Cannabinoids

Cannabis is considered as the most controversial plant worldwide, next to the important medical use, and it is also the most frequently consumed drug of abuse in European countries [1]. Cannabis products can be consumed in a variety of ways, such as smoking, vaporizing, preparing cannabis tea and using it in baked products [2]. The use of cannabis products (e.g. marijuana, hashish), particularly among the young generations, is increased lately and it has been studied in many epidemiological surveys [3]. Marijuana continues to be the most readily available drug of abuse in Albania and the number and size of marijuana seizures have also been increased. Since nineteen's, Albania has become the major supplier of cannabis to other countries, such as Greece and Italy [4]. Following large societal concerns and neighbor countries' pressure, very restrictive policies have been put in force from the Albanian legislative power; since 2004 only the industrial hemp can be cultivated in Albania, and the fiber-type seeds should not exceed an amount of 0.1% of tetrahydrocannabinol, according to the actual law [5]. Delta-9-tetrahydrocannabinol (THC) is one of the major cannabinoids in Cannabis sativa and it has been proven to be the compound that possesses the psychoactive properties [6]. The endocannabinoid system includes two receptors, CB 1 and CB 2 ; and possibly others, expressed in the central nervous system, in the peripheral nervous system as well in a variety of circulating immune cells [7]. An oral dose of 20 mg of THC produces effects of mood, memory, motor coordination, cognitive ability, sensorium and self-perception; most commonly there is an increased sense of well-being or euphoria, followed from relaxation and sleepiness [8]. Rewarding effects and equivalents of a withdrawal syndrome are described, particularly with behavioral manifestations [9].

All too often neglected, maximal quality improvement in the setting of life-limiting illness and noxious symptomatology is a worthy medical, public health, and humanitarian goal. The World Health Organization estimates that, globally, about 60% of all people who die would benefit from palliative care before death; however, palliative care is not exclusively reserved for patients at the end of life 1 .

Cannabinoids have been reported to provide neuroprotection in acute and chronic neurodegeneration. In this study, we examined whether they are also effective against the toxicity caused by 6-hydroxydopamine, both in vivo and in vitro, which may be relevant to Parkinson's disease (PD). First, we evaluated whether the administration of cannabinoids in vivo reduces the neurodegeneration produced by a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. As expected, 2 weeks after the application of this toxin, a significant depletion of dopamine contents and a reduction of tyrosine hydroxylase activity in the lesioned striatum were noted, and were accompanied by a reduction in tyrosine hydroxylase-mRNA levels in the substantia nigra. None of these events occurred in the contralateral structures. Daily administration of D 9 -tetrahydrocannabinol (D 9 -THC) during these 2 weeks produced a significant waning in the magnitude of these reductions, whereas it failed to affect dopaminergic parameters in the contralateral structures. This effect of D 9 -THC appeared to be irreversible since interruption of the daily administration of this cannabinoid after the 2-week period did not lead to the re-initiation of the 6-hydroxydopamine-induced neurodegeneration. In addition, the fact that the same neuroprotective effect was also produced by cannabidiol (CBD), another plant-derived cannabinoid with negligible affinity for cannabinoid CB 1 receptors, suggests that the antioxidant properties of both compounds, which are cannabinoid receptorindependent, might be involved in these in vivo effects, although an alternative might be that the neuroprotection exerted by both compounds might be due to their anti-inflammatory potential. As a second objective, we examined whether cannabinoids also provide neuroprotection against the in vitro toxicity of 6-hydroxydopamine. We found that the non-selective cannabinoid agonist HU-210 increased cell survival in cultures of mouse cerebellar granule cells exposed to this toxin. However, this effect was significantly lesser when the cannabi-noid was directly added to neuronal cultures than when these cultures were exposed to conditioned medium obtained from mixed glial cell cultures treated with HU-210, suggesting that the cannabinoid exerted its major protective effect by regulating glial influence to neurons. In summary, our results support the view of a potential neuroprotective action of cannabinoids against the in vivo and in vitro toxicity of 6hydroxydopamine, which might be relevant for PD. Our data indicated that these neuroprotective effects might be due, among others, to the antioxidant properties of certain plant-derived cannabinoids, or exerted through the capability of cannabinoid agonists to modulate glial function, or produced by a combination of both mechanisms. D

The active ingredient of marijuana is(−)-Δ 9 -tetrahydrocannabinol(Δ 9 -THC).Δ 9 -THC and other natural and synthetic cannabinoids such as CP-55, 940 inhibit spontaneous activity and produce catalepsy in animals in a receptor-mediated fashion. Tolerance develops to the motor ...

Muitos estudos têm chamado atenção para a Cannabis sativa (Cs), pelo seu potencial analgésico e pela sua capacidade de aliviar sintomas relacionados com doenças do sistema nervoso central. Porém, a maconha, como é popularmente conhecida, por ser a mais popular das drogas ilegais em todo o mundo, gera preconceito tanto entre leigos como entre profissionais que atuam na área da saúde. Objetivou-se pesquisar o nível de conhecimento atual e suas perspectivas de utilização para compreender melhor suas ações e seus efeitos, na pesquisa experimental e na prática médica, em pacientes com doenças degenerativas neurológicas ou naqueles que não tenham possibilidades de cura, atendidos em programas de cuidados paliativos. CONTEÚDO: Seu uso terapêutico não é recente. O presente estudo fornece uma revisão do histórico e farmacologia da Cs, o desenvolvimento de seu uso terapêutico por meio dos canabinóides sintéticos, o conhecimento científico atual, suas conseqüências orgânicas e psíquicas, demonstrando suas opções de uso clínico e perspectivas futuras. CONCLUSÕES: O delta-9-tetrahidrocanabinol (∆ 9-THC) puro e seus análogos apresentam aplicabilidade clínica, demonstrando benefícios. O desenvolvimento das substâncias sintéticas puras, buscando a atenuação de efeitos psicoativos indesejáveis aponta para perspectivas favoráveis a sua utilização no futuro. Estudos mais detalhados deverão ser realizados. Debates amplos serão necessários para criar normas de formulação e disponibilização com a finalidade médica, por se tratar de uma substância que gera preconceito pela sua comercialização e utilização ilegal e a seu uso ser atribuído misticismo.

Keywords: Endocannabinoid; cannabinoid receptor; Afferent; Nerve; Rat; Urinary bladder Word counts of Abstract: 250/250 Word counts of manuscript (main text+abstract): 2999/3000 words Number of references: 30/30 ABSTRACT Purpose: Fatty acid amide hydrolase (FAAH) degrades endocannabinoids and fatty acid

This article is organized as follows. The background section describes the case of newly legalized recreational marijuana. It introduces Portland, Oregon as a hub of ethical consumerism and environmental mobilization; outlines the status of recreational marijuana in Oregon and in the United States; highlights environmental issues related to the cannabis production; and describes an uptick in ethical consumerism of other recreational drugs in the United States. Next, the theoretical framework organizes extant research on political consumerism and suggests how this study may contribute to knowledge on emerging industries, the role of stigmas in framing, and power dynamics at the retail level of analysis. Following, the methodology section describes the three methods used in this study: qualitative analysis of internet research, networking, and semi­structured interviews; quantitative analysis of data collected at a random sample of 64 dispensaries; and spatial and statistical analysis relating the dispensary findings to socio­demographic indicators. The findings section offers what the author believes to be the first account of ethical consumerism in the licit recreational marijuana sector. It demonstrates that there is, indeed, a nascent “political consumerism movement” in the licit, recreational marijuana sector. The movement is largely industry­driven and is marked by an absence of third sector actors (such as environmental NGOs, fair trade certification organizations, and agricultural justice advocates). Mobilization efforts are challenged by two distinct stigmas: cannabis cultivation as a “natural” (and thus necessarily environmentally­friendly) process, and the marijuana industry as a “criminal” enterprise (which may deter potential allies). Interestingly, the distribution of “ethical” pot is quite consistent across neighborhoods of different socio­economic compositions­­in contrast to most ethically­oriented products. The paper closes with a discussion of these findings, their implications, and suggestions for further research.

Cannabinoids exert complex actions on neurotransmitter systems involved in cognition, locomotion, appetite, but no information was available so far on the interactions between the endocannabinoid system and histaminergic neurons that command several, similar behavioural states and memory. In this study, we investigated the effect of cannabimimetic compounds on histamine release using the microdialysis technique in the brain of freely moving rats. We found that systemic administration of the cannabinoid receptors 1 (CB1-r) agonist arachidonyl-2′chloroethylamide/N-(2chloroethyl)-5Z, 8Z,11Z,14Z-eicosatetraenamide (ACEA; 3 mg/kg) increased histamine release from the posterior hypothalamus, where the histaminergic tuberomamillary nuclei (TMN) are located. Local infusions of ACEA (150 nM) or R(+)-methanandamide (mAEA; 1μM), another CB1-r agonist, in the TMN augmented histamine release from the TMN, as well as from two histaminergic projection areas, the nucleus basalis magnocellularis and the dorsal striatum. When the endocannabinoid uptake inhibitor AM404 was infused into the TMN, however, increased histamine release was observed only in the TMN. The cannabinoid-induced effects on histamine release were blocked by co-administrations with the CB1-r antagonist AM251. Using double-immunofluorescence labelling and confocal laserscanning microscopy, CB1-r immunostaining was found in the hypothalamus, but was not localized onto histaminergic cells. The modulatory effect of cannabimimetic compounds on histamine release apparently did not involve inhibition of γ-aminobutyric acid (GABA)ergic neurotransmission, which provides the main inhibitory input to the histaminergic neurons in the hypothalamus, as local infusions of ACEA did not modify GABA release from the TMN. These profound effects of cannabinoids on histaminergic neurotransmission may partially underlie some of the behavioural changes observed following exposure to cannabinoid-based drugs.

Serotonin, acting in the peripheral nervous system, can exacerbate sleep-related apnea, and systemically administered serotonin antagonists reduce sleep-disordered respiration in rats and bulldogs. Because cannabinoid receptor agonists are known to inhibit the excitatory effects of serotonin on nodose ganglion cells, we examined the effects of endogenous (oleamide) and exogenous (delta9-tetrahydrocannabinol; delta9THC) cannabimimetic agents on sleep-related apnea. Sleep architecture, respiratory pattern, and apnea expression in rats were assessed by polysomnography. A repeated measures, within-subjects, fully nested crossover design was used in which each animal was recorded on exactly 12 occasions. Eleven adult male Sprague-Dawley rats were instrumented for chronic polysomnography. Animals were recorded following intraperitoneal injection of various doses of delta9THC, oleamide, and serotonin, alone and in combination. Our data show that delta9THC and oleamide each stabilized respi...

Cannabis use is highly prevalent among people with schizophrenia, and coupled with impaired cognition, is thought to heighten the risk of illness onset. However, while heavy cannabis use has been associated with cognitive deficits in long-term users, studies among patients with schizophrenia have been contradictory. This article consists of 2 studies. In Study I, a meta-analysis of 10 studies comprising 572 patients with established schizophrenia (with and without comorbid cannabis use) was conducted. Patients with a history of cannabis use were found to have superior neuropsychological functioning. This finding was largely driven by studies that included patients with a lifetime history of cannabis use rather than current or recent use. In Study II, we examined the neuropsychological performance of 85 patients with first-episode psychosis (FEP) and 43 healthy nonusing controls. Relative to controls, FEP patients with a history of cannabis use (FEP 1 CANN; n 5 59) displayed only selective neuropsychological impairments while those without a history (FEP 2 CANN; n 5 26) displayed generalized deficits. When directly compared, FEP 1 CANN patients performed better on tests of visual memory, working memory, and executive functioning. Patients with early onset cannabis use had less neuropsychological impairment than patients with later onset use. Together, these findings suggest that patients with schizophrenia or FEP with a history of cannabis use have superior neuropsychological functioning compared with nonusing patients. This association between better cognitive performance and cannabis use in schizophrenia may be driven by a subgroup of ''neurocognitively less impaired'' patients, who only developed psychosis after a relatively early initiation into cannabis use.

Abstract: Cannabis is a federally controlled substance, it’s very familiar to many but its neurobiological substrates are not well-characterized. In the brain, most areas prevalently having cannabinoid receptors have been associated with behavioral control and cognitive effects due to cannabinoids. Study over the last several decades suggested cannabinoids (CBs) exert copious oftentimes opposite effects on countless neuronal receptors and processes. In fact, owing to this plethora of effects, it’s still cryptic how CBs trigger neuronal circuits. Cannabis use has been revealed to cause cognitive deficits from basic motor coordination to more complex executive functions, for example, the aptitude to plan, organize, make choices, solve glitches, remember, and control emotions as well as behavior. Numerous factors like age of onset and duration of cannabis use regulate the severity of the difficulties. People with the cannabis-linked deficiency in executive functions have been found to ...

Cannabinoids are often excluded from postmortem toxicology screens due to their ubiquitous nature, interpretative difficulties and unanswered questions regarding their postmortem redistribution. In this study, we review 30 postmortem cases where a drug screen gave a positive cannabinoids result and a confirmation identified ∆ ∆ 9-tetrahydrocannabinol (THC), 11-hydroxy-∆ ∆ 9-tetrahydrocannabinol (11-OH-THC), and/or 11-nor-9-carboxy-∆ ∆ 9-tetrahydrocannabinol (THC-COOH) in peripheral (BL-P) or cardiac/central blood (BL-C) and/or urine (UR). Had cannabinoids not been included in these toxicologic evaluations, incomplete or erroneous inferences would have been drawn in a substantial number of cases regarding cause/manner of death. THC was detected in 28 BL-C and in all 30 BL-P. THC and THC-COOH were confirmed present in 2 and 23 UR, respectively. 11-OH-THC was detected in 4 BL-C, 6 BL-P, and 0 UR. The mean THC concentrations in BL-C and BL-P were 8.0 and 15.8 ng/mL, respectively. The mean THC-COOH concentrations in BL-C and BL-P were 55.2 and 60.6 ng/mL, respectively. The mean 11-OH-THC concentrations in BL-C and BL-P were 17.0 and 12.5 ng/mL, respectively. Postmortem interval (PMI) for each case was determined and evaluated in relation to BL-C/BL-P concentration ratios with THC-COOH exhibiting a possible trend. This study is the first of its kind and demonstrates the usefulness of cannabinoid analyses as part of death investigations. Furthermore, it provides distribution data that will improve the ability of toxicologists and pathologists to evaluate cannabinoid concentrations in human postmortem specimens.

Cannabinoids modulate nociceptive processing in models of acute, inflammatory and neuropathic pain. We have investigated the location and function of cannabinoid receptors on cultured neonatal dorsal root ganglion (DRG) neurones and F-11 cells, a dorsal root ganglion×neuroblastoma hybridoma which displays several of the features of authentic DRG neurones. CB 1 receptor immunolabelling was observed on the cell bodies and as fine puncta on processes of both cultured DRG neurones and F-11 cells. Additionally, fluorescence-activated cell sorting (FACS) analysis provided evidence that both CB 1 and CB 2 receptors are expressed on populations of cells within the cultured DRG and F-11 cells. The cannabinoid receptor agonist (+)-WIN55212 (10 and 100 nM) inhibited the mean voltage-activated Ca 2+ current in DRG neurones by 21% and 30%, respectively. The isomer, (Ϫ)-WIN55212 (10 and 100 nM) produced significantly less inhibition of 6% and 10% respectively. The CB 1 selective receptor antagonist SR141716A (100 nM) enhanced the peak high voltage-activated Ca 2+ current by 24% and simultaneous application of SR141716A (100 nM) and (+)-WIN55212 (100 nM) resulted in a significant attenuation of the inhibition obtained with (+)-WIN55212 alone. These data give functional evidence for the hypothesis that the analgesic actions of cannabinoids may be mediated by presynaptic inhibition of transmitter release in sensory neurones.

. In this study we have assessed the effect of the intracerebroventricular administration of anandamide ANA as well as its precursor Ž . metabolite arachidonic acid AA , on the sleep-wakefulness cycle, memory formation, locomotor activity and pain perception. Our Ž . Ž . results have indicated that ANA strikingly increases slow-wave sleep SWS 2 and rapid-eye movement REM sleep at the expense of Ž . wakefulness W ; while deteriorating memory consolidation. ANA also increases locomotor activity but does not modify pain perception threshold. In contrast, AA increases W and reduces SWS2, while deteriorating memory consolidation and increasing locomotor activity. AA has no effect on pain perception. These results suggest that the brain cannabinoid system participates in the modulation of the vigilance states and mnemonic processes. Additionally, they suggest that the effect on pain perception may be a peripheral rather than a central effect. q

Cannabinoids and opioids interact in a number of ways that could be therapeutically beneficial. The CB1 re- ceptors are implicated with the endocannabinoid-mediated modulation of stress, pain, visceral sensation, synaptic plasticity in the thalamus via GABAergic signaling. Thalamic reticular nucleus (TRN) is a thin sheet of GABAergic neurons surrounding anterolateral surface of the thalamus. In our immunohistochem- ical study we demonstrated expression of CB1 immunoreactive neurons in a light microscope during a nor- mal condition and after the acute stress in the rats. We found higher expression of CB 1 immunoreactivity in stressed animals compared with control group. Opioids and cannabinoids have been shown to have analgesic properties and they are considered as drug tar- gets for the treatment of numerous neurological disorders, pain and stress. Key words: Thalamic reticular nucleus, CB 1 receptors, immobilization stress, rat

A series of C3 cyclic side-chain analogues of classical cannabinoids were synthesized to probe the ligand binding pocket of the CB1 and CB2 receptors. The analogues were evaluated for CB1 and CB2 receptor binding affinities relative to Á 8-THC. The C3 side-chain geometries of the analogues were studied using high field NMR spectroscopy and quantum mechanical calculations. The results of these studies provide insights into the geometry of the ligand binding pocket of the CB1 and CB2 receptors.

The emergence of numerous cannabinoid designer drugs has been tied to large spikes in emergency room visits and overdoses. Identifying these substances is difficult for the following reasons: (1) the compounds are novel, closely structurally related, and do not usually test positive in drug screens; (2) novel analogs rapidly appear on the market; (3) no standard protocols exist for their identification; and (4) customized and extensive sample preparation/extraction and analysis procedures are required to demonstrate their presence. METHODS: Direct analysis in real time mass spectrometry (DART-MS) employing collision-induced dissociation (CID) provided confirmatory structural information that was useful in characterizing the various cannabinoid analogs, including those contained in mixtures. CID analysis illustrated that, although closely related compounds fragment in a similar fashion, their structural differences still resulted in multiple diagnostic peaks that provided additional confidence towards structural identification. RESULTS: DART-MS spectra were acquired under CID conditions to rapidly differentiate among five synthetic cannabinoids contained within 'herbal' products purchased locally in New York State (USA). The spectra exhibited [M+H] + ions and product ions unique to each cannabinoid that corresponded to major structural features. Five different cannabinoid analogs, alone and as mixtures of at least two cannabinoids, were identified in six herbal products and differentiated by their CID product ion patterns. CONCLUSIONS: Illicit synthetic cannabinoid products continue to be readily available despite national and international restrictions. These products contain a wide range of active components, and, in many cases, multiple active ingredients. DART-MS allows rapid analyses of these synthetic cannabinoids based on the exact masses of their [M+H] + ions and product ion peaks generated using CID.

The abuse of synthetic psychoactive substances known as "designer drugs," or "new psychoactive substances" (NPS), is increasing at an alarming rate. NPS are purchased as alternatives to traditional illicit drugs of abuse and are manufactured to circumvent laws regulating the sale and use of controlled substances. Synthetic cathinones (i.e., "bath salts") and synthetic cannabinoids (i.e., "spice") are two types of NPS that have received substantial media attention. Although low recreational doses of bath salts or spice compounds can produce desirable effects, high doses or chronic exposure often leads to dangerous medical consequences, including psychosis, violent behaviors, tachycardia, hyperthermia, and even death. Despite the popularity of NPS, there is a paucity of scientific data about these drugs. Here we provide a brief up-to-date review describing the mechanisms of action and neurobiological effects of synthetic cathinones and cannabino...

The effects of a high affinity cannabinoid receptor agonist were evaluated in rats subjected to chronic constriction injury of the sciatic nerve (CCI) or a sham operation. Intraperitoneal (i.p.) injections of the active, but not the inactive enantiomer, alleviated the pain behavior exhibited by CCI animals in a dose dependent manner. Moreover, at doses ranging from 0.43 to 4.3 mg/kg effects on sensitivity to a heat stimulus were observed neither in the paw contralateral to the sciatic ligation, nor in animals subjected to sham surgery. Animals subjected to CCI and treated with 4.3 mg/kg exhibited hypoalgesia in the paw ipsilateral to the ligated sciatic, i.e. heat hypoalgesia was completely reversed. The hypoalgesia is presumed to be the results of unmasking of a sensory deficit reflecting the known loss of C and A delta with CCI. Although side effects were present in some CCI animals subjected to the high dose (4.3 mg/kg), a moderate dose (2.14 mg/kg) completely alleviated the thermal and mechanical hyperalgesia, and mechanical allodynia without side effects. In addition to identifying a potential drug treatment for painful neuropathy, this study suggests that changes in cannabinoid receptors occurs in nerve injured animals.

The drug design has several branches of development, such as irrational selection, rational search and newer layering, computer subtraction, biological mapping of biological objects, simulation of the target and the drug.
One way or another, the share of rational search and human intellectual activity in the process of developing the design of preparations is, as before, great. Biomolecular mapping and mathematical models are not able to replace the accumulated experience in the design, and as a result, the drug design develops new theoretical methods. One of these methods is to regulate the activity and strength of the drug, through the use of radicals with more or less complementary interaction forces.
The degree of conformity of the chemical compound drug and the target is measured by several quantities: This is the geometric correspondence of the placement of the necessary chemical radicals. This is a quantitative match and a qualitative match. As well as compliance with the degree of mobility, the dynamic behavior of the molecule. Regulation of the activity of a substance is an important parameter that allows you to create drugs with convenient dosage or high safety.
To achieve high safety performance, a method of reducing the energy of the bond between the drug and the target is used. This approach makes it possible to establish a low ceiling of maximum activity. Even in case of overdose. these drugs show low activity, which eliminates the development of critical side effects. .. ...

Background and purpose:Evidence indicates that the endocannabinoid, 2-arachidonoylglycerol (2-AG), increases food intake when injected into the nucleus accumbens shell (NAcS), thereby potentially activating hypothalamic nuclei involved in food intake regulation. We aimed to evaluate potential orexigenic effects of the endocannabinoid anandamide and of AA5HT, a fatty acid amide hydrolase (FAAH) inhibitor, and OMDM-1, an inhibitor of anandamide uptake, injected in the NAcS, as well as the effect of these treatments on activation of hypothalamic nuclei.Evidence indicates that the endocannabinoid, 2-arachidonoylglycerol (2-AG), increases food intake when injected into the nucleus accumbens shell (NAcS), thereby potentially activating hypothalamic nuclei involved in food intake regulation. We aimed to evaluate potential orexigenic effects of the endocannabinoid anandamide and of AA5HT, a fatty acid amide hydrolase (FAAH) inhibitor, and OMDM-1, an inhibitor of anandamide uptake, injected in the NAcS, as well as the effect of these treatments on activation of hypothalamic nuclei.Experimental approach:Drugs were given into the NAcS of rats and food intake quantified during the next 4 h. In other groups, after the same treatments the brains were processed for c-Fos immunohistochemistry with focus on hypothalamic nuclei. Additional groups were used to quantify endocannabinoid levels in the nucleus accumbens and the hypothalamus after AA5HT and OMDM-1 intra-NAcS injections.Drugs were given into the NAcS of rats and food intake quantified during the next 4 h. In other groups, after the same treatments the brains were processed for c-Fos immunohistochemistry with focus on hypothalamic nuclei. Additional groups were used to quantify endocannabinoid levels in the nucleus accumbens and the hypothalamus after AA5HT and OMDM-1 intra-NAcS injections.Key resultsOur results indicate that the above treatments stimulate food intake during 4 h post-injection. They also increase c-Fos immunoreactivity in hypothalamic nuclei. The CB1 antagonist, AM251, blocked these effects. Finally, we found elevated levels of 2-AG, but not anandamide, after intra-NAcS injections of AA5HT.Our results indicate that the above treatments stimulate food intake during 4 h post-injection. They also increase c-Fos immunoreactivity in hypothalamic nuclei. The CB1 antagonist, AM251, blocked these effects. Finally, we found elevated levels of 2-AG, but not anandamide, after intra-NAcS injections of AA5HT.Conclusions and implications:These data support the involvement of the endocannabinoid system in feeding behavior at the level of the NAcS and hypothalamus. In addition, this is the first experimental demonstration that the pharmacological inhibition of endocannabinoid inactivation in the NAcS stimulates food intake, suggesting that the endocannabinoid degrading proteins can be a target for treating eating disorders.British Journal of Pharmacology (2007) 151, 1109–1116; doi:10.1038/sj.bjp.0707313These data support the involvement of the endocannabinoid system in feeding behavior at the level of the NAcS and hypothalamus. In addition, this is the first experimental demonstration that the pharmacological inhibition of endocannabinoid inactivation in the NAcS stimulates food intake, suggesting that the endocannabinoid degrading proteins can be a target for treating eating disorders.British Journal of Pharmacology (2007) 151, 1109–1116; doi:10.1038/sj.bjp.0707313

The ability of Cannabis sativa to promote eating has been documented for many centuries, with the drug reported by its users to promote strong cravings for, and an intensification of the sensory and hedonic properties of food. These effects are now known to result from the actions of cannabinoid molecules at specific cannabinoid receptor sites within the brain, and to reflect the physiological role of their natural ligands, the endocannabinoids, in the control of appetite. Recent developments in the biochemistry and pharmacology of endocannabinoid systems have generated convincing evidence from animal models for a normal role of endocannabinoids in the control of eating motivation. The availability of specific cannabinoid receptor agonists and antagonists raises the possibility of improved therapies for disorders of eating and body weight: not only in the suppression of appetite to counter our susceptibility to the over-consumption of highly pleasurable and energydense foods; but also in the treatment of conditions that involve reduced appetite and weight loss. Here, we outline some of the findings of the past decade that link endocannabinoid function appetite control, and the possible clinical applications of that knowledge.

This essay is  a comprehensive review on recent studies that related directly with cannabis essential oils. Five journal articles with various of application fields, different locations, in-dept analysis of cannabis chemical compounds, and comparison between hemp and marijuana are compared, and critically analyzed. Each individual journal article was summarized and evaluated to identify strength, weakness, and opportunity for further study. The results show that the trend of cannabis research is not only targeted to medical or few compounds like CBD or THC anymore, but rather than broader range of applications and more focused on terpenes and terpenoids that give different effects to multiple applications. This results study will lead new researchers to the current trend and perhaps, breakthrough of new utilization of cannabis plants.

Non-narcotic opioids and cannabinoids as potential analgesic agents. It is known that cannabinoids and opioids have a central analgesic effect. it is also known that they are active and with local application. For example, ointments based on marijuana are active as well as ointment on the basis of rapidly degrading endogenous endorphins and enkephalins. Such drugs alleviate pain in inflammatory processes, chronic pain, and hypothetically can be effective in cases of injury. But for the full activity of these forms of drugs are not sufficiently active. Overcoming chronic pain is an unresolved issue, despite the development of numerous drugs, various groups and types of actions and other efforts. In this paper, it is proposed to consider in more detail the possibilities of the drug design in this area, with examples of opioids and cannabinoids, in order to achieve new results at a new level of quality and safety: Local application provides a precise influence on the process, standard application affects the entire chain of passage of the pain signal, from the point of origin to the point of recognition and perception. If we use drugs that do not cross the blood-brain barrier, but are active opiates or cannabinoids, we can probably get something in between. The brain and spinal cord will not receive even one-hundredth of the drugs, but the peripheral nervous system is almost open to substances that do not pass through the lipid barrier. In this case, we do not need to worry about the drug not to defund into the bloodstream, for fear of a narcotic effect. We can increase the dose, make a subcutaneous injection, inject the drug intravenously or orally as a tablet form. Without fear of narcotic effects, addiction. Tolerance and dependence can manifest at the peripheral level, but this is in no way compared to the syndrome of drug opiate withdrawal. Nature has many examples of substances that somehow do not pass the barriers of bioavailability. These are biolabile substances, surface-active substances, substances not absorbed by the digestive system, quaternary ammonium salts that do not cross the blood-brain barrier. There are few natural cannabinoids and opiates among such substances, these are exclusively endogenous cannabinoids and opioids, they are biolabile, and this is a small window of opportunity. But chemical compounds of a similar nature are also scarce, these are topical preparations such as Loperamide (which is not absorbed in the digestive tract) and Quaternary bases of morphine derivatives (acting as laxatives, because they are alkylated in the responsible part of the molecule). The figure shows examples of a fundamentally new approach to drug design of quaternary bases from this area. These are quaternary bases which probably retain their functionality and activity, but when transformed into tertiary or secondary bases, they are inactivated. For these examples of substances, activity is possible only in the form of quaternary bases. This is a very important quality. because it eliminates the narcotic activity of catabolites. Also, such substances are characterized by high safety against overdose. As the drug is known, the design of opiates requires a very high-quality and subtle approach; otherwise, overdose and respiratory arrest are possible, even at medium dosages. But substances that do not pass through the blood-brain barrier do not require this complex adjustment during design, this requirement is absent, since even metabolites are not narcotic.

Cannabis is a federally controlled substance, it's very familiar to many but its neurobiological substrates are not well-characterized. In the brain, most areas prevalently having cannabinoid receptors have been associated with behavioral control and cognitive effects due to cannabinoids. Study over the last several decades suggested cannabinoids (CBs) exert copious oftentimes opposite effects on countless neuronal receptors and processes. In fact, owing to this plethora of effects, it's still cryptic how CBs trigger neuronal circuits. Cannabis use has been revealed to cause cognitive deficits from basic motor coordination to more complex executive functions, for example, the aptitude to plan, organize, make choices, solve glitches, remember, and control emotions as well as behavior. Numerous factors like age of onset and duration of cannabis use regulate the severity of the difficulties. People with the cannabis-linked deficiency in executive functions have been found to have trouble learning and applying the skills requisite for fruitful recovery, setting them at amplified risk for deterioration to cannabis use. Exploring the impacts of cannabis on the brain is imperative. Therefore the intention of this study was to analyze the neuropsychological effects and the impact of CBs on the dynamics of neural circuits, and its potential as the drug of addiction.

Introduction: The recent emergence and widespread availability of many new synthetic cannabinoids support the need for an accurate and high-throughput urine screen for these new designer drugs. We evaluated performance of the immunalysis homogeneous enzyme immunoassay (HEIA) to sensitively, selectively, and rapidly identify urinary synthetic cannabinoids. Methods: 2443 authentic urine samples were analyzed with the HEIA that targets JWH-018 N-pentanoic acid, and a validated LC-MS/MS method for 29 synthetic cannabinoids and metabolites. Semiquantitative HEIA results were obtained, permitting performance evaluation at and around three cutoffs (5, 10 and 20 mg/L), and diagnostic sensitivity, specificity and efficiency determination. Performance challenges at AE25 and AE50% of each cutoff level, cross-reactivity and interferences also were evaluated. Results: Sensitivity, specificity, and efficiency of the immunalysis HEIA K2 Spice kit with the manufacturer's recommended 10 mg/L cutoff were 75.6%, 99.6% and 96.8%, respectively, as compared to the reference LC-MS/MS method with limits of detection of 0.1-10 mg/L. Performance at 5 mg/L was 92.2%, 98.1% and 97.4%, and for the 20 mg/L cutoff were 62.9%, 99.7% and 95.4%. Semi-quantitative results for in-house prepared standards were obtained from 2.5-30 mg/L, and documented acceptable linearity from 5-25 mg/L, with inter-day imprecision <30% (n = 17). Thirteen of 74 synthetic cannabinoids evaluated were classified as highly cross-reactive (!50% at 10 mg/L); 4 showed moderate cross-reactivity (10-50% at 10 mg/L), 30 low cross-reactivity (<10% at 500 mg/L), and 27 <1% cross-reactivity at 500 mg/L. There was no interference from 102 investigated compounds. Only a mixture containing 1000 mg/L each of buprenorphine/norbuprenorphine produced a positive result above our proposed cutoff (5 mg/L) but below the manufacturer's recommended cutoff concentration (10 mg/L).

Introduction : Cannabis is the world's most popular illicit drug. Episodic memory in long-term users has been frequently investigated but little research has examined the impact of cannabis use on semantic memory. Psychotic symptoms such as thought disorder have also been theoretically linked to semantic memory impairments in patients with schizophrenia. In addition to investigating the long-term effects of cannabis on semantic memory, this study also aimed to investigate if any schizophrenia-like symptoms observed in this population were related to semantic memory abnormalities. Method: In a naturalistic study (n=74) using an acute-onchronic and chronic design, 36 cannabis users were compared with 38 controls whilst under the influence of cannabis and then three to five days later when participants were not intoxicated. Drug use was verified by urinanalysis. Semantic memory was assessed using a semantic priming task with both a long and short stimulus onset asynchrony (SOA) to assess automatic and controlled semantic processing. State and trait schizotypy were also indexed. Results: Under the influence of cannabis, users showed increased automatic semnatic priming and schizotypal symptoms than controls. Three to five days later following abstinence from cannabis, users exhibited hyper-priming at long SOAs on a direct priming task with a trend for reduced priming at the short SOA. Cannabis users did not differ in trait schizotypy and were similar to controls on state schizotypy when not intoxicated. Conclusions: Acutely, cannabis increases semantic priming which may be related to some of the psychotomimetic effects of the drug. Regular cannabis use produces semantic abnormalities when not under the influence of the drug. The pattern of long-term semantic abnormalities differs markedly from those observed in patients with schizophrenia and looks similar to that observed in individuals scoring highly on a schizotypy scale.

Cannabis is one of the most commonly abused drugs worldwide. There is a distinct clinical correlation between cannabis abuse and mental disorders. However, it is essential to establish cannabis intake in the abusers in order to establish causality between cannabis and psychiatric illness. The limitations of current detection methods using commercial cassettes prompted us to standardize the method of extraction and detection of cannabinoids in the urine samples of cannabis abusers attending a de-addiction centre in south India. In this study, diagnostic tests on 102 male patients suspected with cannabis abuse were done. Liquid-liquid extraction of cannabinoids from urine was done and screened by Duquenois-Levine, fast blue B salt and p-dimethylaminobenzaldehyde (p-DMAB) tests. All the results were confirmed by high performance thin layer chromatography (HPTLC). Samples were considered positive for cannabis based on the positive indication in colour test and by detection of 11-nor-del...

Rational design is applied in the discovery of novel lead drugs. Its rapid development is mainly attributed to the tremendous advancements in the computer science, statistics, molecular biology, biophysics, biochemistry, medicinal chemistry, pharmacokinetics and pharmacodynamics experienced in the last few decades. The promising feature that characterizes the application of rational drug design is that it uses for developing potential leads in drug discovery all known theoretical and experimental knowledge of the system under study. The utilization of the knowledge of the molecular basis of the system ultimately aims to reduce human power cost, time saving and laboratory expenses in the drug discovery. In this review paper various strategies applied for systems which include: (i) absence of knowledge of the receptor active site; (ii) the knowledge of a homology model of a receptor, (iii) the knowledge of the experimentally determined (i.e. X-ray crystallography, NMR spectroscopy) coordinates of the active site of the protein in absence and (iv) the presence of the ligand will be analyzed.

Cannabinoids, including the bioactive constituents of the marijuana plant, their synthetic analogs, and endogenous lipids with cannabinoid-like activity, produce their biological effects by interacting with specific receptors. To date, two G protein-coupled cannabinoid receptors have been identified by molecular cloning, CB 1 receptors mainly expressed in the brain and mediating most of the neurobehavioral effects of cannabinoids and CB 2 receptors expressed by immune and hematopoietic tissues. Recent findings indicate that some cannabinoid effects are not mediated by either CB 1 or CB 2 receptors, and in some cases there is compelling evidence to implicate additional receptors in these actions. These include transient receptor potential vanilloid 1 (TRPV 1 ) receptors and as-yet-unidentified receptors implicated in the endothelium-dependent vasodilator effect of certain cannabinoids and in the presynaptic inhibition of glutamatergic neurotransmission in the hippocampus. The case for these additional receptors is being reviewed here. D

A clinical study to investigate the pharmacokinetics and pharmacodynamics of oral tetrahydrocannabinol was performed. This randomized, double-blind, placebo-controlled, within-subject, inpatient study compared the effects of THC-containing hemp oils in liquid and capsule form to dronabinol (synthetic THC) in doses used for appetite stimulation. The National Institute on Drug Abuse Institutional Review Board approved the protocol and each participant provided informed consent. Detection times and concentrations of THC, 11-hydroxy-Delta-tetrahydrocannabinol (11-OH-THC), and 11-nor-9-carboxy-Delta-tetrahydrocannabinol (THCCOOH) in plasma were determined by gas chromatography-mass spectrometry [limits of quantification (LOQ)=0.5, 0.5, and 1.0 ng/mL, respectively] after oral THC administration. Six volunteers ingested liquid hemp oil (0.39 and 14.8 mg THC/d), hemp oil in capsules (0.47 mg THC/d), dronabinol capsules (7.5 mg THC/d), and placebo. Plasma specimens were collected during and after each dosing condition. THC and 11-OH-THC concentrations were low and never exceeded 6.1 ng/mL. Analytes were detectable 1.5 hour after initiating dosing with the 7.5 mg THC/d regimen and 4.5 hour after starting the 14.8 mg THC/d sessions. THCCOOH was detected 1.5 hour after the first dose, except for the 0.47 mg THC/d session, which required 4.5 hour for concentrations to reach the LOQ. THCCOOH concentrations peaked at 3.1 ng/mL during dosing with the low-dose hemp oils. Plasma THC and 11-OH-THC concentrations were negative for all participants at all doses within 15.5 hours after the last THC dose. Plasma THCCOOH persisted for at least 39.5 hours after the end of dosing and at much higher concentrations (up to 43.0 ng/mL). This study demonstrated that subjects who used high THC content hemp oil (347 mug/mL) as a dietary supplement had THC and metabolites in plasma in quantities comparable to those of patients using dronabinol for appetite stimulation. There was a significant correlation between body mass index and Cmax and body mass index and number of specimens positive for THC and 11-OH-THC.