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Very low doses of Δ8-THC increase food consumption and alter neurotransmitter levels following weight loss
Abstract
We have investigated the effect of 0.001 mg/kg delta(8)-tetrahydrocannabinol (THC) on food consumption, cognitive function, and neurotransmitters in mice. Sabra mice were treated with vehicle, THC, or THC+CB1 antagonist (SR141716A). The mice were fed for 2.5 h a day for 9 or 50 days. In the 9-day schedule, THC-treated mice showed a 16% increase in food intake compared with controls (P<.001). This effect was reversed by the antagonist (P<.01). In the long-term schedule a 22% increase in intake (P<.05) was recorded. During the course of the 9- and 50-day experimental protocol, all mice lost about 20% and 10% of their original weight, respectively, to reach approximately the same weights, which were not significantly different between the different treatment groups. In addition, THC caused an increase in activity (P<.05). Cognitive function showed a tendency to improve (P<.06) in the THC-treated mice, which was reversed by the antagonist for Days 4 and 5 of the maze (P<.01, and P<.05, respectively). Significant decreases in dopamine and serotonin (5-HT) levels were found both in the hypothalamus (P<.01) and the hippocampus (P<.01, P<.05), respectively, while norepinephrine (NE) levels showed tendency to increase in both the hypothalamus and hippocampus. Delta(8)-THC increased food intake significantly more (P<.05) than did delta(9)-THC, while performance and activity were similar. Thus, delta(8)-THC (0.001 mg/kg) caused increased food consumption and tendency to improve cognitive function, without cannabimimetic side effects. Hence, a low dose of THC might be a potential therapeutic agent in the treatment of weight disorders.
... [40] Interestingly, when assessing very low doses in mice, Avraham et al. found noradrenaline was elevated while serotonin (5HT) and dopamine were decreased in the mouse brain. [42] The authors suggest that variability in dose and cannabinoid may cause changes in the effect on extrapyramidal dopaminergic system activity. [42] Mechanism of changes in food intake may be correlated with changes in 5HT activity; however, Darmani confounds the true effect of changes in presynaptic serotonin modulation by noting a change in post-synaptic serotonergic activity from a decrease in 5HT2A receptor-mediated behavioural activity. ...
... [42] The authors suggest that variability in dose and cannabinoid may cause changes in the effect on extrapyramidal dopaminergic system activity. [42] Mechanism of changes in food intake may be correlated with changes in 5HT activity; however, Darmani confounds the true effect of changes in presynaptic serotonin modulation by noting a change in post-synaptic serotonergic activity from a decrease in 5HT2A receptor-mediated behavioural activity. [42,43] Since many of the previously noted changes can parallel a stress response, Maclean et al. explored changes in behaviour and catecholamine metabolism with exposure to novel and normal environments. ...
... [42] Mechanism of changes in food intake may be correlated with changes in 5HT activity; however, Darmani confounds the true effect of changes in presynaptic serotonin modulation by noting a change in post-synaptic serotonergic activity from a decrease in 5HT2A receptor-mediated behavioural activity. [42,43] Since many of the previously noted changes can parallel a stress response, Maclean et al. explored changes in behaviour and catecholamine metabolism with exposure to novel and normal environments. [44] Under normal conditions (acclimated environment), rats experienced mildly increased noradrenaline synthesis, no changes in dopamine metabolism and minimal behavioural changes upon IP delta-8-THC administration. ...
Objective
Delta-8-tetrahydrocannabinol (THC) is a minor psychoactive phytocannabinoid, similar to delta-9-tetrahydrocannabinol. Recent statements released by the Food and Drug Administration and Center for Disease Control reported around 660 delta-8-THC exposure cases. With the rise in commercially available products, it is crucial to understand the pharmacological and toxicological properties of this compound. The objective of this review is to summarize current literature regarding the pharmacokinetic and pharmacologic properties of delta-8-THC.
Methodology
Searches were performed in MEDLINE (Ovid), Scopus, Web of Science Core Collection and Cochrane Central Register of Controlled Trials (CENTRAL). The searches used database-specific advanced search techniques.
Key findings
A total of 772 references were retrieved, with 517 references identified after the removal of duplicate articles. The references were imported into Rayyan (Rayyan.ai), and the retrieved articles (100) were reviewed and summarized. The scoping review is divided into sections focussing on the pharmacokinetic (12) and pharmacologic (88) properties of delta-8-THC. The majority of pharmacological studies examined the central nervous system effects of delta-8-THC. The findings suggest that it exhibits distinct pharmacological effects, and while its psychoactive profile may be milder compared to delta-9-THC, caution should still be exercised when considering its use. Pharmacologic effects often express a dose-dependent relationship with the potential for tolerance development.
Conclusions
In conclusion, this review provides a comprehensive examination of the current state of knowledge of delta-8-THC. Moreover, the review highlights several gaps in the existing literature, emphasizing the need for further research to fully elucidate the mechanisms of action, long-term effects and potential interactions with other drugs.
... There remains a need for effective and sustainable treatment for AN (Steinhausen, 2002b) [22]. Several animal models have been developed to investigate AN, including diet restriction (DR), activity wheel, and separation stress [3] [6] [18] [2]. Clearly, no single animal model is a true replica of the human disease, but the various assays are useful for focusing on different aspects of this condition. ...
... In addition, it affects AMPK (Adenosine Monophosphate kinase) [12]. Restoration of these systems by administration of tyrosine or cannabinoids or omega 3 fatty acids may have therapeutic potential [3] [2,9]. Insulin is one of the most powerful anabolic hormones. ...
... In addition, it affects AMPK(Adenosine Monophosphate kinase) [12]. Restoration of these systems by administration of tyrosine or cannabinoids or omega 3 fatty acids or insulin may have therapeutic potential [3] [2]. ...
Introduction
: Anorexia nervosa is a psycho-socio-biological disease, characterized by self-starvation and distorted perception of body weight. Patients often over-exercise. Insulin is an anabolic hormone that increases food intake and restores body fat and is present in low levels in anorexia nervosa patients: thus may have therapeutic potential in treating anorexia nervosa.
Aims
: to explore whether low levels insulin administration may result in recovery of cerebral function and restoration of metabolic disorder providing a treatment option for anorexia nervosa.
Methods
: Female Sabra mice maintained on DR of 2.0 hours per day for 32 days, in cages with or without wheel attached to an electronic counter (activity wheel). They were then permitted to eat ad libitum for additional 15 days. On the second week, mice were injected ip with 0.5U/kg long acting Insulin(Lantus) or saline and cognitive function was evaluated. Insulin administered three times a week during days 8-32. Mice euthanized on day 48 and cerebral levels of monoamines, 2-AG and expression of genes associated with metabolic status were evaluated.
Results
: Activity wheel mice decreased body weight, 2-AG, dopamine levels and 5-HT1A and increased Camkk2 and SIRT1 gene expression compared to mice without it. Insulin increased body weight, decreased revolutions, enhanced NPY and normalized Camkk2, SIRT-1, BDNF, elevated 2-AG and improved cognition in the wheel group.
Conclusion
: low dose insulin administration to animal model of anorexia associated with exercise, led to alterations and normalization in brain metabolic status and improved cognition. Insulin should be further explored as potential novel treatment for anorexia nervosa.
... weight loss might affect brain function may assist in better understanding the etiology and lead to the development of new therapeutic strategies. In order to accomplish it we have developed three experimental animal models of AN which represent different aspects of the disorder: diet restriction, activity wheel and separation stress (7)(8)(9). ...
... The plant Cannabis sativa and its active ingredient, Δ 9 -tetrahydrocannabinol (Δ 9 -THC) are known appetite stimulators (8,9). Following the discovery of the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG) (amide and ester of the essential fatty acid arachidonic acid respectively that bind to the cannabinoid receptors), we tested their effects on appetite in these mice models (10,11). ...
... A decrease in dopamine and 5-HT and increase in NE were observed without any addictive effects. SR 141716A reversed these effects (8). AN is also characterized by anhedonia whereby patients experience little pleasure or reward. ...
Background:
Δ9-Tetrahydrocannabinol (Δ9-THC) is the active compound of Cannabis sativa with appetitestimulating properties. This study evaluated the effect of low doses of oral Δ9-THC on self-reported symptoms of patients suffering from chronic anorexia nervosa (AN).
Methods:
Nine female subjects over 18 years of age participated in the study. Six were diagnosed according to DSM-IV criteria with AN restrictive type and three with active AN binge-purge type. Their mean age was 45.0±3.2 years and their BMI was 16.1±1.6 kg/M2. They completed questionnaires before and after treatment with Δ9-THC (1 mg/day for one week and 2 mg/day for three weeks). The primary outcome was improvement in the way patients perceived their eating behavior.
Results:
Significant improvements were found in selfreported body care, sense of ineffectiveness, asceticism and depression. There were no significant changes in BMI.
Conclusions:
Δ9-THC may be an effective component in treating the psychological symptoms of AN.
... Research which has been done thus far in the area has been performed in rats, and the levels of 2-AG involved were relatively high and produced cannabinomimetic side effects. Our goals were to investigate the effects of very low doses (0.001 mg/kg) of 2-AG, which do not produce cannabinomimetic side effects (Sulcova et al., 1998) on cognitive function and food consumption, which were improved following administration of low doses (0.001mg/kg i.p.) of the cannabinoids ANA, THC and noladin and fish oil in diet-restricted mice (Hao et al., 2000) (Avraham et al., , 2004) (Avraham et al., 2011). Food consumption was also shown to be increased by low dose of 2-AG in rats (Kirkham et al., 2002). ...
... Searching for mechanisms downstream to the CB 1 receptor, which may account for the increased food consumption, and since low dose cannabinoids were shown to affect catecholamines in the hypothalamus, which are related to feeding behavior (Hao et al., 2000) (Avraham et al., , 2004, we measured catecholamine levels in the hypothalamus. However, these were not found to change significantly (only a trend of increased NE was noticed). ...
... This improvement was reversed by SR141716A. Experiments with other cannabinoids showed the same results: 0.001mg/kg ANA improved the cognitive performance of mice on diet restriction (Hao et al., 2000), as did 0.001mg/kg THC (Avraham et al., 2004) . ...
We have investigated the effects of 0.001mg/kg 2-arachidonoylglycerol (2-AG) administered in combination with compounds present in the body alongside 2-AG like 2-palmitoylglycerol and 2-linoleylglycerol (also termed “entourage”), on cognitive function,food intake, and neurotransmitter levels in the hippocampus and hypothalamus of mice under diet restriction. Young female Sabra mice were treated with vehicle, 2-AG, 2-AG + entourage, 2-AG + entourage + 5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)- 4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide (SR141716A, a CB1 antagonist) and SR141716A. The mice were fed for 2.5h a day for 14 days. Cognitive function was evaluated by the eight arm maze test, and neurotransmitter (norepinephrine, dopamine, L-DOPA and serotonin) levels were measured in the hippocampus and hypothalamus by high-performance liquid chromatography-electrochemical detection. Food intake was increased by 2-AG and, to an even greater extent, by 2-AG + entourage. SR141716A reversed the effect of 2-AG + entourage. The administration of 2-AG + entourage improved cognitive function compared to the vehicle mice, and this improvement was blocked by SR141716A. 2-AG + entourage-treated mice showed an increase in norepinephrine (NE), dopamine and L-DOPA levels in the hippocampus. SR141716A normalized NE and L-DOPA levels. There were no significant changes in hypothalamic neurotransmitter levels. The use of very low doses of the endocannabinoid 2-AG + entourage can improve cognitive function by elevating norepinephrine and L-DOPA levels in the hippocampus, without cannabinomimetic side effects. These findings may have implications for cognitive enhancement in anorexia nervosa.
... Research which has been done thus far in the area has been performed in rats, and the levels of 2-AG involved were relatively high and produced cannabinomimetic side effects. Our goals were to investigate the effects of very low doses (0.001 mg/kg) of 2-AG, which do not produce cannabinomimetic side effects (Sulcova et al., 1998) on cognitive function and food consumption, which were improved following administration of low doses (0.001mg/kg i.p.) of the cannabinoids ANA, THC and noladin and fish oil in diet-restricted mice (Hao et al., 2000) (Avraham et al., , 2004) (Avraham et al., 2011). Food consumption was also shown to be increased by low dose of 2-AG in rats (Kirkham et al., 2002). ...
... Searching for mechanisms downstream to the CB 1 receptor, which may account for the increased food consumption, and since low dose cannabinoids were shown to affect catecholamines in the hypothalamus, which are related to feeding behavior (Hao et al., 2000) (Avraham et al., , 2004, we measured catecholamine levels in the hypothalamus. However, these were not found to change significantly (only a trend of increased NE was noticed). ...
... This improvement was reversed by SR141716A. Experiments with other cannabinoids showed the same results: 0.001mg/kg ANA improved the cognitive performance of mice on diet restriction (Hao et al., 2000), as did 0.001mg/kg THC (Avraham et al., 2004) . ...
Aberrant accumulation and self-assembly of α-synuclein are tightly linked to several neurodegenerative diseases called synucleinopathies, including idiopathic Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy. Deposition of fibrillar α-synuclein as insoluble inclusions in affected brain cells is a pathological hallmark of synucleinopathies. However, water-soluble α-synuclein oligomers may be the actual culprits causing neuronal dysfunction and degeneration in synucleinopathies. Accordingly, therapeutic approaches targeting the toxic α-synuclein assemblies are attractive for these incurable disorders. The "molecular tweezer" CLR01 selectively remodels abnormal protein self-assembly through reversible binding to Lys residues. Here, we treated young male mice overexpressing human wild-type α-synuclein under control of the Thy-1 promoter (Thy1-aSyn mice) with CLR01 and examined motor behavior and α-synuclein in the brain. Intracerebroventricular administration of CLR01 for 28 days to the mice improved motor dysfunction in the challenging beam test and caused a significant decrease of buffer-soluble α-synuclein in the striatum. Proteinase-K-resistant, insoluble α-synuclein deposits remained unchanged in the substantia nigra, whereas levels of diffuse cytoplasmic α-synuclein in dopaminergic neurons increased in mice receiving CLR01 compared with vehicle. More moderate improvement of motor deficits was also achieved by subcutaneous administration of CLR01, in 2/5 trials of the challenging beam test and in the pole test, which requires balance and coordination. The data support further development of molecular tweezers as therapeutic agents for synucleinopathies.
... There may be potential benefits to using delta-8 THC; however, there is limited related information. Peer-reviewed studies examining the potential benefits of delta-8 THC use have been almost exclusively studied in laboratory settings using animal or cell models [52][53][54][55][56][57][58][59][60][61][62][63]. Results suggest that delta-8 THC use may be associated with decreased chemotherapy side effects, analgesic effects, decreased seizure activity, lower intra-ocular eye pressure, decreased cancer cell proliferation, decreased depressive symptoms and decreased nicotine use and withdrawal [53,54,[56][57][58][59][60][61][62][63][64]. ...
... Peer-reviewed studies examining the potential benefits of delta-8 THC use have been almost exclusively studied in laboratory settings using animal or cell models [52][53][54][55][56][57][58][59][60][61][62][63]. Results suggest that delta-8 THC use may be associated with decreased chemotherapy side effects, analgesic effects, decreased seizure activity, lower intra-ocular eye pressure, decreased cancer cell proliferation, decreased depressive symptoms and decreased nicotine use and withdrawal [53,54,[56][57][58][59][60][61][62][63][64]. However, only one study used human subjects to assess potential benefits (i.e. ...
Background and Aims
Delta‐8 tetrahydrocannabinol (THC) is a psychoactive substance from the Cannabis plant that has been rising in popularity in the United States since the 2018 US Farm Bill implicitly legalized it. This study reviewed research from peer‐reviewed and non‐peer‐reviewed (e.g. anecdotal and news) reports related to delta‐8 THC to summarize current knowledge and implications for public health and safety.
Methods
A scoping review was conducted using PubMed, Scopus, Google Scholar and Google as search engines, leading to the identification of 103 documents that were summarized. The themes that emerged were (1) legality, (2) use (popularity, motives, psychoactivity/potency, benefits/consequences), (3) synthesis (byproducts, laboratory testing) and (4) retail (availability, price, packaging, youth‐oriented marketing). A second author independently coded 20% of the documents, which verified the categorization of articles by these emergent themes.
Results
Most research used animal/cell models or focused upon ways to identify the chemical structure of delta‐8 THC in various products. Findings suggest that people often use delta‐8 THC as a substitute for other substances. Anecdotally, delta‐8 THC is a less potent psychoactive than delta‐9 THC; however, several negative consequences have been reported. There is no federal age restriction for purchase/possession of delta‐8 THC products. Delta‐8 THC is readily accessible on‐line, is typically less expensive than delta‐9 THC and is often marketed in ways that would seemingly appeal to children. There are no regulations on synthesis, resulting in products being contaminated and/or yielding inconsistent effects. There have been thousands of calls to US poison control centers due to accidental delta‐8 THC exposure among minors.
Conclusions
Most research on delta‐8 THC is largely anecdotal, not peer‐reviewed and does not involve human subjects. Future research should examine delta‐8 THC use using nationally representative samples to more clearly understand the prevalence and consequences of use. Laws are needed to mitigate the risks of using delta‐8 THC, particularly quality control of synthesis and minimum purchase age.
... Administration induces hyperphagia ( Williams and Kirkham, 2002a) OEA ( Bachur et al., 1965) An endogenously produced lipid involved in the control of fat intake and satiety ( Gaetani et al., 2010) and produced on demand in the gut (Rodriguez de Fonseca et al., 2001). Activates VR 1 ( Ahern, 2003) Phytocannabinoids Δ 8 THC ( Ben-Zvi et al., 1970) Partial agonism at CB 1 R and CB 2 R ( Pertwee, 2001), more stable than Δ 9 THC ( Avraham et al., 2004) Δ 9 THC ( Gaoni and Mechoulam, 1964a) ...
... This early study importantly demonstrated that very low concentrations of orally administered Δ 9 THC could substantially change an animal's motivation to consume; particularly given that a considerable percentage of the administered drug would have undergone first pass metabolism as a result of oral administration. Intriguingly, a later study by Avraham ( Avraham et al., 2004) also showed that extremely low Δ 8 THC doses (a pCB similar to Δ 9 THC but regarded as more stable; 0.001 mg/kg; intraperitoneal; i.p.) increased feeding in mice. These studies suggest that subtle modulation of the eCB system can be achieved without the manifestation of the nonspecific behavioural side effects traditionally associated with C. sativa administration ( Howlett et al., 2004). ...
The herb Cannabis sativa (C. sativa) has been used in China and on the Indian subcontinent for thousands of years as a medicine. However, since it was brought to the UK and then the rest of the western world in the late 19th century, its use has been a source of controversy. Indeed, its psychotropic side effects are well reported but only relatively recently has scientific endeavour begun to find valuable uses for either the whole plant or its individual components. Here, we discuss evidence describing the endocannabinoid system, its endogenous and exogenous ligands and their varied effects on feeding cycles and meal patterns. Furthermore we also critically consider the mounting evidence which suggests non-Δ(9) tetrahydrocannabinol phytocannabinoids play a vital role in C. sativa-induced feeding pattern changes. Indeed, given the wide range of phytocannabinoids present in C. sativa and their equally wide range of intra-, inter- and extra-cellular mechanisms of action, we demonstrate that non-Δ(9) tetrahydrocannabinol phytocannabinoids retain an important and, as yet, untapped clinical potential.
... Noticeable reductions in dopamine and serotonin concentrations were observed in both the hypothalamus and the hippocampus, respectively. Meanwhile, norepinephrine levels tended to rise in both the hypothalamus and hippocampus [108]. Observable reductions in serotonin concentration were also detected in another study upon the uptake of ∆ 8 -THC [109]. ...
Cannabis sativa is one of the oldest plants utilized by humans for both economic and medical purposes. Although the use of cannabis started millennia ago in the Eastern hemisphere, its use has moved and flourished in the Western nations in more recent centuries. C. sativa is the source of psychoactive cannabinoids that are consumed as recreational drugs worldwide. The C21 aromatic hydrocarbons are restricted in their natural occurrence to cannabis (with a few exceptions). Delta-9-tetrahydrocannabinol (Δ9-THC) is the main psychoactive component in cannabis, with many pharmacological effects and various approved medical applications. However, a wide range of side effects are associated with the use of Δ9-THC, limiting its medical use. In 1966, another psychoactive cannabinoid, Delta-8-tetrahydrocannabinol (Δ8-THC) was isolated from marijuana grown in Maryland but in very low yield. Δ8-THC is gaining increased popularity due to its better stability and easier synthetic manufacturing procedures compared to Δ9-THC. The passing of the U.S. Farm Bill in 2018 led to an increase in the sale of Δ8-THC in the United States. The marketed products contain Δ8-THC from synthetic sources. In this review, methods of extraction, purification, and structure elucidation of Δ8-THC will be presented. The issue of whether Δ8-THC is a natural compound or an artifact will be discussed, and the different strategies for its chemical synthesis will be presented. Δ8-THC of synthetic origin is expected to contain some impurities due to residual amounts of starting materials and reagents, as well as side products of the reactions. The various methods of analysis and detection of impurities present in the marketed products will be discussed. The pharmacological effects of Δ8-THC, including its interaction with CB1 and CB2 cannabinoid receptors in comparison with Δ9-THC, will be reviewed.
... Noticeable reductions in dopamine and serotonin concentrations were observed in both the hypothalamus and the hippocampus, respectively. Meanwhile, norepinephrine levels tended to rise in both the hypothalamus and hippocampus [105]. 15 Observable reductions in serotonin concentration were also detected in another study upon the uptake of Δ 8 -THC [106]. ...
Cannabis sativa is one of the oldest plants utilized by humans for both economic and medical purposes. Although the use of cannabis started millennia ago in the Eastern part of the hemisphere, its use has moved and flourished in the Western Nations in more recent centuries. C. sativa is the source of psychoactive cannabinoids that are consumed as recreational drugs worldwide. The C21 aromatic hydrocarbons are restricted in their natural occurrence to cannabis (with a few exceptions). Delta-9-tetrahydrocannabinol (Δ9-THC) is the main psychoactive component in cannabis with many pharmacological effects and various approved medical applications. However, a wide range of side effects are associated with the use of Δ9-THC, limiting its medical use. In 1966, another psychoactive cannabinoid, Delta-8-tetrahydrocannabinol (Δ8-THC) was isolated from marijuana grown in Maryland but in very low yield. Δ8-THC is gaining increased popularity due to its better stability and easier synthetic manufacturing procedures compared to Δ9-THC. Passing the U.S. Farm Bill in 2018 led to an increase in the sale of Δ8-THC in the United States. The marketed products contain Δ8-THC from synthetic sources. In this review, methods of extraction, purification, and structure elucidation of Δ8-THC will be presented. The issue of whether Δ8-THC is a natural compound or an artifact will be discussed, and the different strategies for its chemical synthesis will be presented. Δ8-THC of synthetic origin is expected to contain some impurities due to residual amounts of starting materials and reagents as well as side products of the reactions. The various methods of analysis and detection of impurities present in the marketed products will be discussed. The pharmacological effects of Δ8-THC, including its interaction with CB1 and CB2 cannabinoid receptors in comparison with Δ9-THC, will be reviewed.
... Partial agonist Appetite stimulant ** [194,195] CB2 Agonist Not reported [194] *: Pre-clinical in vitro study; **: pre-clinical in vivo study; ***: clinical study; N.B.: This table is non-exhaustive, broadly elucidating selected compounds and some of their potential pharmacological effects currently present in the pre-clinical literature. Depending on study parameters, the compounds show differing, sometimes biphasic, affinities and effects at different targets, thus highlighting the contradictory and equivocal evidence state. ...
The ‘entourage effect’ term was originally coined in a pre-clinical study observing endogenous bio-inactive metabolites potentiating the activity of a bioactive endocannabinoid. As a hypothetical afterthought, this was proposed to hold general relevance to the usage of products based on Cannabis sativa L. The term was later juxtaposed to polypharmacy pertaining to full-spectrum medicinal Cannabis products exerting an overall higher effect than the single compounds. Since the emergence of the term, a discussion of its pharmacological foundation and relevance has been ongoing. Advocates suggest that the ‘entourage effect’ is the reason many patients experience an overall better effect from full-spectrum products. Critics state that the term is unfounded and used primarily for marketing purposes in the Cannabis industry. This scoping review aims to segregate the primary research claiming as well as disputing the existence of the ‘entourage effect’ from a pharmacological perspective. The literature on this topic is in its infancy. Existing pre-clinical and clinical studies are in general based on simplistic methodologies and show contradictory findings, with the clinical data mostly relying on anecdotal and real-world evidence. We propose that the ‘entourage effect’ is explained by traditional pharmacological terms pertaining to other plant-based medicinal products and polypharmacy in general (e.g., synergistic interactions and bioenhancement).
... Comparatively, it is less expensive to produce and more stable because it does not easily oxidize to cannabinol as delta-9-THC does, which lends itself to a longer shelf life [10]. As a result, it has previously been investigated in animal studies as a low-dose therapy for eating disorders to increase food intake [11]. It has also been studied as an oral antiemetic in pediatric oncology patients and has been shown to effectively prevent vomiting in children receiving chemotherapy with minimal side effects [10]. ...
Introduction:
Delta-8-tetrahydrocannabinol (THC) is a known isomer of delta-9-THC, both found naturally in the Cannabis sativa plant and thought to have similar potency. Delta-8-THC products are widely accessible in retail shops which may lead to a rise in pediatric exposures with substantial clinical effects.
Case report:
This is a case series of four pediatric patients that were seen between June and September 2021. The patients presented with varied clinical symptoms including confusion, somnolence, seizure-like activity, hypotension, and tachycardia after exposure to delta-8-THC products obtained in retail shops. Basic urine drug screen immunoassays revealed positive results for cannabinoids in all patients. Subsequent confirmatory drug analysis of residual biological samples of blood and/or urine was sent to the University of California San Francisco Clinical Toxicology and Environment Biomonitoring Laboratory with the assistance of the Drug Enforcement Administration's Toxicology Testing Program (DEA TOX). Confirmatory testing revealed 11-nor-9-carboxy-delta-8-THC, the metabolite of delta-8-THC. Delta-9-THC and its metabolites were not detected on confirmatory testing in any of the cases.
Discussion:
Clinical effects of delta-8-THC in children include but are not limited to altered mental status, seizure-like activity, and vital sign abnormalities. Delta-8-THC exposure may lead to a positive urine drug screen for cannabinoids, but confirmatory testing is needed to differentiate from delta-9-THC.
... When administered acutely, Δ 8 -THC produces cannabimimetic effects in male ddN, ICR, and Swiss-Webster mice, including catalepsy (Watanabe et al., 1983), antinociception, decreased locomotor activity (Compton et al., 1991;Dewey et al., 1970), and hypothermia (Ham and Jong, 1974;Yamamoto et al., 1985). Increased food intake, mobility, and performance in the 8-arm radial maze, as well as decreased hippocampal dopamine and serotonin release, have also been reported in female Sabra mice at a very low dose of Δ 8 -THC (0.001 mg/kg) (Avraham et al., 2004). Given the recent increase in human consumption of products with high Δ 8 -THC content, there is a critical need for empirical assessment of acute and repeated Δ 8 -THC exposure. ...
Delta-8-tetrahydrocannabinol (Δ⁸-THC) is a psychotropic cannabinoid produced in low quantities in the cannabis plant. Refinements in production techniques, paired with the availability of inexpensive cannabidiol substrate, have resulted in Δ⁸-THC being widely marketed as a quasi-legal, purportedly milder alternative to Δ⁹-THC. Yet, little research has probed the behavioral and physiological effects of repeated Δ⁸-THC use. The present study aimed to evaluate the effects of acute and repeated exposure to Δ⁸-THC. We hypothesized that Δ⁸-THC produces effects similar to Δ⁹-THC, including signs of drug tolerance and dependence. Adult male and female C57BL/6 J mice were treated acutely with Δ⁸-THC (6.25-100 mg/kg, i.p.) or vehicle and tested in the tetrad battery to quantify cannabimimetic effects (i.e., catalepsy, antinociception, hypothermia, immobility) as compared with a non-selective synthetic cannabinoid (WIN 55,212-2) and Δ⁹-THC. As previously reported, Δ⁸-THC (≥12.5 mg/kg) induced cannabimimetic effects. Pretreatment with the CB1 receptor-selective antagonist rimonabant (3 mg/kg, i.p.) blocked each of these effects. In addition, repeated administration of Δ⁸-THC (50 mg/kg, s.c.) produced tolerance, as well as cross-tolerance to WIN 55,212-2 (10 mg/kg, s.c.) in tetrad, consistent with downregulated CB1 receptor function. Behavioral signs of physical dependence in the somatic signs, tail suspension, and marble burying assays were also observed following rimonabant-precipitated withdrawal from Δ⁸-THC (≥10 mg/kg BID for 6 days). Lastly, Δ⁸-THC produced Δ⁹-THC-like discriminative stimulus effects in both male and female mice. Together, these findings demonstrate that Δ⁸-THC produces qualitatively similar effects to Δ⁹-THC, including risk of drug dependence and abuse liability.
... There is limited information related to Delta-8 THC in the scientific literature. Although further validation is needed in humans, the pharmacological properties of Delta-8-THC include anti-emetic, anxiolytic, appetite-stimulating, analgesic and neuroprotective properties (8)(9)(10)(11). ...
In the past 3 years, widespread interest in cannabinoid products containing delta-8 tetrahydrocannabinol (delta-8 THC) has increased (1), as have debates about its legal status (2–4) in the USA. Delta-8 THC is an isomer of delta-9 THC, the most prominent psychoactive component in Cannabis sativa. Delta-8 THC is estimated to have ∼60% of the psychoactive potency of delta-9 THC (5) and comparable to one-third of binding affinity at both cannabinoid receptor (CB) 1 and CB2 (6, 7), so is a drug of forensic concern. Toxicology laboratories are facing increasing requests to identify and quantify delta-8 THC and to provide opinions interpreting its presence in human blood in driving under the influence of drugs (DUID) investigation casework. However, many laboratories lack capabilities to resolve and identify these isomers of THC in their testing which adversely affects reporting. Consequently, little is known about the likely range of delta-8 THC concentrations in forensic casework. Our laboratory performs testing for cannabinoids in human whole blood by liquid chromatography with tandem mass spectrometry (LC–MS-MS) (8). While the method separates the delta-8 and delta-9 isomers, we currently do not report delta-8 THC concentrations from the routine DUID toxicology testing due to the lack of availability of a deuterated delta-8 THC internal standard (D9-delta-8 THC) at the time the test was developed in 2019. We recently performed a ranging study to provide an estimate of typical delta-8 THC concentrations in 118 randomly selected blood samples from forensic human performance casework, with a view to establishing a routine quantitative method capable of reporting both delta-8 and delta-9 THC.
... On contrary, it was found to exhibit significant anticonvulsant, sedative and other pharmacological activities by interacting with the effects of THC. Studies have shown that CBN decreases heart rate, intestinal mobility and inhibits platelet aggregation [96,[98][99][100][101]. ...
Cannabinoids are the major chemical constituents of the plant Cannabis sativa L. and are known to exhibit a wide range of pharmacological effects viz., psychotropic, analgesic, anticancer, antiinflammatory, antidiabetic, anticonvulsive, antibacterial and antifungal etc. The use of cannabis, cannabinoids and their products is restricted in several countries due to the high risk of misuse. Recently, cannabinoids have regained the interest of the researchers due to their therapeutic applications. Ever since the discovery of the cannabinoids, most of the studies carried out on the evaluation of their biological activities were limited to only preclinical levels. The quality of the preclinical data still remains only low to moderate, thus, leaving behind an uncertainty in their use for therapeutic applications. Problems associated with the solubility, stability and bioavailability of the cannabinoid drugs are also a major concern in the quality of the study. Nanoparticle based drug delivery system could be a potential method to increase the reliability of the data. While considering the immense pharmacological properties of the cannabinoids, there is an urgency to perform intensive clinical trials and to know their mechanism of action in various disease conditions, evaluate their efficacy and safety, and register them as drug candidates. This review highlights the chemistry, types and biological activities of the cannabinoids such as THC, CBD and CBN in focus with their anticancer activity, neuroprotective effect and nanoformulating the cannabinoid drugs.
... There is limited information related to delta-8 THC in the scientific literature. Although further validation is needed in humans, the pharmacological properties of delta-8-THC include anti-emetic, anxiolytic, appetite-stimulating, analgesic and neuroprotective properties (8)(9)(10)(11). ...
Cannabinoids is the most frequently reported illicit drug class in Driving Under the Influence of Drugs (DUID) investigation casework. In recent years, our laboratory observed an increasing rate of overlapping peaks for the cannabinoids confirmation performed using two-dimensional (2D)-High Performance Liquid Chromatography/Tandem Mass Spectrometry (LC-MS/MS). Starting in early 2018, the incidence of unresolved interfering substances increased, contributing to a higher rate of canceled testing that peaked at 3.7% in February 2019. The observed interference demonstrates a distinctive pattern affecting identifications and quantification of both Delta-9 THC and Delta-9 carboxy THC. An improved quantitative method was developed and validated to separate Delta-8 and -9 isomers and their metabolites in blood. All acceptance criteria were met with identical measurement ranges from the original method (lower limit of quantitation: 0.5 ng/mL for Delta-9 THC, 1.0 ng/mL for 11-Hydroxy Delta-9 THC, and 5.0 ng/mL for Delta-9 carboxy THC). Cannabinoids were extracted from whole blood using liquid-liquid extraction, separated in a 2D liquid chromatography system over a run-time of 10 min and detected by a tandem mass spectrometry system equipped with ESI source operating in positive ionization mode with scheduled multiple reaction mass spectrometric monitoring (MRM). The LC system consisted of a pair of Phenomenex® SecurityGuard™ C6 Phenyl (4x2 mm) cartridges for extracting the compounds with 5 mM ammonium formate buffer in deionized (DI) water and 0.1% formic acid in methanol as mobile phase, and a Phenomenex® Kinetex C18 column (100x3 mm) with 0.1% formic acid in DI water and 0.1% formic acid in methanol for LC separation at 45°C. Each set of isomers was fully resolved by the longer run-time method. To the authors' knowledge, this is the first report of a method that successfully quantitates these primary cannabinoids in blood specimens where significant concentrations of both Delta-9 and Delta-8 isomers are present.
... However, under the HFD condition, t-test revealed that the COM rats tended to have higher visceral adiposity compared with the CTLs: ^p < 0.06 and lower trunk insulin compared with the EtOH group # p < 0.007. low dose (0.001 mg/kg) of ∆ 8 -THC, which is supposedly a more stable and potent CB 1 R agonist than ∆ 9 -THC, stimulated food intake but did not promote weight gain in mice 39 . Notwithstanding, our observed null effect of oral THC on daily caloric intake goes against the acclaimed hyperphagic effects of cannabis or THC 13,35,40 . ...
Cannabis and alcohol co-use is common, and the trend may increase further given the current popularity of cannabis legalization. However, the metabolic consequences of such co-use are unclear. Here, we investigated how co-administration of alcohol and ∆9-tetrahydrocannabinol (THC), the main psychoactive constituent of cannabis, affects body weight and visceral adiposity, and glucose and insulin homeostasis in rats. For 16 consecutive days during adolescence, male rats drank saccharin or alcohol after receiving subcutaneous oil or THC injections in Experiment 1 and voluntarily consumed alcohol, THC edible, or both drugs in Experiment 2. Experiment 1 showed that following abstinence, drug co-exposure reduced visceral fat and the amount of insulin required to clear glucose during an oral glucose tolerance test (OGTT). In Experiment 2, rats received a high-fat diet (HFD) after 3-week abstinence. Although adolescent drug use did not interact with the HFD to worsen hyperglycemia and hyperinsulinemia during an OGTT, HFD-fed rats that co-used alcohol and THC had the lowest insulin levels 75 min after an insulin injection, suggesting an altered rate of insulin secretion and degradation. These results suggest that THC and alcohol co-exposure can distinctly alter the physiology of glucose and insulin homeostasis in a rodent model.
... Podíl ostatních kanabinoidů na omamných účincích konopí nebyl dosud uspokojivě objasněn, předpokládá se však, že průběh intoxikace do jisté míry ovlivňují, protože byly zjištěny určité rozdíly při použití konopí a čistého syntetického THC (Galal et al., 2009). Izomer THC, delta-8-THC, již v malých dávkách významně ovlivňuje příjem potravy a vede ke snížení váhy pokusných myší (Avraham et al., 2004). Kanabidiol (CBD) se rovněž vyskytuje téměř ve všech odrůdách konopí od velmi nízkých hodnot až po zhruba 95 % přítomných kanabinoidů. ...
... Although the observations that marijuana stimulates appetite and food consumption are known for many years (Abel 1971;Foltin et al. 1986), the experimental evidence for CB-induced hyperphagia has been not demonstrated until more recently. In the late 1990s and early 2000s, Williams et al. (1998) showed that Δ 9 -THC exerts hyperphagic action in prefed rats and free-feeding rats (Koch 2001), a similar effect to that reported using Δ8-THC (Avraham et al. 2004). In addition, Kirkham et al. (2002) reported that AEA and 2-AG levels are elevated by after food deprivation in the limbic forebrain, whereas 2-AG is reduced in the hypothalamus during the feeding state but increased during the deprived state, which suggests a role of eCBs in motivation toward food. ...
The herb Cannabis sativa has been traditionally used in many cultures and all over the world for thousands of years as medicine and recreation. However, because it was brought to the Western world in the late 19th century, its use has been a source of controversy with respect to its physiological effects as well as the generation of specific behaviors. In this regard, the CB1 receptor represents the most relevant target molecule of cannabinoid components on nervous system and whole-body energy homeostasis. Thus, the promotion of CB1 signaling can increase appetite and stimulate feeding, whereas blockade of CB1 suppresses hunger and induces hypophagia. Taste and flavor are sensory experiences involving the oral perception of food-derived chemicals and drive a primal sense of acceptable or unacceptable for what is sampled. Therefore, research within the last decades focused on deciphering the effect of cannabinoids on the chemical senses involved in food perception and consequently in the pattern of feeding. In this review, we summarize the data on the effect of cannabinoids on chemical senses and their influences on food intake control and feeding behavior.
... Studies of repeated THC dosing have yielded complex, region-specific effects, such as increased total striatal dopamine levels in rats 60 but reduced hippocampal dopamine levels in mice 61 . Reduced dopamine metabolism was found in the medial PFC in two rat studies 60 , an effect that was not observed in the striatum or the NAc 62 . ...
The effects of Δ9-tetrahydrocannabinol (THC), the main psychoactive ingredient in cannabis, are a pressing concern for global mental health. Patterns of cannabis use are changing drastically owing to legalization, the availability of synthetic analogues (commonly termed spice), cannavaping and an emphasis on the purported therapeutic effects of cannabis. Many of the reinforcing effects of THC are mediated by the dopamine system. Owing to the complexity of the cannabinoid–dopamine interactions that take place, there is conflicting evidence from human and animal studies concerning the effects of THC on the dopamine system. Acute THC administration causes increased dopamine release and neuron activity, whereas long-term use is associated with blunting of the dopamine system. Future research must examine the long-term and developmental dopaminergic effects of THC.
... We have investigated the effect of very low doses (without canabinomimetic side effects) of synthetic cannabinoids D 8 -THC [40], anandamide [19] and 2-arachidonylglyceryl-ether (noladin) [41] on food consumption, cognitive function and neurotransmitter levels in mice as potential therapeutic options in anorexia. THC-treated mice showed an 18% increase in food intake that was reversed by the CB 1 antagonist SR141716A. ...
Alexandre Steiner – Systemic Inflammation Laboratory, St Joseph's Hospital and Medical Center, Phoenix, AR, USA
... 22−28 Orally administered endocannabinoids can affect food intake and digestive processes via their effects on peristalsis 29 and catecholamines. 26,27 Anandamide (AEA) and the other N-acylethanolamines, e.g., oleoylethanolamide (OEA), palmitoylethanolamide (PEA), and linoleoylethanolamide (LEA) (Figure 1), are formed by several enzymatic pathways from their precursors which are the Nacylated ethanolamine phospholipids. Endogenous OEA and PEA are thought to inhibit food intake by acting on receptors in the intestine. ...
ABSTRACT Newly synthesized acylethanolamide derivatives: oleoyl-L-valinolamide (1), oleoyl-D-valinolamide (2), elaidoyl-L-valinolamide (3), elaidoyl-D-valinolamide (4) stearoyl-L-valinolamide (5) and palmitoyl-L-valinolamide (6) were investigated in mice as anti-obesity compounds. Compounds 1, 2, 5, 6 significantly decreased body weight by c6.57% following 8 injections of 1mg/kg i.p. during 39 days, while 3 and 4 showed no such activity. Receptor binding indicated that no compound activated CB1, CB2, PPARα or TRPV1 receptors. Hypothalamic RT-PCR showed that mRNA expression of the anorexigenic genes POMC and CART were upregulated by 1, 2, 5 and 1, 2 respectively, while those of the orexigenic genes: NPY and CaMKK2 were downregulated by the respective compounds 1, 5, 6 and 1, 2, 5. Oleoyl-L-valinolamide (1) enhances anorectic pathways and lead to decreased glucose levels, enhanced locomotor activity and improved cognition. Effects of oleoyl-L-valinolamide (1) on weight were dose-dependent and it could be given orally. 1, 2, 4, 5 down regulated FAAH mRNA expression.
... Inhibition of AMPK activity conversely leads to hepatic gluconeogenesis, lipogenesis , and glycogen synthesis (Lim et al., 2010). Acute injections of ghrelin and cannabinoids have been shown to increase appetite in rats (Kirkham, 2003; Wren et al., 2001b) and mice (Avraham et al., 2004; Kola et al., 2008; Sun et al., 2004; Wiley et al., 2005). HU210 is a highly potent synthetic cannabinoid receptor agonist (K i values of 0.061 and 0.52 nM at cloned human CB1 and CB2 receptors respectively – data from Tocris Bioscience). ...
Introduction:
Ghrelin is a potent orexigenic brain-gut peptide with lipogenic and diabetogenic effects, possibly mediated by growth hormone secretagogue receptor (GHS-R1a). Cannabinoids also have orexigenic and lipogenic effects. AMPK is a regulator of energy homeostasis and we have previously shown that ghrelin and cannabinoids stimulate hypothalamic AMPK activity while inhibiting it in the liver and adipose tissue, suggesting that AMPK mediates both the central appetite-inducing and peripheral effects of ghrelin and cannabinoids.
Aims:
Using GHS-R KO mice, we investigated whether the known ghrelin receptor GHS-R1a is required for the tissue-specific effects of ghrelin on AMPK activity, and if an intact ghrelin signalling pathway is necessary for the effects of cannabinoids on AMPK activity.
Methods:
Wild-type and GHS-R KO mice were treated intraperitoneally with ghrelin 500 ng/g bodyweight or CB1 agonist HU210 20 ng/g and hypothalamic, hepatic and adipose AMPK activity was studied using a functional kinase assay.
Results:
Ghrelin and HU210 significantly stimulated hypothalamic AMPK activity in wild-type animals (mean±SEM, 122.5±5.2% and 128±11.6% of control, p<0.05) and inhibited it in liver (55.1±4.8% and 62.2±14.5%, p<0.01) and visceral fat (mesenteric fat (MF): 54.6±16% and 52.0±9.3%, p<0.05; epididymal fat (EF): 47.9±12.1% and 45.6±1.7%, p<0.05). The effects of ghrelin, and interestingly also HU210, on hypothalamic, visceral fat and liver AMPK activity were abolished in the GHS-R KO mice (hypothalamus: 107.9±7.7% and 87.4±13.3%, liver: 100.5±11.6% and 116.7±5.4%, MF: 132.1±29.9% and 107.1±32.7%, EF: 89.8±7.3% and 91.7±18.3%, p>0.05).
Conclusions:
Ghrelin requires GHS-R1a for its effect on hypothalamic, liver and adipose tissue AMPK activity. An intact ghrelin signalling pathway is necessary for the effects of cannabinoids on AMPK activity.
... Additionally from day 7, daily THC (0.5 mg kg − 1 ) or vehicle injections were administered for a further 8 days. A wide variety of doses of THC and related cannabinoids have been shown to increase feeding, depending on species, strain, and prior feeding state (pre-fed, fasted or ad libitum) (Avraham et al., 2004;Avraham et al., 2005;Hao et al., 2000;Rahminiwati and Nishimura, 1999;Wiley et al., 2005). However, there have been no previous studies using THC in the ABA model, nor in this strain of mouse in any paradigm. ...
The activity-based anorexia (ABA) paradigm is one of the few animal models of human anorexia nervosa. We present here the translation of this approach to C57/BL6 mice, a common background for genetically modified mice, and investigate the effects of the cannabinoid agonist, Delta(9)-tetrahydrocannabinol (THC) and the endocannabinoid uptake inhibitor, OMDM-2 in this model. The ABA paradigm was optimised so that food-restricted wheel-running mice displayed anorexia, reduced body weight and disrupted activity and circadian cycles. These conditions produced a murine ABA model with a defined stage and stability to allow for pharmacological intervention. Daily Delta(9)-THC (0.5 mg/kg) decreased survival in the ABA animals but increased feeding in the survivors, OMDM-2 (3 mg/kg) increased food intake, but not sufficiently to reverse weight loss. The effects of this model on endocannabinoid tone in the brain remain to be determined. Since the endocannabinoid system may be implicated in anorexia nervosa and in view of the positive modulation by cannabinoids of some aspects of ABA in this study, further investigation of the effects of cannabinoids in ABA is warranted.
... Otros agonistas como el 2-araquidoni- lglicerol (2-AG) (Kirkham, Williams, Fezza y Di Marzo, 2002) y el noladin eter (Avraham, Menachem, Okun, Zlotarav, Abel, Mechoulam et al. 2005) producen un efecto similar. Recientemente se ha descrito que el ∆ 8 THC, con menos efectos psicoactivos que el ∆ 9 THC, podría tener un efecto orexígeno más potente (Avraham, Ben-Shushan, Breuer, Zolotarev, Okon, Fink et al. 2004). El efecto orexígeno se observa con la administración de agonistas en centros cerebrales relacionados con la regulación de la ingesta, como el núcleo VMH (Jamshidi y Taylor, 2001); en el núcleo accumbens (NAc) (Kirkham et al. 2002 ) o en el cuarto ventrículo por la proximidad del núcleo parabraquial (Miller, Murray, Freeman y Edwards, 2004). ...
Cada vez disponemos de más información que sugiere que el sistema cannabinoide es un mecanismo crucial en la regulación de la ingesta alimentaria y en el metabolismo energético. De ahí que próximamente se vaya a comercializar un antagonista cannabinoide, el rimonabant, para su uso en obesidad que, además de una pérdida de peso, consigue una mejora del denominado síndrome metabólico, con unos cambios en el metabolismo lipídico y glucídico no observados por otros fármacos antiobesidad actualmente comercializados. Se presenta una revisión de los conocimientos actuales sobre el tema y los datos de estudios propios: estudios genéticos de dicho sistema en los trastornos de la conducta alimentaria y en obesidad y estudios de localización de receptores cannabinoides en sitios relacionados con la ingesta. Dichos estudios apoyan un estado de hiperactividad cannabinoide en la obesidad y, además, dicha hiperactividad puede constituir un factor pronóstico.
... We chose to examine the effects of WIN 55,212-2 and AM 251 on food intake in presatiated rats to further delineate the role of endogenous cannabinoids in energy balance. Our data represent the first attempt to directly examine the effect of cannabinoids on serotonin (5-HT) release; there are few reports in the literature examining the interactions of catecholamine and cannabinoids and the resulting effect on food intake (16) . ...
The effect of intracerebroventricular or intraperitoneal administration of cannabinoid receptor agonist WIN 55,212-2 or inverse agonist AM 251 on food intake and extracellular levels of serotonin and acetic acid 5-hydroxy-indol from presatiated rats was studied. Compared to the vehicle-injected control, the intracerebroventricular administration of WIN 55,212-2 was associated with a significant increase in food intake, whereas the administration of AM 251 caused a significant reduction in this respect. These results were accompanied by considerable reductions or increases in serotonin and acetic acid 5-hydroxy-indol levels compared to the vehicle-injected control and the baseline values for the different experimental groups studied. Intraperitoneal administration of WIN 55,212-2 at doses of 1 and 2 mg/kg promoted hyperphagia up to 6 h after injection, whereas administration of a higher dose (5 mg/kg) significantly inhibited food intake and motor behaviour in partially satiated rats. Administration of any of the AM 251 doses studied (0.5, 1, 2, 5 mg/kg) led to a significant decrease in the amount of food ingested from 2 h after the injection, compared to the vehicle-injected control group, with the most striking effect being observed when the 5 mg/kg dose was injected.
... Indeed, oral formulations of D 9 -THC are currently used therapeutically to treat cachexia in cancer and AIDS patients (Beal et al., 1995; Jatoi et al., 2002). In rodents, D 9 -THC and D 8 -THC also increased food intake (present study; Williams et al., 1998; Koch, 2001; Avraham et al., 2004). Further, this effect was selective; that is, the dose range at which D 9 -THC produced this effect did not entirely overlap that at which it decreased locomotor activity. ...
Marijuana's appetite‐increasing effects have long been known. Recent research suggests that the CB 1 cannabinoid receptor antagonist SR141716A may suppress appetite. This study represents a further, systematic investigation of the role of CB 1 cannabinoid receptors in the pharmacological effects of cannabinoids on food intake.
Mice were food‐restricted for 24 h and then allowed access to their regular rodent chow for 1 h. Whereas the CB 1 antagonist SR141716A dose‐dependently decreased food consumption at doses that did not affect motor activity, Δ ⁹ ‐tetrahydrocannabinol (Δ ⁹ ‐THC) increased food consumption at doses that had no effect on motor activity. O‐3259 and O‐3257, structural analogs of SR141716A, produced effects similar to those of the parent compound.
Amphetamine (a known anorectic) and diazepam (a benzodiazepine and CNS depressant) decreased food consumption, but only at doses that also increased or decreased motor activity, respectively. The CB 2 cannabinoid receptor antagonist SR144528 and the nonpsychoactive cannabinoid cannabidiol did not affect food intake nor activity.
SR141716A decreased feeding in wild‐type mice, but lacked pharmacological activity in CB 1 knockout mice; however, basal food intake was lower in CB 1 knockout mice. Amphetamine decreased feeding in both mouse genotypes.
These results suggest that SR141716A may affect the actions of endogenous cannabinoids in regulating appetite or that it may have effects of its own aside from antagonism of cannabinoid effects (e.g., decreased feeding behavior and locomotor stimulation). In either case, these results strongly suggest that CB 1 receptors may play a role in regulation of feeding behavior.
British Journal of Pharmacology (2005) 145 , 293–300. doi: 10.1038/sj.bjp.0706157
... Williams et al. (1998) have previously reported increased consumption of normal rat chow in animals that were mildly food-deprived (removal of the regular chow for 4 h before D 9 -THC administration). Thus, within a limited, usually low, dose range, it appears that D 9 -THC (as well as D 8 -THC; see Avraham et al., 2004) can produce hyperphagia in rodents. This seems to be the case for the endogenous cannabinoids anandamide and 2-arachidonoylol glycerol (2-AG) as well (Williams and Kirkham, 1999;Hao et al., 2000;Kirkham et al., 2002). ...
This study examined effects of the CB1 receptor antagonist/inverse agonist SR-141716 and the CB1 receptor agonist delta9-tetrahydrocannabinol (delta9-THC) on feeding behavior in male Sprague-Dawley rats. Rats were housed individually with free access to regular pelletized laboratory chow [after a 2 weeks handling phase, animals had access to regular chow for 21 h (Study 1) or 22 h (Study 2); high-fat powder food for 3 h in Study 1 and 2 h in Study 2, respectively], and free access to water. Animals were maintained on a reversed 12-h light/dark cycle (dark beginning at noon). Rats were habituated to this type of feeding and light/dark schedule for 3 weeks until a stable baseline for food intake was achieved. In Study 1, animals were examined after administration of delta9-THC alone (dose range 0.1-1.8 mg/kg), SR-141716 alone (dose range 0.03-0.3 mg/kg), and the two drugs combined; injections were given i.p. at the beginning of the second hour after presenting the high-fat diet and drugs were given twice weekly. There was a dose-related increase in high-fat diet intake, peaking at 0.56-1 mg/kg delta9-THC. SR-141716 alone suppressed the high-fat diet intake below control levels. A combination of 0.3 mg/kg SR-141716 and 0.56 mg/kg delta9-THC counteracted the effects on consumption of either drug alone. In Study 2, experimental rats were treated initially with 0.56 mg/kg delta9-THC for six consecutive days; controls received vehicle. Attenuation of the hyperphagia (high-fat diet) was evident after the second injection. Increasing doses of delta9-THC (1 and 1.8 mg/kg, for two and three consecutive days, respectively) did not reinstate the initial hyperphagia. In conclusion, low-to-moderate doses of delta9-THC produced hyperphagia (to a high-fat food source), which was antagonized by SR-141716. SR-141716 singly suppressed intake of the high-fat diet. Delta9-THC-induced hyperphagia dissipated rapidly upon chronic treatment; however, it is unclear whether this reflects pharmacological tolerance or the emergence of a conditioned taste aversion in Study 2.
... Other agonists like 2-arachidonoyl-glycerol (2-AG) [21] and noladin ether [22] have a similar effect. It has recently been described that Δ 8 -THC, a substance with less psychoactive effects than Δ 9 -THC, may have a stronger orexigenic effect [23]. ...
Cannabinoid system is a crucial mechanism in regulating food intake and energy metabolism. It is involved in central and peripheral mechanisms regulating such behavior, interacting with many other signaling systems with a role in metabolic regulation. Cannabinoid agonists promote food intake, and soon a cannabinoid antagonist, rimonabant, will be marketed for the treatment of obesity. It not only causes weight loss, but also alleviates metabolic syndrome. We present a review of current knowledge on this subject, along with data from our own research: genetic studies on this system in eating disorders and obesity and studies locating cannabinoid receptors in areas related to food intake. Such studies suggest cannabinoid hyperactivity in obesity, and this excessive activity may have prognostic implications.
Objective(s)
Polycystic ovary syndrome (PCOS) is a complex metabolic and endocrine disorder associated with chronic inflammation. However, the effect of ∆ tetrahydrocannabinol-9 (THC) on PCOS has not been evaluated. Therefore, this study aimed to investigate the immunomodulatory effects of THC in an animal model of PCOS.
Materials and Methods
Twenty female Sprague-Dawley rats, aged 4 weeks, were divided into four groups. The control group received a normal diet, the sham group received a vehicle (carboxymethyl cellulose), the PCOS group received a high-fat diet (HFD) for 16 weeks followed by letrozole for 4 weeks, and the THC group received an HFD for 16 weeks followed by letrozole+THC (0.02 mg/kg) for 4 weeks.
Results
The PCOS animals exhibited significantly higher levels of testosterone, insulin, triglycerides, and total cholesterol, along with elevated inflammatory and oxidative stress markers compared to the control group. Flow cytometry and real-time PCR analysis revealed an increase in M1 macrophage markers and a decrease in M2 macrophage markers compared to the control group. However, the administration of a low dose of THC mitigated these disturbances.
Conclusion
Low-dose THC improved inflammatory responses and shifted the balance of M1/M2 macrophage markers towards M2 macrophages in the animal model of PCOS.
Introduction – The obesity pandemic is multifactorial. Nutritional, pharmacologic and surgical interventions are limited in reach and efficacy, raising need for new therapeutics.
Aims – Characterization of anorexigenic and cognitive effect and central mechanism of action of novel N ‐acylethanolamide derivatives.
Methods – Sabra mice divided to similar experimental groups, injected IP with: oleyl‐L‐leucinolamide ( 1 A ), linoleyl‐L‐leucinolamide ( 4 A ), linoleyl‐L‐valinolamide ( 5 A ), oleyl‐oxycarbonyl‐L‐valinolamide ( 1 B ), oleyl‐oxycarbonyl‐D‐valinolamide ( 2 B ), oleylamine‐carbonyl‐L‐valinolamide ( 3 B ), oleylamine‐carbonyl‐D‐valinolamide ( 4 B ), and oleyl‐L‐hydroxyvalineamide ( 5 B ). Control group with vehicle. Body weight and food consumption followed for 39 days. Motor activity and cognitive function by open field test and eight‐arm maze. Mice sacrificed and mechanism of action investigated by qPCR. The genes analyzed involved in energy balance and regulation of appetite. Catecholamines and serotonin evaluated.
Results – Compounds 1 A , 5 A , 1 B – 4 B , caused significant weight loss of 4.2–5.6 % and 5 A , 1 B – 4 B , improved cognitive function following 8 i. p. injections of 1 mg/kg during 39 days, by different mechanisms. 5 A , 3 B and 4 B decreased food consumption, whereas 1 A , 5 A and 2 B increased motor activity. 1 A , 4 A , 1 B and 3 B elevated SIRT‐1, associated with survival. POMC upregulated by 1 B and 2 B , CART by 1 B , 2 B and 1 A . NPY and CAMKK2 downregulated by 5 A . 4 B enhanced 5‐HT levels. 4 A , 5 A , 1 B , 4 B , 5 B decreased FAAH, showing long lasting effect.
Conclusions – These new compounds might be developed for the treatment of obesity and for improved cognitive function.
Social interactions play an important role in the shaping of individual personalities and development of behavioral and physiological disturbances. Animal models represent a valuable tool in the study of the molecular and biochemical basis of social behaviors. Dominant–submissive relationship (DSR)-based models have been developed in both mice and rats for the purposes of studying the molecular basis of social behavior and psychotropic agent screening. These models have been established on the basis of the food competition paradigm. Whereas DSR models have been proven to be valid for drug testing, they have also been associated with different challenges, including low efficiency, experimental reproducibility, and testing time duration. To overcome these challenges, we employed the selective breeding approach, which has allowed us to develop mouse populations with strong characteristics of dominance and submissiveness. This model allows a dramatic increase in test efficiency, stability, and reproducibility as well as a substantial decrease in experimental duration. The selectively-bred dominant (Dom) and submissive (Sub) mice exhibit distinct differences in (a) stress-coping abilities, (b) responses to psychotropic agents, (c) inflammatory profiles, (d) gut microbiome profile, and (e) life span. Herein, we describe in detail the process of selective breeding as well as the behavioral, biochemical, and physiological characteristics of the Dom and Sub mice. We also discuss the different research directions that can be pursued by employing this model.Key wordsDominanceSubmissivenessStress resilienceSelective breedingSocial interactionsDominant–submissive relationship testAntidepressantsPsychotropic agentsDepressionAnxiety
The Cannabis sativa plant has been used medicinally and recreationally for thousands of years, but recently only relatively some of its constituents have been identified. There are more than 550 chemical compounds in cannabis, with more than 100 phytocannabinoids being identified, including Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD). These phytocannabinoids work by binding to the cannabinoid receptors, as well as other receptor systems. Also within cannabis are the aromatic terpenes, more than 100 of which have been identified. Cannabis and its constituents have been indicated as therapeutic compounds in numerous medical conditions, such as pain, anxiety, epilepsy, nausea and vomiting, and post-traumatic stress disorder. This chapter provides an overview of some of the biological effects of a number of the cannabinoids and terpenes, as well as discussing their known mechanisms of action and evidence of potential therapeutic effects.
Opioid receptors (ORs), μOR, δOR, κOR and ORL1 mediate numerous signaling cascades, most importantly, through the modulation of ion channels. Research demonstrates the role of OR mediated signal transduction in treating pain, cancer, neurodegenerative disorders and cardiac insults. Yet, the primary application of drugs that modulate ORs is analgesia. Current opioids like morphine that are mainly μOR orthosteric agonists attract many undesirable side-effects (constipation, urinary retention, respiratory depression and hypotension) and the existing modus operandi against these is the inclusion of a μOR antagonist (for example. naloxone) which itself produces side-effects. As such, there is a current thrust to delineate the anti-nociceptive pathways mediated by ORs from the pathways involved in their induction of debilitating side-effects, in order to develop enhanced lead molecules. This review discusses the effects of natural products on the OR-induced signaling cascades and compares these to current synthetic leads and drugs. Important to these discussions is the complexity of OR signaling which involves OR trafficking, de- and re-sensitization, homo- and hetero-dimerization, the type of ligand binding (agonist, antagonist, reverse antagonist, orthosteric and allosteric agonist and antagonist in the context of biased agonism) and reasons for dysregulation that primarily occur because of inter-individual variations. Our current understanding of the different forms of ORs has expanded, thus introducing the concept of allosterism, which is also discussed. The authors present possible combination therapies to be explored towards developing the 'Holy Grail' of analgesics, for example, ignavine, the natural μOR positive allosteric modulator (PAM) with codeine and the natural fascaplysin, a balanced agonist with fentanyl. There remain many gaps in natural products research on ORs, more so on ORL1 and δ- and ҡ receptors. Furthermore, additional exploration of ORs' modulation is needed for ameliorating other associated disease conditions of global concern.
The organized tightly regulated signaling relays engaged by the cannabinoid receptors (CBs) and their ligands, G proteins and other effectors, together constitute the endocannabinoid system (ECS). This system governs many biological functions including cell proliferation, regulation of ion transport and neuronal messaging. This review will firstly examine the physiology of the ECS, briefly discussing some anomalies in the relay of the ECS signaling as these are consequently linked to maladies of global concern including neurological disorders, cardiovascular disease and cancer. While endogenous ligands are crucial for dispatching messages through the ECS, there are also commonalities in binding affinities with copious exogenous ligands, both natural and synthetic. Therefore, this review provides a comparative analysis of both types of exogenous ligands with emphasis on natural products given their putative safer efficacy and the role of Δ9-tetrahydrocannabinol (Δ9-THC) in uncovering the ECS. Efficacy is congruent to both types of compounds but noteworthy is the effect of a combination therapy to achieve efficacy without the unideal side-effects. An example is Sativex that displayed promise in treating Huntington's disease (HD) in preclinical models allowing for its transition to current clinical investigation. Despite the in vitro and preclinical efficacy of Δ9-THC to treat neurodegenerative ailments, its psychotropic effects limit its clinical applicability to treating feeding disorders. We therefore propose further investigation of other compounds and their combinations such as the triterpene, α,β-amyrin that exhibited greater binding affinity to CB1 than CB2 and was more potent than Δ9-THC and the N-alkylamides that exhibited CB2 selective affinity, the latter can be explored towards peripherally exclusive ECS modulation. The synthetic CB1 antagonist, Rimonabant was pulled from market for the treatment of diabetes, however its analogue SR144528 maybe an ideal lead molecule towards this end and HU-210 and Org27569 are also promising synthetic small molecules.
The pharmacological importance of cannabinoids has been in study for several years. Cannabinoids comprise of (a) the active compounds of the Cannabis sativa plant, (b) endogenous as well as (c) synthetic cannabinoids. Though cannabinoids are clinically used for anti-palliative effects, recent studies open a promising possibility as anti-cancer agents. They have been shown to possess anti-proliferative and anti-angiogenic effects in vitro as well as in vivo in different cancer models. Cannabinoids regulate key cell signaling pathways that are involved in cell survival, invasion, angiogenesis, metastasis, etc. There is more focus on CB1 and CB2, the two cannabinoid receptors which are activated by most of the cannabinoids. In this review article, we will focus on a broad range of cannabinoids, their receptor dependent and receptor independent functional roles against various cancer types with respect to growth, metastasis, energy metabolism, immune environment, stemness and future perspectives in exploring new possible therapeutic opportunities.
The use of psychoactive drugs is a wide spread behaviour in human societies. The systematic use of a drug requires the establishment of different drug use-associated behaviours which need to be learned and controlled. However, controlled drug use may develop into compulsive drug use and addiction, a major psychiatric disorder with severe consequences for the individual and society. Here we review the role of the serotonergic (5-HT) system in the establishment of drug use-associated behaviours on the one hand and the transition and maintenance of addiction on the other hand for the drugs: cocaine, amphetamine, methamphetamine, MDMA (ecstasy), morphine/heroin, cannabis, alcohol, and nicotine. Results show a crucial, but distinct involvement of the 5-HT system in both processes with considerable overlap between psychostimulant and opioidergic drugs and alcohol. A new functional model suggests specific adaptations in the 5-HT system, which coincide with the establishment of controlled drug use-associated behaviours. These serotonergic adaptations render the nervous system susceptible to the transition to compulsive drug use behaviours and often overlap with genetic risk factors for addiction. Altogether we suggest a new trajectory by which serotonergic neuroadaptations induced by first drug exposure pave the way for the establishment of addiction.
The Cannabis plant (Cannabis sativa L.) has a long history as a recreational drug, but also as part of traditional medicine in many cultures. Based on the number of publications, it is one of the best-studied plants in the world. The relatively recent discovery of cannabinoid receptors and the human endocannabinoid system has opened up a new and exciting field of research. But despite the pharmaceutical potential of Cannabis, its classification as a narcotic drug has prevented its successful development into modern medicine.
Fortunately, the chemistry of Cannabis has been studied in much detail. In particular the psychoactive cannabinoid tetrahydrocannabinol (THC) has received great scientific attention, and much is known about its biological effects and mechanisms of action. Besides an extensive description of the chemistry of the cannabinoids, this chapter also introduces the lesser-known terpenoids, flavonoids, and other constituents of the Cannabis plant. Comprehensive information on a variety of subjects is presented, including chromatographic analytical methods, pharmacokinetics, and structure-activity relationships. The known biological effects of Cannabis constituents are discussed in relationship to the development of modern cannabinoid-based medications. Finally, some practical aspects of working with Cannabis are discussed.
Marijuana is one of the most widely used illicit psychoactive substances in the U.S. Recently, negative perceptions of marijuana as an abused substance have been tempered somewhat by the idea that it may also have medicinal properties. Regardless of perception of marijuana, however, investigation of its active substituents and their mechanism of action led to the discovery of an endocannabinoid system that is activated by marijuana as well as by several endogenous cannabinoids, including anandamide and 2-arachidonylglycerol. In this chapter, we review the pharmacology of marijuana and discuss how its interaction with the endocannabinoid system may have implications for understanding the physiology of this system.
This chapter reviews evidence that supports the established therapeutic uses of cannabinoid receptor ligands: CB1 and/or CB2
receptor agonists as anti-emetics, appetite stimulants, and analgesics for the relief of neuropathic pain, and CB1 receptor
antagonists for the treatment of obesity and related metabolic risk factors. It also identifies and discusses some additional
potential therapeutic applications of cannabinoid receptor ligands for which the preclinical and clinical evidence is particularly
promising. These include the use of cannabinoid receptor agonists for the management of multiple sclerosis and inflammatory
pain. In addition, brief mention is made of a range of other possible therapeutic uses for cannabinoid receptor agonists,
antagonists, and inverse agonists.
KeywordsΔ9-Tetrahydrocannabinol-Dronabinol-Marinol®
-Sativex®
-Nabilone-Cesamet®
-SR141716A-Rimonabant-Acomplia®
-Pain-Multiple sclerosis-Spasticity-Appetite-Nausea-Vomiting-Obesity
The purpose of this study was to investigate the effect of cyclodextrins (CDs) on aqueous solubility, stability, and in vitro corneal permeability of delta-8-tetrahydrocannabinol (Δ(8)-THC). Phase solubility of Δ(8)-THC was studied in the presence of 2-hydroxypropyl-β-cyclodextrin (HPβCD), randomly methylated-β-cyclodextrin (RMβCD) and sulfobutyl ether-β-cyclodextrin sodium salt (SβCD). Stability of Δ(8)-THC in 5% w/v aqueous CD solutions, as a function of pH, was studied following standard protocols. In vitro corneal permeation of Δ(8)-THC (with and without CDs) across excised rabbit cornea was also determined. Phase-solubility profile of Δ(8)-THC in the presence of both HPβCD and RMβCD was of the A(P) type, whereas, with SβCD an A(L) type was apparent. Aqueous solubility of Δ(8)-THC increased to 1.65, 2.4, and 0.64 mg/mL in the presence of 25% w/v HPβCD, RMβCD, and SβCD, respectively. Significant degradation of Δ(8)-THC was not observed within the study period at the pH values studied, except for at pH 1.2. Transcorneal permeation of Δ(8)-THC was dramatically improved in the presence of CDs. The results demonstrate that CDs significantly increase aqueous solubility, stability, and transcorneal permeation of Δ(8)-THC. Thus, topical ophthalmic formulations containing Δ(8)-THC and modified beta CDs may show markedly improved ocular bioavailability.
Acute exposure to bacterial lipopolysaccharide (LPS) is a potent inducer of immune response as well as hypophagia. Nevertheless, desensitization of responses to LPS occurs during long-term exposure to endotoxin. We induced endotoxin tolerance, injecting repeated (6LPS) LPS doses compared with single (1LPS) treatment. 1LPS, but not 6LPS group, showed decreased food intake and body weight, which was associated with an increased plasma leptin and higher mRNA expression of OB-Rb, MC4R, and SOCS3 in the hypothalamus. Hypophagia induced by 1LPS was associated with lower levels of 2-arachidonoylglycerol (2-AG), increased number of p-STAT3 neurons, and decreased AMP-activated protein kinase (AMPK) activity. Desensitization of hypophagia in the 6LPS group was related to high 2-AG, with no changes in p-STAT3 or increased p-AMPK. Leptin decreased food intake, body weight, 2-AG levels, and AMPK activity and enhanced p-STAT3 in control rats. However, leptin had no effects on 2-AG, p-STAT3, or p-AMPK in the 1LPS and 6LPS groups. Rats treated with HFD to induce leptin resistance showed neither hypophagia nor changes in p-STAT3 after 1LPS, suggesting that leptin and LPS recruit a common signaling pathway in the hypothalamus to modulate food intake reduction. Desensitization of hypophagia in response to repeated exposure to endotoxin is related to an inability of leptin to inhibit AMPK phosphorylation and 2-AG production and activate STAT3. SOCS3 is unlikely to underlie this resistance to leptin signaling in the endotoxin tolerance. The present model of prolonged inflammatory challenge may contribute to further investigations on mechanisms of leptin resistance.
El objetivo de nuestro estudio fue evaluar el uso de recursos sanitarios en un hospital general tras un programa ambulatorio de tratamiento del alcoholismo. Se incluyeron 46 pacientes que iniciaron el tratamiento. Se estableció una comparación del uso de consultas externas de otras especialidades del hospital, ingresos hospitalarios y urgencias, entre los pacientes que permanecían en tratamiento a los 6 meses de iniciarlo y aquellos que no permanecían ese tiempo. Se calculó un índice de uso de cada recurso considerando el tiempo de seguimiento de cada paciente. Los pacientes que permanecieron en tratamiento de deshabituación 6 meses presentaron un descenso significativo en el uso de urgencias y en los ingresos hospitalarios tanto respecto a su nivel pretratamiento como al compararlos con los pacientes que no permanecieron los 6 meses. No hubo diferencias en el uso de consultas externas. Por lo tanto, los programas de deshabituación producen beneficio al reducir la utilización de algunos recursos sanitarios.
The endocannabinoid system consists of several endogenous lipids, including anandamide and 2-arachidonoyl-glycerol (2-AG), and constitute a retrograde signalling system, which modulates neurotransmitter release and synaptic plasticity. Specific brain-type cannabinoid receptors (CB(1)) are widely distributed in the central nervous system, and are localized presynaptically. Mounting evidence, reviewed here, indicates that cannabinoids can act to increase food consumption, and cannabinoid CB(1) receptor antagonists/inverse agonists reduce food intake and suppress operant responding for food rewards. Hence, endocannabinoids provide the first example of a retrograde signalling system, which is strongly implicated in the control of food intake. Benzodiazepine and opioid palatability-dependent appetite are well-established processes supported by several sources of convergent evidence; they provide pharmacological benchmarks against which to evaluate the endocannabinoids. To date, evidence that endocannabinoids specifically modulate palatability as an affective evaluative process is insufficient and not compelling. Endocannabinoids may have important clinical utility in the treatment of human obesity and forms of eating disorders.
We have investigated the effect of 2-arachidonylglyceryl-ether (Noladin) on food consumption, weight, activity, and cognitive function in mice during diet restriction for 17 days and subsequent ad libitum feeding for 32 days. Female Sabra mice were given food for 2.5 h/day (equal to 60% diet restriction), received Noladin (0.001, 0.01, 0.1 mg/(kg day) intraperitonially (i.p.)) with or without the CB1 antagonist SR141716A (1 mg/kg i.p.) during days 3-17. Noladin (0.001 mg/kg) significantly increased food consumption without a change in body weight, probably due to increased activity and there was no change in cognitive function. A higher dose (0.1 mg/kg) did not affect food consumption, but increased activity and slightly decreased weight 32 days after termination of Noladin administration; however, cognitive deterioration was observed. At all doses tested, Noladin did not affect weight during the diet-restriction period, whereas the CB1 antagonist (with or without Noladin) caused a very significant decline in weight in this phase. Weight catch-up was observed 1 month after administration of Noladin was discontinued. Weight at day 32 after the termination of Noladin (0.1 mg/(kg day)) treatment was 5% less than control. Female C57BL/6 mice (same protocol, with 0.001 mg/(kg day) Noladin) gave similar results to 0.1 mg/kg in Sabra mice as regards weight. CB1 antagonist treatment caused very significant decline in both weight and food consumption; cognition and activity were unchanged. These results indicate that Noladin has a significant dose-dependent effect on food consumption, cognition and weight maintenance after weight loss. Low doses of Noladin may possibly allow an increase in food intake without a gain in weight after dieting. Thus, Noladin could be of potential clinical benefit in treating disorders of body weight. Noladin seems to signal food consumption and weight through CB1 receptors based on effects observed with the CB1 antagonist, while the cognition and activity are probably mediated by non-cannabinoid receptors.
The discovery of cannabinoid receptors, together with the development of selective cannabinoid receptor antagonists, has encouraged a resurgence of cannabinoid pharmacology. With the identification of endogenous agonists, such as anandamide, scientists have sought to uncover the biological role of endocannabinoid systems; initially guided by the long-established actions of cannabis and exogenous cannabinoids such as delta9-tetrahydrocannabinol (THC). In particular, considerable research has examined endocannabinoid involvement in appetite, eating behaviour and body weight regulation. It is now confirmed that endocannabinoids, acting at brain CB1 cannabinoid receptors, stimulate appetite and ingestive behaviours, partly through interactions with more established orexigenic and anorexigenic signals. Key structures such as the nucleus accumbens and hypothalamic nuclei are sensitive sites for the hyperphagic actions of these substances, and endocannabinoid activity in these regions varies in relation to nutritional status and feeding expression. Behavioural studies indicate that endocannabinoids increase eating motivation by enhancing the incentive salience and hedonic evaluation of ingesta. Moreover, there is strong evidence of an endocannabinoid role in energy metabolism and fuel storage. Recent developments point to potential clinical benefits of cannabinoid receptor antagonists in the management of obesity, and of agonists in the treatment of other disorders of eating and body weight regulation.
To date, UCM707, (5Z,8Z,11Z,14Z)-N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide, has the highest potency and selectivity in vitro and in vivo as inhibitor of the endocannabinoid uptake. Its biochemical, pharmacological and therapeutic properties have been intensely studied recently, but the information on its capability to modify neurotransmitter activity, which obviously underlies the above properties, is still limited. In the present study, we conducted a time-course experiment in rats aimed at examining the neurochemical effects of UCM707 in several brain regions following a subchronic administration (5 injections during 2.5 days) of this inhibitor in a dose of 5 mg/kg weight. In the hypothalamus, the administration of UCM707 did not modify GABA contents but reduced norepinephrine levels at 5 h after administration, followed by an increase at 12 h. Similar trends were observed for dopamine, whereas serotonin content remained elevated at 1 and, in particular, 5 and 12 h after administration. In the case of the basal ganglia, UCM707 reduced GABA content in the substantia nigra but only at longer (5 or 12 h) times after administration. There were no changes in serotonin content, but a marked reduction in its metabolite 5HIAA was recorded in the substantia nigra. The same pattern was found for dopamine, contents of which were not altered by UCM707 in the caudate-putamen, but its major metabolite DOPAC exhibited a marked decrease at 5 h. In the cerebellum, UCM707 reduced GABA, serotonin and norepinephrine content, but only the reduction found for norepinephrine at 5 h reached statistical significance. The administration of UCM707 did not modify the contents of these neurotransmitters in the hippocampus and the frontal cortex. Lastly, in the case of limbic structures, the administration of UCM707 markedly reduced dopamine content in the nucleus accumbens at 5 h, whereas GABA content remained unchanged in this structure and also in the ventral-tegmental area and the amygdala. By contrast, norepinephrine and serotonin content increased at 5 h in the nucleus accumbens, but not in the other two limbic structures. In summary, UCM707 administered subchronically modified the contents of serotonin, GABA, dopamine and/or norepinephrine with a pattern strongly different in each brain region. So, changes in GABA transmission (decrease) were restricted to the substantia nigra, but did not appear in other regions, whereas dopamine transmission was also altered in the caudate-putamen and the nucleus accumbens. By contrast, norepinephrine and serotonin were altered by UCM707 in the hypothalamus, cerebellum (only norepinephrine), and nucleus accumbens, exhibiting biphasic effects in some cases.
Obesity is one of the most important health threats to the Western world, and the physiology of appetite-regulating hormones has become a major interest in the last decades. One of the orexigenic hormones, ghrelin is the stomach-derived "brain-gut" peptide, which stimulates energy consumption and storage. Ghrelin promotes gluconeogenesis and adipose tissue deposition. Endocannabinoids, such as anandamide and 2-arachydoglycerol, are lipid-like neurotransmitter molecules activating the cannabinoid receptors. Endocannabinoids, apart from the well-known psychological effects, cause an increase in appetite, and they peripherally promote de novo fatty acid synthesis and gluconeogenesis. Adenosine monophosphate-activated protein kinase (AMPK) is an energy-sensing kinase, which responds to changes in the energy levels of the cell and the whole body in order to maintain adequate ATP levels in the cell. Recently, several hormones have been shown to regulate AMPK activity, and interestingly in a strictly tissue-specific manner. Orexigenic agents such as ghrelin and cannabinoids stimulate hypothalamic AMPK leading to increase in appetite while inhibiting AMPK activity in the liver and adipose tissue, therefore leading to lipogenic and diabetogenic effects. Here we summarize the recent data on hormonal AMPK regulation.
Tested 24 male albino rats on an 8-arm maze in a paradigm of sampling with replacement from a known set of items until the entire set was sampled. Exps I-III demonstrate that Ss performed efficiently, choosing an average of more than 7 different arms within the 1st 8 choices, and did not utilize intramaze cues or consistent chains of responses in solving the task. Exps IV-VI examined some characteristics of Ss' memory storage. There was a small but reliable recency effect with the likelihood of a repetition error increasing with the number of choices since the initial instance. This performance decrement was due to interference from choices rather than just to the passage of time. No evidence was found for a primary effect. The data also suggest that there was no tendency to generalize among spatially adjacent arms. Results are discussed in terms of the memory processes involved in this task and human serial learning. (27 ref) (PsycINFO Database Record (c) 2012 APA, all rights reserved)
Norepinephrine (NE) turnover, as estimated by 3-methoxy-4-hydroxyphenylethyleneglycol concentration, was studied in the mediobasal hypothalamus of control and semistarved adult male rats at eight time points of a 24-h period. The marked circadian periodicity of NE turnover with a peak in the dark phase in control rats is completely suppressed in semistarved rats. The average 24-h concentration of the NE precursor tyrosine in brain and of tyrosine flow into brain (calculated from plasma amino acid concentrations) is reduced in semi starved rats, but both brain tyrosine and tyrosine flow show continuing circadian fluctuations.
Administration of heroin or phenobarbital to pregnant mice evokes neurochemical and behavioral deficits consequent to disruption of septohippocampal cholinergic innervation. The present study evaluates the relationship between the drug-induced biochemical changes and the behavioral deficits, applying two different approaches: neural grafting and within-individual correlations of biochemistry and behavior. Mice were exposed transplacentally to phenobarbital or heroin on gestational days 9–18 and tested in adulthood. Drug-exposed mice displayed impaired radial arm maze performance, increases in presynaptic choline transporter sites (monitored with [3H]hemicholinium-3 binding), upregulation of membrane-associated protein kinase C (PKC) activity, and desensitization of the PKC response to a cholinergic agonist, carbachol. Grafting of cholinergic cells to the impaired hippocampus reversed the behavioral deficits nearly completely and restored basal PKC activity and the PKC response to carbachol to normal; the drug effects on hemicholinium-3 binding were also slightly obtunded by neural grafting, but nevertheless remained significantly elevated. There were significant correlations between the performance in the eight-arm maze and both basal PKC activity and PKC desensitization, and to a lesser extent, between behavioral performance and hemicholinium-3 binding. Taken together, these findings indicate an inextricable link between the biochemical effects of prenatal drug exposure on the PKC signaling cascade and adverse behavioral outcomes. The ability of neural grafting to reverse both the drug-induced changes in PKC and behaviors linked to septohippocampal cholinergic function suggest a mechanistic link between this signaling pathway and neurobehavioral teratology caused by heroin or phenobarbital.
Since pre-history, Cannabis sativa has been exploited for its potent and manifold pharmacological actions. Amongst the most renowned of these actions is a tendency to provoke ravenous eating. The characterization of the psychoactive principals in cannabis (exogenous cannabinoids) and, more recently, the discovery of specific brain cannabinoid receptors and their endogenous ligands (endocannabinoids) has stimulated research into the physiological roles of endocannabinoid systems. In this review, we critically discuss evidence from the literature that describe studies on animals and human subjects to support endocannabinoid involvement in the control of appetite. We describe the hyperphagic actions of the exogenous cannabinoid, Delta9-tetrahydrocannabinol, and the endogenous CB1 ligands, anandamide and 2-arachidonylglycerol, and present evidence to support a specific role of endocannabinoid systems in appetitive processes related to the incentive and reward properties of food. A case is made for more comprehensive and systematic analyses of cannabinoid actions on eating, in the anticipation of improved therapies for disorders of appetite and body weight, and a better understanding of the biopsychological processes underlying hunger.
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.
Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
[3H]CP 55,940, a radiolabeled synthetic cannabinoid, which is 10-100 times more potent in vivo than delta 9-tetrahydrocannabinol, was used to characterize and localize a specific cannabinoid receptor in brain sections. The potencies of a series of natural and synthetic cannabinoids as competitors of [3H]CP 55,940 binding correlated closely with their relative potencies in several biological assays, suggesting that the receptor characterized in our in vitro assay is the same receptor that mediates behavioral and pharmacological effects of cannabinoids, including human subjective experience. Autoradiography of cannabinoid receptors in brain sections from several mammalian species, including human, reveals a unique and conserved distribution; binding is most dense in outflow nuclei of the basal ganglia--the substantia nigra pars reticulata and globus pallidus--and in the hippocampus and cerebellum. Generally high densities in forebrain and cerebellum implicate roles for cannabinoids in cognition and movement. Sparse densities in lower brainstem areas controlling cardiovascular and respiratory functions may explain why high doses of delta 9-tetrahydrocannabinol are not lethal.
The effect of systemically administered delta 9-tetrahydrocannabinol (THC), the psychoactive ingredient in marijuana, on the potassium-evoked release of dopamine (DA) was examined in the neostriatum of the chloral hydrate anesthetized rat. Both in vivo electrochemical and in vivo microdialysis techniques were employed. A low dose of THC (0.5 mg/kg, i.p.) increased the time course of potassium-evoked in vivo electrochemical signals corresponding to released extracellular DA. In vivo microdialysis showed an increase in potassium-evoked DA release following 0.5 and 2.0 mg/kg doses of THC. Potassium-evoked electrochemical signals corresponding to released extracellular DA were augmented in time course following i.p. administration (5.0 mg/kg) of nomifensine, a recognized and potent catecholaminergic reuptake blocker. In addition, in vivo brain microdialysis studies of nomifensine (5.0 mg/kg i.p.) on neostriatal potassium-evoked DA release showed that DA levels were augmented in magnitude over the time course of the microdialysis. Taken together, these studies indicate that THC has a potent presynaptic augmenting effect on at least the neostriatal portions of the mesotelencephalic DA system in the rat, although the possibility that this effect could be mediated transsynaptically cannot be ruled out. Given the previous extensive evidence for an involvement of portions of the mesotelencephalic DA system in mediating the reinforcing and euphorigenic properties of many classes of abused drugs, and in mediating direct electrical brain stimulation reward, we suggest that the presently demonstrated effects of THC on forebrain dopamine function may be related to marijuana's euphorigenic properties and, thus, to its abuse potential.
Norepinephrine (NE) and 3-methoxy-4-hydroxyphenylglycol (MOPEG) were determined in medio-basal hypothalamus of adult male rats using high-performance liquid chromatography to study nutritional modulation of noradrenergic turnover. Acute starvation, as well as 3 weeks of semistarvation with a low-protein high-carbohydrate or high-protein low-carbohydrate diet decreased NE turnover significantly, as estimated by MOPEG concentration. Low-protein semistarvation resulted in subnormal concentrations of large neutral amino acids (LNAA), high-protein semistarvation in elevated concentrations. Tyrosine/LNAA ratio and calculated tyrosine flow into brain and brain tyrosine levels were reduced in both types of semistarvation. Corticosterone was low in low-protein and high in high-protein diet. These results suggest that tyrosine availability in brain potentially contributes to reduced NE turnover in starvation.
In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2--the two cannabinoid receptors identified thus far--with Ki values of 472 +/- 55 and 1400 +/- 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of delta 9-tetrahydrocannabinol (delta 9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of delta 9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than delta 9-THC.
The major active ingredient of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), has been used as a psychoactive agent for thousands of years. Marijuana, and delta 9-THC, also exert a wide range of other effects including analgesia, anti-inflammation, immunosuppression, anticonvulsion, alleviation of intraocular pressure in glaucoma, and attenuation of vomiting. The clinical application of cannabinoids has, however, been limited by their psychoactive effects, and this has led to interest in the biochemical bases of their action. Progress stemmed initially from the synthesis of potent derivatives of delta 9-THC, and more recently from the cloning of a gene encoding a G-protein-coupled receptor for cannabinoids. This receptor is expressed in the brain but not in the periphery, except for a low level in testes. It has been proposed that the nonpsychoactive effects of cannabinoids are either mediated centrally or through direct interaction with other, non-receptor proteins. Here we report the cloning of a receptor for cannabinoids that is not expressed in the brain but rather in macrophages in the marginal zone of spleen.
Two subtypes of cannabinoid receptors have been identified to date, the CB, receptor, essentially located in the CNS, but also in peripheral tissues, and the CB2 receptor, found only at the periphery. The identification of Δ9-tetrahydrocannabinol (Δ9-THC) as the major active component of marijuana (Cannabis sativa), the recent emergence of potent synthetic ligands and the identification of anandamide and sn-2 arachidonylglycerol as putative endogenous ligands for cannabinoid receptors in the brain, have contributed to advancing cannabinoid pharmacology and approaching the neurobiological mechanisms involved in physiological and behavioral effects of cannabinoids. Most of the agonists exhibit nonselective affinity for CB1/CB2 receptors, and Δ9-THC and anandamide probably act as partial agonists. Some recently synthesized molecules are highly selective for CB2 receptors, whereas selective agonists for the CB1 receptors are not yet available. A small number of antagonists exist that display a high selectivity for either CB1 or CB2 receptors. Cannabinomimetics produce complex pharmacological and behavioral effects that probably involve numerous neuronal substrates. Interactions with dopamine, acetylcholine, opiate, and GABAergic systems have been demonstrated in several brain structures. In animals, cannabinoid agonists such as Δ9-THC, WIN 55,212-2, and CP 55,940 produce a characteristic combination of four symptoms, hypothermia, analgesia, hypoactivity, and catalepsy. They are reversed by the selective CB1 receptor antagonist, SR 141716, providing good evidence for the involvement of CB1-related mechanisms. Anandamide exhibits several differences, compared with other agonists. In particular, hypothermia, analgesia, and catalepsy induced by this endogenous ligand are not reversed by SR 141716. Cannabinoid-related processes seem also involved in cognition, memory, anxiety, control of appetite, emesis, inflammatory, and immune responses. Agonists may induce biphasic effects, for example, hyperactivity at low doses and severe motor deficits at larger doses. Intriguingly, although cannabis is widely used as recreational drug in humans, only a few studies revealed an appetitive potential of cannabimimetics in animals, and evidence for aversive effects of Δ9-THC, WIN 55,212-2, and CP 55,940 is more readily obtained in a variety of tests. The selective blockade of CB1 receptors by SR 141716 impaired the perception of the appetitive value of positive reinforcers (food, cocaine, morphine) and reduced the motivation for sucrose, beer and alcohol consumption, indicating that positive incentive and/or motivational processes could be under a permissive control of CB1-related mechanisms. There is little evidence that cannabinoid systems are activated under basal conditions. However, by using SR 141716 as a tool, a tonic involvement of a CB1-mediated cannabinoid link has been demonstrated, notably in animals suffering from chronic pain, faced with anxiogenic stimuli or highly motivational reinforcers. Some effects of SR 141716 also suggest that CB1-related mechanisms exert a tonic control on cognitive processes. Extensive basic research is still needed to elucidate the roles of cannabinoid systems, both in the brain and at the periphery, in normal physiology and in diseases. Additional compounds, such as selective CB1 receptor agonists, ligands that do not cross the blood brain barrier, drugs interfering with synthesis, degradation or uptake of endogenous ligand(s) of CB receptors, are especially needed to understand when and how cannabinoid systems are activated. In turn, new therapeutic strategies would likely to emerge.
Two subtypes of cannabinoid receptors (CB-R) have been identified to date, the CB1-R, essentially located in the CNS, and the CB2-R, found at the periphery. Δ9-Tetrahydrocannabinol (Δ9-THC) is the major active component of Cannabis sativa, anandamide is a putative endogenous ligand, WIN 55,212-2 and CP 55,940, HU-210, are potent synthetic ligands, all are CB1/CB2 non-selective agonists. In animals, they produce a characteristic combination of four symptoms, hypothermia, analgesia, hypoactivity and catalepsy, all reversed by the selective CB1-R antagonist, SR 141716. Anandamide exhibits several differences, compared to other agonists since hypothermia, analgesia and catalepsy are not reversed by SR 141716. Cannabinoid-related processes seem also involved in cognition, memory, anxiety, control of appetite, emesis, intraocular pressure, inflammatory and immune responses. Intriguingly, although Cannabis is widely used as recreational drug in humans, only a few studies revealed an appetitive potential of cannabimimetics in animals, and evidence for aversive effects of Δ9-THC and other agonists is more readily obtained in a variety of tests. SR 141716 impairs the perception of the appetitive value of positive reinforcers (food, cocaine, morphine), and reduces the motivation for sucrose, beer and alcohol consumption, indicating that positive incentive and/or motivational processes could be under a permissive control of CB1-related mechanisms. There is little evidence that cannabinoid systems are activated under basal conditions. However, a tonic involvement of a CB1-mediated cannabinoid link has been demonstrated, notably in animals suffering from chronic pain, faced with anxiogenic stimuli or highly motivational reinforcers. CB1-related mechanisms might also exert a tonic control on cognitive processes.
• Patients with anorexia nervosa have disturbances of mood, appetite, and neuroendocrine function. Central nervous system monoamine pathways modulate these systems, and alterations in function of these systems may occur in anorexia nervosa. Because monoamine metabolism can be influenced by nutritional intake, we studied anorectics before and at intervals after correction of weight loss. Underweight anorectics had a 30% decrease in CSF homovanillic acid level and a 20% decrease in CSF 5-hydroxyindoleacetic acid concentration; these values returned to normal shortly after weight recovery. The CSF level of norepinephrine (NE) in underweight anorectics and in these patients a few weeks after weight restoration was similar to that in normal subjects. Long-term weight-recovered (20 ± 7 months) anorectics, however, had a 50% decrease in CSF NE level compared with that of controls. Underweight anorectics have state-associated disturbances in dopamine and serotonin metabolism. Changes in NE metabolism are more complex and state independent. These abnormalities in neurotransmitter metabolism are part of the neurobiological syndrome of anorexia nervosa and may contribute to the characteristic changes in mood, behavior, and neuroendocrine function.
[DELTA]9-Tetrahydrocannabinol ([DELTA]9-THC), the most prominent psychoactive cannabinoid in Cannabis sativa L. (marijuana), has been reported to have properties of appetite stimulation, promotion of weight gain, and antiemetic efficacy in selected patient populations. In this 4-week, double-blind, crossover study, 11 female patients with primary anorexia nervosa (PAN) were evaluated on [DELTA]9-THC and on an active placebo, diazepam. All patients participated in a standardized behavior modification treatment program. The following data were obtained: (1) daily weight, (2) daily caloric intake, and (3) weekly psychiatric assessments. The two groups were comparable on all measures at baseline except for two items on the behavioral rating scales. The only significant differences found between the changes over time on [DELTA]9-THC versus diazepam were more pathology on [DELTA]9-THC for somatization, interpersonal sensitivity, and sleep disturbance. Three patients experienced severe dysphoric reactions consisting of paranoid ideation and feelings of loss of control during [DELTA]9-THC administration. One week after the study ended, each subject was given the highest dose level of [DELTA]8-THC achieved in the study, and periodic blood samples were obtained coincident with self-rated "subjective high" assessments and pulse measurements. Quantitative analyses of these samples indicated peak times of 1 to 5 hours postdose for [DELTA]9- THC and for its primary active metabolite, 11-hydroxy-THC, which generally coincided with peak times for "subjective high" and pulse rate. The results of this clinical investigation suggest that [DELTA]9-THC is not efficacious, in short-term administration, in the treatment of primary anorexia nervosa and is associated with significant psychic disturbance in some PAN patients.
The existence of an endogenous cannabinoid system was demonstrated conclusively with the discovery of endogenous brain constituents capable of activating the cannabinoid receptors functionally. These compounds are synthesized by neuronal cells and inactivated through re-uptake and enzymatic hydrolysis by both neurons and astrocytes. In analogy with the endorphins they can be referred to as endocannabinoids. Apart from the identification of their metabolic pathways, research carried out in the past six years has focused on the possible cellular and molecular targets for the actions of endocannabinoids. These studies have confirmed a similarity between the endocannabinoids and the psychoactive substance in marijuana, Δ9(−)-tetrahydrocannabinol, and have suggested a role for endocannabinoids in the modulation of neurotransmitter action and release.
A reproducible behavior correlate of aging in rodents is deficient performance of inhibitory avoidance memory tasks. Impaired performance has been attributed, in part, to age-related changes in brain norepinephrine (NE) system function. To determine whether supplemenation of brain NE can ameliorate avoidanace deficits in aged animals, we transplanted noradrenergic locus coeruleus neurons from fetal rat donors into the cerebral ventricle of 24-month-old male F344 rats. Aged rats that received NE-containing grafts exhibited significant improvement of inhibitory avoidance retention performance compared to both unoperated aged animals and aged animals that received grafts of cerebellar tissue. Improved behavioral performance was prevented by pretreatment of NE graft recipients with the β-adrenergic receptor blocking agent, propranolol, and was mimicked by chronic intraventricular infusion of NE. Taken together, our findings support the view that age-related declines in brain NE content contribute to age-related deficits in inhibitory avoidance performance, and that NE replacement therapy can improve performance of this task in aged rats.
In this study, we report the isolation from canine intestines of 2-arachidonyl glycerol (2-Ara-Gl). Its structure was determined by mass spectrometry and by direct comparison with a synthetic sample. 2-Ara-Gl bound to membranes from cells transiently transfected with expression plasmids carrying DNA of either CB1 or CB2—the two cannabinoid receptors identified thus far—with Ki values of 472 ± 55 and 1400 ± 172 nM, respectively. In the presence of forskolin, 2-Ara-Gl inhibited adenylate cyclase in isolated mouse spleen cells, at the potency level of Δ9-tetrahydrocannabinol (Δ9-THC). Upon intravenous administration to mice, 2-Ara-Gl caused the typical tetrad of effects produced by THC: antinociception, immobility, reduction of spontaneous activity, and lowering of the rectal temperature. 2-Ara-Gl also shares the ability of Δ9-THC to inhibit electrically evoked contractions of mouse isolated vasa deferentia; however, it was less potent than Δ9-THC.
The effect of the cannabinoid CB1 receptor antagonist, SR 141716, on food intake and body weight was assessed in adult, non-obese Wistar rats. The daily administration of SR 141716 (2.5 and 10 mg/kg; i.p.) reduced dose-dependently both food intake and body weight. Tolerance to the anorectic effect developed within 5 days; in contrast, body weight in SR 141716-treated rats remained markedly below that of vehicle-treated rats throughout the entire treatment period (14 days). The results suggest that brain cannabinoid receptors are involved in the regulation of appetite and body weight.
This investigation reports the possible role of the endocannabinoid anandamide on modulating the behavioral and neurochemical consequences of semi-starvation. We studied the effect of very low dose anandamide (0.001 mg/kg) administration on food intake, cognitive function and catecholaminergic and serotonergic pathways in two murine brain areas concerned with appetite (hypothalamus) and learning (hippocampus), and the peripheral corticosterone response to the stress of 40% diet restriction. Anandamide-treated mice consumed 44% more food (P<0.05) during 1 week of 2.5-h feeding each day. In the hypothalamus, there were significantly increased concentrations of norepinephrine (P<0.01), dopamine (P<0.05) and 5-hydroxytryptamine (5-HT) (P<0.001). In the hippocampus, anandamide increased significantly norepinephrine and dopamine, but decreased 5-HT (all at P<0.001). Diet restriction was accompanied in both areas by a significant decrease in all neurotransmitter concentrations that were partially restored by anandamide for dopamine and 5-HT, but not for norepinephrine. In animals on diet restriction, anandamide significantly improved impaired maze performance. Norepinephrine turnover and plasma corticosterone levels were also raised significantly by anandamide. The fact that low dose anandamide improved food intake, cognitive function and reversed some of the neurotransmitter changes caused by diet restriction, might have implications for the treatment of cachexia associated with acquired immunodeficiency syndrome (AIDS) and cancer, for mood changes sometimes associated with dieting, and in the extreme case, of patients with anorexia.
The involvement of cannabinoid processes in positive reinforcement was studied using an unbiased, one-compartment, conditioned place preference (CPP) procedure in rats. This was achieved by examining the ability of the selective antagonist of the CB1 cannabinoid receptor subtype, SR 141716, to counteract the CPP supported by classical reinforcers. The acquisition of CPP induced by cocaine (2 mg/kg), morphine (4 mg/kg) and food (standard chow and sucrose pellets) was dose-dependently blocked by pre-pairing administration of SR 141716 (0.03-3 mg/kg). However, SR 141716 (up to 10 mg/kg) did not significantly counteract the expression of cocaine-induced CPP. On the other hand, the synthetic CB receptor agonist, WIN 55212-2 (0.3-1 mg/kg), established a robust place aversion (CPA), as already described with other agonists, and CPP was never observed, even at 100-fold lower doses. The aversive effect of WIN 55212-2 was reversed by SR 141716 (0.3-1 mg/kg), suggesting that it was accounted for by the stimulation of CB1 receptors. These findings indicate that, on their own, CB receptor agonists are unable to generate the processes necessary to induce a pleasurable state in animals, as assessed in place conditioning procedures. Nevertheless, a cannabinoid link may be involved in the neurobiological events, allowing the perception of the rewarding value of various kinds of reinforcers. However, a permanent endogenous cannabinoid tone seems unlikely to be necessary to ensure the organism a basal hedonic level since, given alone, SR 141716 supported neither CPP nor CPA.
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.
The activity of tyrosine hydroxylase (TH), the rate-limiting enzyme in norepinephrine synthesis, was determined in the mediobasal hypothalamus of adult male rats during acute and semistarvation. 3,4-Dihydroxyphenylalanine (DOPA) formed by TH was measured using high-performance liquid chromatography (HPLC). Acute starvation, as well as 3 weeks of semistarvation on a high-protein low-carbohydrate diet (CST PR) reduced TH activity significantly. Three weeks of a low-protein high-carbohydrate diet (CST KH) did not affect TH activity. While maximal velocity (Vmax) is significantly diminished in acute starvation and in semistarvation with a high-protein low-carbohydrate diet, Kd-values for tyrosine were not changed. These results suggest that TH activity in the brain contributes to decreased norepinephrine (NE) turnover in starvation.
Adult female rats received daily oral doses of delta 9-tetrahydrocannabinol (delta 9-THC), delta 8-THC and cannabidiol (CBD) throughout gestation and lactation. The offspring were sacrificed at various ages and tissue samples of cerebral cortex and striatum were assayed for alpha 1-adrenergic and D2-dopaminergic receptors, respectively. In addition, tyrosine hydroxylase activity was determined in the striatum. The Kd for ligand binding to alpha 1 receptors in the cerebral cortex was significantly increased in 10-day-old offspring exposed to CBD. Significant increases in the Bmax of these receptors occurred at 20 days of age following perinatal exposure to delta 9-THC or delta 8-THC. Exposure to CBD increased the Kd of D2 receptors in the striatum of 10 and 20-day-old offspring compared to control. There were no significant treatment effects on the Bmax of D2 receptors in the striatum at any age. Tyrosine hydroxylase activity was significantly decreased only at 60 days of age in offspring exposed to delta 8-THC or CBD. These results differ from those previously reported with a crude marihuana extract, suggesting that changes in the development of brain catecholamine mechanisms resulting from perinatal exposure to marihuana extracts may be due to an additional constituent of the extract, interactions between specific cannabinoids or other unknown factors.
The effects of chronic administration of delta 9-tetrahydrocannabinol (delta 9-THC) on the plasma and brain catecholamine (CA) levels were measured using high performance liquid chromatography-electrochemical detection (LC-EC) system. Intact male rats were injected daily with vehicle (50 microliter oil) or with delta 9-THC (3 mg/kg body wt) over a period of 25 days. Trunk plasma and tissue from preoptic area (POA) and mediobasal hypothalamus (MBH) were collected and catecholamine levels were detected by LC-EC system coupled to an electronic integrator. Alumina extract of tissue and plasma samples, spiked with the internal standard (dihydroxybenzylamine), were injected into the LC-EC system; the CA were chromatographed and eluted within 12 minutes using sodium phosphate buffer as the mobile phase. delta 9-THC treatment resulted in a significant decrease in plasma and MBH levels of norepinephrine (NE), epinephrine (E), POA levels of NE; and significant increases in MBH levels of dopamine (DA) and dihydroxyphenylacetic acid (DOPAC). Our study indicates for the first time that delta 9-THC treatment significantly alters not only the POA and MBH CA levels, but also the plasma CA levels.
Repeated oral administration of the non-psychoactive cannabinol (CBN; 5 or 50 mg/kg) significantly reduced the concentration of norepinephrine (NE) in median eminence and greatly reduced NE levels 1 and 2 hrs after administration of alpha-methylparatyrosine (alpha-MPT). The levels of dopamine (DA) in median eminence were significantly different, as indicated by the differences in slopes obtained in CBN- treated and control mice before and after alpha-MPT. Plasma levels of luteinizing hormone (LH) were significantly reduced in CBN-exposed mice before alpha-MPT, elevated at 1 hr post-injection, but were also reduced 2 hrs post-injection at 50 mg/kg CBN. Follicle-stimulating hormone (FSH) levels were increased at 1 hr post-alpha-MPT in mice receiving 50 mg/kg CBN. Oral administration of CBN at 50 mg/kg for 4 days enhanced testicular testosterone (T) production in response to intratesticular in vivo injection of 2.5 or 25 mIU human chorionic gonadotropin (hCG). A single oral dose of the psychoactive delta 9-tetrahydrocannabinol (THC) enhanced the production of T 15 min after intratesticular LH (10 ng) injection. However, at 45 or 60 min post-THC treatment, the response to LH was significantly attenuated. These studies demonstrate that both psychoactive and non-psychoactive components of marihuana alter testicular responsiveness to gonadotropins in vivo. These effects may be biphasic, involving stimulation and inhibition of responsiveness, and appear to be correlated with alterations in plasma LH levels. Alterations in plasma gonadotropins may be mediated by cannabinoid effects on catecholamine concentrations in median eminence and THC-induced alterations in testicular responsiveness to gonadotropin probably also involve direct effects of THC at the gonadal level.
The present study was designed to examine the influence of delta 9-tetrahydrocannabinol (THC) on the central dopaminergic system using circling behavior. THC 5 mg/kg i.p. produced ipsilateral circling in rats with unilateral nigral lesion by 6-hydroxy-dopamine. THC-induced ipsilateral circling was completely antagonized by 0.2 mg/kg of haloperidol. These findings suggest that THC may cause a presynaptic stimulation of nigrostriatal dopaminergic neurons.
Studies performed during the past decade have shown that the rates at which certain neurons produce and release their neurotransmitters can be affected by precursor availability, and thus by the changes in plasma composition that occur after ingestion of the precursors in purified form or as constituents of foods. Thus, tryptophan administration or a plasma ratio of tryptophan to other large neutral amino acids, thereby raising brain tryptophan levels, increasing the substrate saturation of tryptophan hydroxylase, and accelerating the synthesis and release of serotonin. Tyrosine administration or a high-protein meal similarly elevates brain tyrosine and can accelerate catecholamine synthesis in the CNS and sympathoadrenal cells, while the consumption of lecithin or choline increases brain choline levels and neuronal acetylcholine synthesis. The physiologic and biochemical mechanisms that must exist in order for nutrient consumption to affect neurotransmitte synthesis have been characterized and include: 1) the lack of significant feedback control of plasma levels of the precursor; 2) the lack of a real "bloodbrain barrier" for the precursor, i.e. the ability of the plasma level of the precursor to control its influx into, or efflux from, the CNS; 3) the existence of a low-affinity (and thus unsaturated) transport system mediating the flux of the precursor between blood and brain; 4) low-affinity kinetics for the enzyme that initiates the conversion of the precursor to the transmitter; and, 5) the lack of end-product inhibition of the enzyme, in vivo, by its ultimate product, the neurotransmitter. The extent to which neurotransmitter synthesis in any particular aminergic neuron happens to be affected by changes in the availability of its precursor probably varies directly with the neuron's firing frequency. This relationship allows precursor administration to produce selective physiologic effects by enhancing neurotransmitter release from some but not all of the neurons potentially capable of utilizing the precursor for this purpose. It also allows the investigator to predict when administering the precursor might be useful for amplifying a physiologic process, or for treating a pathologic state. (for example, tyrosine administration raises blood pressure in hypotensive rats, lowers it in hypertensive animals, and has little effect on blood pressure in normotensive animals; the elevation in blood pressure probably reflects enhanced catecholamine release from sympathoadrenal cells, while the reduction in hypertensive animals probably results from increased catecholamine release within the brain-stem.) Such predictions are now being tested clinically in many institution. Available evidence suggests that lecithin or cholie administration can diminish the frequency of abnormal movements in patients with tardive dyskinesia...
Patients with anorexia nervosa have disturbances of mood, appetite, and neuroendocrine function. Central nervous system monoamine pathways modulate these systems, and alterations in function of these systems may occur in anorexia nervosa. Because monoamine metabolism can be influenced by nutritional intake, we studied anorectics before and at intervals after correction of weight loss. Underweight anorectics had a 30% decrease in CSF homovanillic acid level and a 20% decrease in CSF 5-hydroxyindoleacetic acid concentration; these values returned to normal shortly after weight recovery. The CSF level of norepinephrine (NE) in underweight anorectics and in these patients a few weeks after weight restoration was similar to that in normal subjects. Long-term weight-recovered (20 +/- 7 months) anorectics, however, had a 50% decrease in CSF NE level compared with that of controls. Underweight anorectics have state-associated disturbances in dopamine and serotonin metabolism. Changes in NE metabolism are more complex and state independent. These abnormalities in neurotransmitter metabolism are part of the neurobiological syndrome of anorexia nervosa and may contribute to the characteristic changes in mood, behavior, and neuroendocrine function.
CSF tyrosine, tryptophan, 5-hydroxyindoleacetic acid, 3-methoxy-4-hydroxyphenylglycol (MHPG), homovanillic acid (HVA), gamma-aminobutyric acid, choline, and calcium were compared in 33 anorexic and 14 normal women. The only significant difference between groups was a lower tyrosine level in the anorexic patients; their MHPG level was nonsignificantly higher. No significant group differences in body weight or depressive subgroup were found. HVA levels were positively related to body weight, and choline was negatively correlated with anorexia severity. The role of tyrosine requires furth