation memory in adolescent mice, as well as spatial navigation memory in adult mice. The transcriptomics results revealed different alterations in age-enriched signaling pathways affected by 4F-ABUTINACA, such as Alzheimer’s disease, Parkinson’s disease, and neurodegenerative diseases. In addition, 4F-ABUTINACA causes selective downregulation of transcription of genes involved in stress response and mitochondrial expression in adolescent mice, whereas no significant differences were observed in adult mice. This study provides an innovative resource on the behavioral and molecular landscape of age-specific changes in cognitive function by synthetic cannabinoids and offers new opportunities for follow-up studies to target age-specific functional significance and related molecular mechanisms to be mined.

A Thematic Text Analysis of Cannabis Edibles Brand Names

2025-06-20

Beth A. Reboussin , Shelby Lake , E. Alfonso Romero‐Sandoval +7 more | Cannabis and Cannabinoid Research

Introduction: This study explores whether the cannabis edibles industry uses brand names that might impact consumer appeal and harm perceptions. Materials and Methods: An exploratory thematic text analysis of brand … Introduction: This study explores whether the cannabis edibles industry uses brand names that might impact consumer appeal and harm perceptions. Materials and Methods: An exploratory thematic text analysis of brand names for 1344 cannabis edible products from 250 brands advertised online between June and November 2022 was performed. Brands marketing only delta-9-tetrahydrocannabinol (THC) products (n = 80), THC and cannabidiol (CBD) products (n = 130), and only CBD products (n = 40) were compared. Results: Five core themes emerged: cannabis culture (42% of brands, n = 106), product characteristics (30%, n = 76), medicine and health (23%, n = 58), environment and nature (20%, n = 51), and identity and culture (14%, n = 34), with 15 subthemes. Brands only marketing CBD products more often had names with medicine and health (45%, n = 18) themes with subthemes of health and wellness (30%, n = 12) and expected effects (18%, n = 7) in contrast to brands marketing THC products (18%, n = 14; 2%, n = 2; 11%, n = 9 THC-only; 20%, n = 26; 5%, n = 6; 13%, n = 17 THC and CBD). Brands marketing THC products more often had names with cannabis (12%, n = 10 THC-only; 18%, n = 23 THC and CBD; 8%, n = 3 CBD-only) and spiritual/mystical (9%, n = 7 THC-only; 9%, n = 12, THC and CBD; 0%, CBD-only) subthemes. Food type subthemes were also more common among brands marketing THC products (19%, n = 15 THC-only; 21%, n = 27 THC and CBD; 8%, n = 3 CBD-only). Unconventionality (6%, n = 5 THC-only; 2%, n = 2 THC and CBD; 0% CBD-only) and names and places (16%, n = 13 THC-only; 5%, n = 8 THC & CBD; 5%, n = 2 CBD-only) were subthemes more common among brands only marketing THC products. Conclusions: This study identified distinct cannabis edibles brand name marketing strategies for THC versus CBD products that may affect consumer appeal and perceptions of harm, underscoring the need to monitor and potentially regulate cannabis edibles marketing to ensure that it does not mislead consumers or downplay potential risks.

Aplicaciones terapéuticas de Cannabis sativa en neuropatías: Revisión sistemática en América Latina

2025-06-19

E. Sierra , Luis García De Diego López , E. Maldonado +4 more | Portal de la Ciencia

Este artículo presenta una revisión sistemática de la literatura sobre las aplicaciones terapéuticas de Cannabis sativa en el tratamiento del dolor neuropático en América Latina, con énfasis en neuropatías diabéticas … Este artículo presenta una revisión sistemática de la literatura sobre las aplicaciones terapéuticas de Cannabis sativa en el tratamiento del dolor neuropático en América Latina, con énfasis en neuropatías diabéticas y neuralgia postherpética. Los cannabinoides, especialmente tetrahidrocannabinol (THC) y cannabidiol (CBD), actúan en el sistema endocannabinoide, modulando procesos inflamatorios y nociceptivos, lo que les confiere propiedades analgésicas relevantes. Diversos estudios reportan que estos compuestos reducen significativamente el dolor, sobre todo en pacientes con condiciones resistentes a tratamientos convencionales. Sin embargo, los efectos varían según la dosis y la vía de administración, lo que evidencia la necesidad de un enfoque estandarizado para optimizar su uso. A pesar de sus beneficios, el consumo de C. sativa también se asocia con efectos adversos como somnolencia, mareos, alteraciones cognitivas y pérdida de coordinación motora, especialmente en dosis elevadas. Estos efectos pueden intensificarse con el uso prolongado y representar un riesgo en pacientes con enfermedades preexistentes. Por ello, es esencial ajustar la dosificación y monitorizar a los pacientes para prevenir complicaciones como la sedación excesiva y la ataxia. En cuanto a la regulación en la región, los países enfrentan desafíos significativos debido a disparidades legales, culturales y sociales. Uruguay ha adoptado un modelo regulatorio integral, mientras que otros países, como Colombia y México, enfrentan obstáculos relacionados con la legalidad del consumo, la producción y el narcotráfico. La falta de consenso sobre el autocultivo, el comercio y el uso medicinal crea vacíos legales que dificultan la implementación efectiva de políticas públicas. La metodología del estudio se basó en el modelo PRISMA, con un enfoque deductivo. En conclusión, aunque C. sativa muestra un potencial terapéutico prometedor en el tratamiento del dolor neuropático, su uso en América Latina está limitado por la escasez de estudios clínicos estandarizados y por barreras regulatorias. Es indispensable profundizar la investigación para establecer dosis óptimas y pautas claras que permitan su integración segura en la práctica médica convencional.

Land of the Free, Home of the Blazed: Legalized Recreational Cannabis Among Undergraduate College Students

2025-06-19

Pietro A. Sasso , Shelley Price-Williams | Innovative Higher Education

Abstract Within the United States, attitudes toward cannabis consumption, especially among college students, have grown increasingly positive. Parallel to this trend, various additional social, cultural, and legal shifts have continued … Abstract Within the United States, attitudes toward cannabis consumption, especially among college students, have grown increasingly positive. Parallel to this trend, various additional social, cultural, and legal shifts have continued to occur in support of open cannabis consumption, though not without potential consequences. This phenomenological qualitative study explored undergraduate college students’ ( n = 22) a priori experiences with cannabis use in states with legalized recreational cannabis. Findings in this study suggested a general lack of knowledge regarding cannabis consumption within the surrounding legal framework but a desire to practice safe consumption and receive a more meaningful education. Recommendations for practice included the need for higher education institutions to increase education on safe practices and challenge stigma and misperceptions surrounding cannabis.

Early Detection of Sex and Cannabinoid Chemotypes in Cannabis sativa: SCAR Marker Validation in Indigenous Indian Germplasm

2025-06-19

Yash Pandey , Trishna Chaturvedi , Nivedita Singh +3 more | Biochemical Genetics

Hypothermia drives fatty acid transporter 1 upregulation and lipid accumulation in renal tubules: evidence from forensic cases

2025-06-19

Kie Horioka , Hiroki Tanaka , Akira Hayakawa +4 more | International Journal of Legal Medicine

Cannabis tolerance reduces symptom relief

2025-06-19

Sarah S. Stith , Xiaoxue Li , Franco Brockelman +3 more | Frontiers in Pharmacology

Objectives We measure for the first time how tolerance from repeated consumption of medical cannabis affects acute symptom management. Methods Using the Releaf App, medical cannabis patients recorded their symptoms, … Objectives We measure for the first time how tolerance from repeated consumption of medical cannabis affects acute symptom management. Methods Using the Releaf App, medical cannabis patients recorded their symptoms, product type, cannabis consumption method, major cannabinoid levels, dosing patterns, and real-time symptom intensity levels prior to and following each cannabis administration session, as well as any side effects from usage. The sample consists of the first ten cannabis self-administration sessions recorded by 16,395 medical cannabis patients between 06/05/2016 and 09/19/22, yielding a sample of 120,691 symptom-specific treatment-level observations, recorded during 42,005 sessions. This study uses fixed effects least-squares regression analyses to analyze the effects of the session count on symptom relief. Results On average, people experienced a 0.5% decrease in symptom relief with each subsequent session (p &lt; 0.001). Combustible products offered more therapeutic relief than vaping, eating or drinking; higher doses offered greater relief; and the reduction in symptom relief with subsequent usage was similar whether patients were treating pain, depression, or anxiety. Cannabis products’ THC levels were positively associated with symptom relief; however, patients showed no changes in the THC levels of products with subsequent consumption. Patients increased the dose consumed as they completed more sessions. The results are robust to alternative treatment measures, including days since the first session was recorded. Subsample regressions indicate that experienced users drive most of the effects. Analyses assessing side effects show that factors, such as THC and dose, that increased symptom relief also increased side effects experienced. Conclusion and implications The findings suggest the majority of patients experience decreased symptom relief after repeated use of medical cannabis, counterbalanced by improvements in negative side effects. Of direct clinical relevance, THC levels and the dose can be adjusted to customize medical cannabis patient treatment, increase medication compliance, and improve treatment outcomes.

Development and validation of the Comprehensive Cannabis Motives Questionnaire (CCMQ)

2025-06-19

John A. Moffitt , Carl Roberts , Paul Christiansen | Journal of Psychopharmacology

Background: Existing scales that measure cannabis use motives have failed to incorporate the full range of motives that underpin cannabis consumption, especially with the increased use of medical cannabis. The … Background: Existing scales that measure cannabis use motives have failed to incorporate the full range of motives that underpin cannabis consumption, especially with the increased use of medical cannabis. The current research aimed to develop a novel, psychometrically robust scale that comprehensively measures cannabis use motives. Here, we report the development and validation of the Comprehensive Cannabis Motives Questionnaire (CCMQ). Method: Cannabis users completed a 45-item questionnaire measuring a range of cannabis use motives. A UK English-speaking sample ( n = 450) provided data for exploratory factor analysis. A second UK English-speaking sample ( n = 200) was used for confirmatory factor analysis. Test–retest reliability was based on a third English-speaking sample ( n = 45) who completed the revised, 41-item CCMQ twice across 2 weeks. A US-based sample ( N = 216) was used to test measurement invariance of the scale across countries. Results: Exploratory and subsequent confirmatory factor analysis provided an eight-factor solution. The eight factors were food, medicinal, sleep, social, high, coping, conformity and creative. All the factors had good to excellent internal reliability with McDonald’s ω ranging between 0.85 and 0.97. Test–retest reliability was obtained for the revised 41-item questionnaire (Intraclass correlation’s 0.5+ for Total Cannabinoid Eating Experience Questionnaire and each subscale). The eight factors were correlated with Cannabis Use Disorder Identification Test – Revised to assess relationships with problematic use. Finally, strict measurement invariance was achieved in comparisons between males and females and a UK sample against a US sample. Conclusion: The CCMQ provided a valid, reliable assessment of the motivations that underlie cannabis use.

Assisted Extraction of Hemp Oil and Its Application to Design Functional Gluten-Free Bakery Foods

2025-06-19

Noemi Baldino , Mario F. O. Paleologo , Mariateresa Chiodo +3 more | Molecules

Cannabis sativa L. is known for its high-value compounds, like Cannabidiol (CBD) and Cannabidiolic Acid (CBDA). It is widely used in the pharmaceutical and food industries. Different extraction methods, like … Cannabis sativa L. is known for its high-value compounds, like Cannabidiol (CBD) and Cannabidiolic Acid (CBDA). It is widely used in the pharmaceutical and food industries. Different extraction methods, like Soxhlet and maceration, are commonly employed to obtain its extracts. High temperature and long extraction time can influence the yield and the purity of the extracts, affecting the quality of the final product. This study focused on optimizing CBD oil extraction from hemp inflorescences and its incorporation into a gluten-free bakery product for functionalization. Dynamic maceration (DME), assisted by ultrasound and microwave irradiation, was used. Our study explored the impact of varying sonication times (three distinct durations) and microwave powers (three levels, applied for two different irradiation times) on the resulting extracts. HPLC analysis was performed on these extracts. Subsequently, we used hemp flour and hemp oil to bake gluten-free cupcakes, which were fortified with the extracted CBD oil. Rheological characterization was used to investigate the cupcake properties, along with stereoscopic, color and puncture analysis performed on the baked samples. The most effective extraction parameters identified were 30 s of microwave irradiation at 700 W, yielding 45.2 ± 2.0 g of CBD extract, and 15 min of sonication, which resulted in 53.2 ± 2.5 g. Subsequent rheological characterization indicated that the product exhibited mechanical properties and a temperature profile comparable to a benchmark, evidenced by a height of 4.1 ± 0.2 cm and a hardness of 1.9 ± 0.2 N. These promising values demonstrate that hemp oil and hemp flour are viable ingredients for traditional cakes and desserts, notably contributing increased nutritional value through the CBD-enriched hemp oil and the beneficial profile of hemp flour.

Discovery of reversible monoacylglycerol lipase (MAGL) inhibitors based on ortho-hydroxyanilide scaffold

2025-06-19

Giulia Bononi , Francesca Gado , Samuele Masoni +7 more | Bioorganic Chemistry

Age–period–cohort analysis of past 12‐month cannabis use in Germany (1995–2021)

2025-06-19

Natalie S. Schöllner , Adrian Glos , Justin Möckl +3 more | Addiction

Abstract Background and Aims In 2024, cannabis was partially legalized for recreational purposes in Germany. With a growing prevalence of persons who used cannabis in the past 12 months, and … Abstract Background and Aims In 2024, cannabis was partially legalized for recreational purposes in Germany. With a growing prevalence of persons who used cannabis in the past 12 months, and the health risks associated with cannabis use, it is imperative to examine usage behavior patterns in greater detail. The present analysis measured the impact of age, time period and birth cohort on the prevalence of cannabis consumption in the past 12 months in Germany. Design Longitudinal study using data from 10 waves (1995–2021) of the German Epidemiological Survey of Substance Abuse (ESA), a cross‐sectional nationally representative household survey of individuals between the ages of 18 and 59 or 64 years. Setting Germany. Participants N total = 78 678 German‐speaking adults between the ages of 18 and 59 years. Measurements Self‐report of cannabis use in the last 12 months as well as alcohol use and smoking conventional tobacco products in the last 30 days. Findings We employed binary logistic regression using a generalized additive model to examine age, period and cohort effects, as well as covariate effects on past 12‐month cannabis use. Over time, both period and cohort had an increasing effect, while an increase in age corresponded to a decrease in prevalence. Specifically, the odds ratio (OR) for cannabis use decreased from 9.44 [95% confidence interval (CI) = 8.17−10.9] at age 18 years to 0.13 (95 CI = 0.10−0.17) at age 59 years. Period effects also showed an increase, with the OR rising from 0.33 (95% CI = 0.26−0.43) in 1995 to 2.96 (95% CI = 2.55−3.43) in 2021, while cohort effects increased from 0.02 (95% CI = 0.001−0.05) for those born in 1936 to 16.69 (95% CI = 13.8−20.8) for those born in 2002. Additionally, persons using cannabis had a higher likelihood of also drinking alcohol and smoking conventional tobacco products in the last 30 days. Conclusions In Germany, the odds of being a past‐12‐month cannabis consumer appears to decline with increasing age, indicating that only a small proportion of consumers engage in cannabis use throughout their whole lives, with a peak prevalence occurring at a younger age.

Cannabidiol (CBD) as a potential therapeutic agent for liver cancer: a comprehensive review of current evidence

2025-06-18

Mojtaba Esmaeli , Maryam Dehghanpour Dehabadi | Cancer Cell International

Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality with limited treatment options. Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has shown anticancer properties. This review analyzes CBD's … Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality with limited treatment options. Cannabidiol (CBD), a non-psychoactive compound from Cannabis sativa, has shown anticancer properties. This review analyzes CBD's therapeutic potential in HCC, focusing on mechanisms, preclinical/clinical findings, and integration into treatment strategies. A systematic search (PubMed, Scopus, Web of Science, Google Scholar) up to March 2025 identified 16 relevant studies (in vitro, in vivo, clinical). CBD exerts antitumor effects via multiple pathways, including apoptosis, autophagy regulation, metastasis suppression, and tumor microenvironment modulation. CBD interacts with the endocannabinoid system (ECS), inhibits oncogenic signaling (PI3K/AKT/mTOR), and enhances chemotherapeutic efficacy (sorafenib, cabozantinib). Studies show CBD induces pyroptosis via caspase-3/GSDME, and modulates autophagy by inhibiting the PI3K/Akt/mTOR pathway. It also sensitizes HCC cells to sorafenib and cabozantinib. Preclinical results are promising, but clinical studies are limited. Challenges like bioavailability and potential hepatotoxicity require investigation. Future research should optimize formulations, determine dosing, and conduct clinical trials to validate CBD's efficacy/safety in HCC patients. Validated CBD could offer an innovative HCC management option.

Cannabis and Synthetic Cannabinoids Are Used for Different Reasons: Comparing Functional Motives of Use Based on the European Web Survey on Drugs

2025-06-18

Anna Péterfi , Róbert Urbán , João Matias +1 more | International Journal of Mental Health and Addiction

Interactions Between Iron Metabolism and the Endocannabinoid System in Bacterial Infections

2025-06-18

Kayle Dickson , Juan Zhou , Christine Lehmann | Antibiotics

Iron is a key nutritional requirement for a variety of physiological functions, and its metabolism is tightly controlled under homeostatic conditions. The endocannabinoid system (ECS) represents an additional physiological system … Iron is a key nutritional requirement for a variety of physiological functions, and its metabolism is tightly controlled under homeostatic conditions. The endocannabinoid system (ECS) represents an additional physiological system with a key role in maintaining homeostasis that is known for its role in modulating immune responses. Recent research has highlighted intriguing interactions between these systems, including the suppression of iron uptake by the ECS and alterations to the iron-catalyzed Fenton reaction. These interactions are particularly interesting in the context of bacterial infections. As iron is a vital nutrient for bacteria, modulating iron levels using the ECS may be able to control bacterial growth. This review aims to explore the current understanding of how the ECS affects iron homeostasis and its implications for bacterial pathogenesis. In this study, we provide an overview of both iron metabolism and the ECS, focusing on harnessing these systems to develop novel therapeutic strategies to modulate iron metabolism in bacterial infections. By elucidating these complex interactions, we hope to provide new insights into the development of novel treatments for bacterial infections.