Tag Archives: marijuana

Cannabinoids as novel anti-inflammatory drugs

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Figure 1

“Cannabinoids are a group of compounds that mediate their effects through cannabinoid receptors. The discovery of Δ9-tetrahydrocannabinol (THC) as the major psychoactive principle in marijuana, as well as the identification of cannabinoid receptors and their endogenous ligands, has led to a significant growth in research aimed at understanding the physiological functions of cannabinoids. Cannabinoid receptors include CB1, which is predominantly expressed in the brain, and CB2, which is primarily found on the cells of the immune system. The fact that both CB1 and CB2 receptors have been found on immune cells suggests that cannabinoids play an important role in the regulation of the immune system. Recent studies demonstrated that administration of THC into mice triggered marked apoptosis in T cells and dendritic cells, resulting in immunosuppression. In addition, several studies showed that cannabinoids downregulate cytokine and chemokine production and, in some models, upregulate T-regulatory cells (Tregs) as a mechanism to suppress inflammatory responses. The endocannabinoid system is also involved in immunoregulation. For example, administration of endocannabinoids or use of inhibitors of enzymes that break down the endocannabinoids, led to immunosuppression and recovery from immune-mediated injury to organs such as the liver. Manipulation of endocannabinoids and/or use of exogenous cannabinoids in vivo can constitute a potent treatment modality against inflammatory disorders. This review will focus on the potential use of cannabinoids as a new class of anti-inflammatory agents against a number of inflammatory and autoimmune diseases that are primarily triggered by activated T cells or other cellular immune components.”

“Cannabis, commonly known as marijuana, is a product of the Cannabis sativa plant and the active compounds from this plant are collectively referred to as cannabinoids. For several centuries, marijuana has been used as an alternative medicine in many cultures and, recently, its beneficial effects have been shown in: the treatment of nausea and vomiting associated with cancer chemotherapy; anorexia and cachexia seen in HIV/AIDS patients; and in neuropathic pain and spasticity in multiple sclerosis. Cannabinoid pharmacology has made important advances in recent years after the discovery of the cannabinoid receptors (CB1 and CB2). Cannabinoid receptors and their endogenous ligands have provided an excellent platform for the investigation of the therapeutic effects of cannabinoids. It is well known that CB1 and CB2 are heterotrimeric Gi/o-protein-coupled receptors and that they are both expressed in the periphery and the CNS. However, CB1 expression is predominant in the CNS, especially on presynaptic nerves, and CB2 is primarily expressed on immune cells.”

“Cannabinoids are potent anti-inflammatory agents and they exert their effects through induction of apoptosis, inhibition of cell proliferation, suppression of cytokine production and induction of T-regulatory cells (Tregs).”

“Executive summary

  • Cannabinoids, the active components of Cannabis sativa, and endogenous cannabinoids mediate their effects through activation of specific cannabinoid receptors known as cannabinoid receptor 1 and 2 (CB1 and CB2).
  • The cannabinoid system has been shown both in vivo and in vitro to be involved in regulating the immune system through its immunomodulatory properties.
  • Cannabinoids suppress inflammatory response and subsequently attenuate disease symptoms. This property of cannabinoids is mediated through multiple pathways such as induction of apoptosis in activated immune cells, suppression of cytokines and chemokines at inflammatory sites and upregulation of FoxP3+ regulatory T cells.
  • Cannabinoids have been tested in several experimental models of autoimmune disorders such as multiple sclerosis, rheumatoid arthritis, colitis and hepatitis and have been shown to protect the host from the pathogenesis through induction of multiple anti-inflammatory pathways.
  • Cannabinoids may also be beneficial in certain types of cancers that are triggered by chronic inflammation. In such instances, cannabinoids can either directly inhibit tumor growth or suppress inflammation and tumor angiogenesis.”                      http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2828614/

Therapeutic potential of cannabinoid-based drugs.

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Abstract

“Cannabinoid-based drugs modeled on cannabinoids originally isolated from marijuana are now known to significantly impact the functioning of the endocannabinoid system of mammals. This system operates not only in the brain but also in organs and tissues in the periphery including the immune system. Natural and synthetic cannabinoids are tricyclic terpenes, whereas the endogenous physiological ligands are eicosanoids. Several receptors for these compounds have been extensively described, CB1 and CB2, and are G protein-coupled receptors; however, cannabinoid-based drugs are also demonstrated to function independently of these receptors. Cannabinoids regulate many physiological functions and their impact on immunity is generally antiinflammatory as powerful modulators of the cytokine cascade. This anti-inflammatory potency has led to the testing of these drugs in chronic inflammatory laboratory paradigms and even in some human diseases. Psychoactive and nonpsychoactive cannabinoid-based drugs such as Delta9-tetrahydrocannabinol, cannabidiol, HU-211, and ajulemic acid have been tested and found moderately effective in clinical trials of multiple sclerosis, traumatic brain injury, arthritis, and neuropathic pain. Furthermore, although clinical trials are not yet reported, preclinical data with cannabinoid-based drugs suggest efficacy in other inflammatory diseases such as inflammatory bowel disease, Alzheimer’s disease, atherosclerosis, and osteoporosis.”

http://www.ncbi.nlm.nih.gov/pubmed/17713029

Cannabidiol enhances anandamide signaling and alleviates psychotic symptoms of schizophrenia

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“Cannabidiol is a component of marijuana that does not activate cannabinoid receptors, but moderately inhibits the degradation of the endocannabinoid anandamide. We previously reported that an elevation of anandamide levels in cerebrospinal fluid inversely correlated to psychotic symptoms. Furthermore, enhanced anandamide signaling let to a lower transition rate from initial prodromal states into frank psychosis as well as postponed transition. In our translational approach, we performed a double-blind, randomized clinical trial of cannabidiol vs amisulpride, a potent antipsychotic, in acute schizophrenia to evaluate the clinical relevance of our initial findings. Either treatment was safe and led to significant clinical improvement, but cannabidiol displayed a markedly superior side-effect profile. Moreover, cannabidiol treatment was accompanied by a significant increase in serum anandamide levels, which was significantly associated with clinical improvement. The results suggest that inhibition of anandamide deactivation may contribute to the antipsychotic effects of cannabidiol potentially representing a completely new mechanism in the treatment of schizophrenia.”

“Cannabidiol is a non-psychotropic component of marijuana that binds to CB1 receptors with only comparably very low affinity and is devoid of overt cannabimimetic or pro-psychotic properties. Biochemical studies indicate that cannabidiol may enhance endogenous anandamide signaling indirectly, by inhibiting the intracellular degradation of anandamide catalyzed by the enzyme fatty acid amide hydrolase (FAAH).Furthermore, preliminary clinical case reports suggest that cannabidiol might exert antipsychotic effects in schizophrenic patients. In addition, experimental studies show that cannabidiol reduces psychosis-like effects of Δ9-tetrahydrocannabinol and synthetic analogs.“

Read more:: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3316151/

Marijuana Compound Treats Schizophrenia with Few Side Effects:Clinical Trial

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“A compound found in marijuana can treat schizophrenia as effectively as antipsychotic medications, with far fewer side effects, according to a preliminary clinical trial.

“Because it comes from marijuana, there are obvious political issues surrounding its use. Extracting it from the plant is also expensive. But the biggest barrier may be that CBD is a natural compound, and therefore can’t be patented the way new drugs are. That means that despite the possibility that it could outsell their current blockbuster antipsychotic drugs, pharmaceutical companies aren’t likely to develop it — a particularly striking fact when you consider that every major manufacturer of new generation antipsychotics in the U.S. has so far paid out hundreds of millions or billions of dollars in fines for mismarketing these drugs. Yet they still reaped huge profits.”

“For people with schizophrenia and their families, of course, it is likely to be infuriating that non-scientific issues like marijuana policy and patenting problems could stand in the way of a treatment that could potentially be so restorative. While it’s possible that these study results may not hold up or that researchers could discover problems related to long-term use of CBD,  it’s hard to imagine that they could be any worse than what patients already experience.”

Read more: http://healthland.time.com/2012/05/30/marijuana-compound-treats-schizophrenia-with-few-side-effects-clinical-trial/

Cannabinoids as Therapeutic Agents for Ablating Neuroinflammatory Disease

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“Cannabinoids have been reported to alter the activities of immune cells in vitro and in vivo. These compounds may serve as ideal agents for adjunct treatment of pathological processes that have a neuroinflammatory component. As highly lipophilic molecules, they readily access the brain. Furthermore, they have relatively low toxicity and can be engineered to selectively target cannabinoid receptors. To date, two cannabinoid receptors have been identified, characterized and designated CB1 and CB2. CB1 appears to be constitutively expressed within the CNS while CB2 apparently is induced during inflammation. The inducible nature of CB2 extends to microglia, the resident macrophages of the brain that play a critical role during early stages of inflammation in that compartment. Thus, the cannabinoid-cannabinoid receptor system may prove therapeutically manageable in ablating neuropathogenic disorders such as Alzheimer’s disease, multiple sclerosis, amyotrophic.”

“The marijuana plant, Cannabis sativa, has been consumed therapeutically and recreationally for centuries because of its medicinal and psychotropic attributes. Cannabis contains a complex array of substances, including a group of terpenoid-like, highly lipophilic compounds referred to as cannabinoids. To date, over 60 cannabinoids have been identified from the marijuana plant. Cannabinoids account for the majority of the effects attributed to marijuana that users experience, including euphoria, impaired perception and memory, and mild sedation. While cannabinoids have been used to abolish loss of appetite and to ablate nausea and pain in patients suffering from severe medical disorders, these compounds also possess immune modulatory properties that may prove detrimental to human health. However, accumulating evidence suggests that cannabinoids also may serve as therapeutic agents in neuropathogenic diseases, pathologically hallmarked by elicitation of pro-inflammatory factors by cells of the central nervous system (CNS) and infiltrated peripheral immunocytes. Cannabinoids have the potential to be ideal therapeutic candidates in abolishing inflammatory neuropathies in that they can readily penetrate the blood brain barrier (BBB) to access the brain, have low levels of toxicity, and can specifically exert their effects through cannabinoid receptors. The major cannabinoid receptor type that appears to be targeted in neuroinflammation is cannabinoid receptor 2 (CB2). This receptor has been identified in select cells of the CNS, can be induced on demand during early inflammatory events, and has been shown to attenuate pro-inflammatory cytokine production by microglia, the resident macrophages of the brain that play a central role in many neuropathological processes.”

“In the present review the immune modulatory properties of cannabinoids, including their relation to interaction with cannabinoid receptors as linked to inflammatory neuropathies will be discussed. Included in this review will be an overview of the signal transduction cascades associated with cannabinoid receptors, and the effects of cannabinoid receptor signaling on immune cell function and immunity, and more importantly in the CNS. These discussions will lay the groundwork for the critical element of this review, in which we explore the potential of cannabinoid receptors to serve as therapeutic targets to attenuate the elicitation of pro-inflammatory mediators during neuropathogenic diseases and disorders such as Alzheimer’s disease (AD), Multiple Sclerosis (MS), Amyotrophic Lateral Sclerosis (ALS), HIV Encephalitis (HIVE), Closed Head Injury (CHI) and Granulomatous Amebic Encephalitis (GAE).”

“It is apparent that therapeutic intervention at an early stage of neuroinflammation is critical. The recognition that microglia express CB2 and that its activation results in ablation of untoward immune responses indicates that this receptor may serve as an ideal therapeutic target. Cannabinoids, as highly lipophilic compounds, can readily penetrate the BBB and access the brain. Furthermore, these compounds can be designed to have low toxicity, minimal psychotropic properties, and to selectively target cells that express the CB2, particularly microglia that serve as endogenous immune cells of the CNS and that play a prominent role in neuroinflammatory processes.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2750822/

Nonpsychotropic Cannabinoid Receptors Regulate Microglial Cell Migration

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“During neuroinflammation, activated microglial cells migrate toward dying neurons, where they exacerbate local cell damage. The signaling molecules that trigger microglial cell migration are poorly understood. In this paper, we show that pathological overstimulation of neurons by glutamate plus carbachol dramatically increases the production of the endocannabinoid 2-arachidonylglycerol (2-AG) but only slightly increases the production of anandamide and does not affect the production of two putative endocannabinoids, homo-γ-linolenylethanolamide and docosatetraenylethanolamide. We further show that pathological stimulation of microglial cells with ATP also increases the production of 2-AG without affecting the amount of other endocannabinoids. Using a Boyden chamber assay, we provide evidence that 2-AG triggers microglial cell migration. This effect of 2-AG occurs through CB2 and abnormal-cannabidiol-sensitive receptors, with subsequent activation of the extracellular signal-regulated kinase 1/2 signal transduction pathway. It is important to note that cannabinol and cannabidiol, two nonpsychotropic ingredients present in the marijuana plant, prevent the 2-AG-induced cell migration by antagonizing the CB2 and abnormal-cannabidiol-sensitive receptors, respectively. Finally, we show that microglial cells express CB2 receptors at the leading edge of lamellipodia, which is consistent with the involvement of microglial cells in cell migration. Our study identifies a cannabinoid signaling system regulating microglial cell migration. Because this signaling system is likely to be involved in recruiting microglial cells toward dying neurons, we propose that cannabinol and cannabidiol are promising nonpsychotropic therapeutics to prevent the recruitment of these cells at neuroinflammatory lesion sites.”

“Because marijuana produces remarkable beneficial effects, patients with multiple sclerosis, for example, commonly use this plant as a therapeutic agent; however, we still lack essential information on the mechanistic basis of these beneficial effects.”

“The marijuana plant, Cannabis sativa, contains >60 cannabinoid compounds, the best known being Δ9-tetrahydrocannabinol (THC), cannabinol (CBN), and cannabidiol (CBD) (for review, see. Cannabinoid compounds produce their biological effects by acting through at least three cannabinoid receptors (see Table1). These include the cloned cannabinoid CB1 receptors, which are expressed predominately in the CNS, the cloned cannabinoid CB2 receptors, which are expressed predominately by immune cells, and the abnormal-cannabidiol-sensitive receptors (hereafter referred to as abn-CBD receptors). The latter receptors have not been cloned yet, but they have been pinpointed pharmacologically in mice lacking CB1 and CB2 receptors and are also known as anandamide (AEA) receptors.”

“We also show that CBN and CBD, two nonpsychotropic bioactive compounds of marijuana, may antagonize the 2-AG-induced recruitment of microglial cells. This is in agreement with the fact that nabilone, a synthetic analog of THC, produces minimal palliative effects against multiple sclerosis symptoms, whereas smoking cannabis is reported to be beneficial. Therefore, our results suggest that bioactive cannabinoids present in the marijuana plant, such as CBN and CBD, are likely to underlie the increased efficacy of cannabis versus nabilone and therefore hold promise as nonpsychotropic therapeutics to treat neuroinflammation.”

http://www.jneurosci.org/content/23/4/1398.long

The endocannabinoid system in ageing: a new target for drug development.

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Abstract

“Endocannabinoids are a new class of lipids, which include amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol are the main endogenous agonists of cannabinoid receptors able to mimic several pharmacological effects of Delta(9)-tetrahydrocannabinol, the active principle of Cannabis sativa preparations like hashish and marijuana. AEA is released “on demand” from membrane lipids, and its activity at the receptors is limited by cellular uptake followed by intracellular hydrolysis. Together with AEA and congeners, the proteins which bind, synthesize, transport and hydrolyze AEA form the “endocannabinoid system”. Endogenous cannabinoids are present in the central nervous system and in peripheral tissues, suggesting a physiological role as broad spectrum modulators. This review summarizes the main features of the endocannabinoid system, and the latest advances on its involvement in ageing of central and peripheral cells. In addition, the therapeutic potential of recently developed drugs able to modulate the endocannabinoid tone for the treatment of ageing and age-related human pathologies will be reviewed.”

http://www.ncbi.nlm.nih.gov/pubmed/17100593

Marijuana To Control Alcohol Abuse

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By Senior News Editor
Reviewed by John M. Grohol, Psy.D. on December 1, 2009

New Strategy Uses Pot To Control Alcohol Abuse “A new research effort has a provocative outcome as University of California-Berkeley researchers suggest substituting cannabis for treatment of heavy alcohol abuse.

Research published in BioMed Central’s open access Harm Reduction Journal features a poll of 350 cannabis users, finding that 40 percent used cannabis to control their alcohol cravings, 66 percent as a replacement for prescription drugs and 26 percent for other, more potent illegal drugs.

Amanda Reiman carried out the study at the UC-Berkeley Patient’s Group, a medical cannabis dispensary.

She said, “Substituting cannabis for alcohol has been described as a radical alcohol treatment protocol. This approach could be used to address heavy alcohol use in the British Isles – people might substitute cannabis, a potentially safer drug than alcohol with less negative side effects, if it were socially acceptable and available.”

Reiman found that 65 percent of people reported using cannabis as a substitute because it has fewer adverse side effects than alcohol, illicit or prescription drugs, 34 percent because it has less withdrawal potential and 57.4 percent because cannabis provides better symptom management.

Reiman believes this discovery brings up two important points.

“First, self-determination, the right of an individual to decide which treatment or substance is most effective and least harmful for them. Secondly, the recognition that substitution might be a viable alternative to abstinence for those who can’t or won’t completely stop using psychoactive substances.”

Speaking about legalization of cannabis, Reiman added, “The economic hardship of the Great Depression helped bring about the end of alcohol prohibition. Now, as we are again faced with economic struggles, the U.S. is looking to marijuana as a potential revenue generator.

“Public support is rising for the legalization of recreational use and remains high for the use of marijuana as a medicine. The hope is that this interest will translate into increased research support and the removal of current barriers to conducting such research, such as the Schedule I/Class B status of marijuana.””

http://psychcentral.com/news/2009/12/01/marijuana-to-control-alcohol-abuse/9863.html

Role of endocannabinoids and cannabinoid CB1 receptors in alcohol-related behaviors.

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Abstract

“This review presents the remarkable research during the past several years indicating that some of the pharmacological and behavioral effects of alcohol, including alcohol drinking and alcohol-preferring behavior, are mediated through one of the most abundant neurochemical systems in the central nervous system, the endocannabinoid signaling system. The advances, with the discovery of specific receptors and the existence of naturally occurring cannabis-like substances in the mammalian system and brain, have helped in understanding the neurobiological basis for drugs of abuse, including alcoholism. The cDNA and genomic sequences encoding G-protein-coupled cannabinoid receptors (CB1 and CB2) from several species have now been cloned. This has facilitated discoveries of endogenous ligands (endocannabinoids). To date, two fatty acid derivatives characterized to be arachidonylethanolamide and 2-arachidonylglycerol have been isolated from both nervous and peripheral tissues. Both these compounds have been shown to mimic the pharmacological and behavioral effects of Delta9-tetrahydrocannabinol, the psychoactive component of marijuana. The involvement of the endocannabinoid signaling system in tolerance development to drugs of abuse, including alcohol, were unknown until recently. Studies from our laboratory demonstrated for the first time the downregulation of CB1 receptor function and its signal transduction by chronic alcohol. The observed downregulation of CB1 receptor binding and its signal transduction results from the persistent stimulation of receptors by the endogenous CB1 receptor agonists arachidonylethanolamide and 2-arachidonylglycerol, the synthesis of which is increased by chronic alcohol treatment. The deletion of CB1 receptor has recently been shown to block voluntary alcohol intake in mice, which is consistent with our previous findings where the DBA/2 mice known to avoid alcohol intake had significantly reduced brain CB1 receptor function. These findings suggest a role for the CB1 receptor gene in excessive alcohol drinking behavior and development of alcoholism. Ongoing investigations may lead to the development of potential therapeutic agents to modulate the endocannabinoid signaling system, which will be helpful for the treatment of alcoholism.”

http://www.ncbi.nlm.nih.gov/pubmed/15542757

Neuromodulatory role of the endocannabinoid signaling system in alcoholism: an overview.

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Abstract

“The current review evaluates the evidence that some of the pharmacological and behavioral effects of ethanol (EtOH), including EtOH-preferring behavior, may be mediated through the endocannabinoid signaling system. The recent advances in the understanding of the neurobiological basis of alcoholism suggest that the pharmacological and behavioral effects of EtOH are mediated through its action on neuronal signal transduction pathways and ligand-gated ion channels, receptor systems, and receptors that are coupled to G-proteins. The identification of a G-protein-coupled receptor, namely, the cannabinoid receptor (CB1 receptor) that was activated by Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the major psychoactive component of marijuana, led to the discovery of endogenous cannabinoid agonists. To date, two fatty acid derivatives identified to be arachidonylethanolamide (AEA) and 2-arachidonylglycerol (2-AG) have been isolated from both nervous and peripheral tissues. Both these compounds have been shown to mimic the pharmacological and behavioral effects of Delta(9)-THC. The involvement of the endocannabinoid signaling system in the development of tolerance to the drugs of abuse including EtOH has not been known until recently. Recent studies from our laboratory have demonstrated for the first time the down-regulation of CB1 receptor function and its signal transduction by chronic EtOH. The observed down-regulation of CB1 receptor binding and its signal transduction results from the persistent stimulation of the receptors by the endogenous CB1 receptor agonists, AEA and 2-AG, the synthesis of which has been found to be increased by chronic EtOH treatment. This enhanced formation of endocannabinoids may subsequently influence the release of neurotransmitters. It was found that the DBA/2 mice, known to avoid EtOH intake, have significantly reduced brain-CB1-receptor function consistent with other studies, where the CB1 receptor antagonist SR141716A has been shown to block voluntary EtOH intake in rodents. Similarly, activation of the CB1 receptor system promoted alcohol craving, suggesting a role for the CB1 receptor gene in excessive EtOH drinking behavior and development of alcoholism. Ongoing investigations may lead to the development of potential therapeutic strategies for the treatment of alcoholism.”

http://www.ncbi.nlm.nih.gov/pubmed/12052043