Cannabis as an adjunct to or substitute for opiates in the treatment of chronic pain.

Abstract

“There is a growing body of evidence to support the use of medical cannabis as an adjunct to or substitute for prescription opiates in the treatment of chronic pain. When used in conjunction with opiates, cannabinoids lead to a greater cumulative relief of pain, resulting in a reduction in the use of opiates (and associated side-effects) by patients in a clinical setting. Additionally, cannabinoids can prevent the development of tolerance to and withdrawal from opiates, and can even rekindle opiate analgesia after a prior dosage has become ineffective. Novel research suggests that cannabis may be useful in the treatment of problematic substance use. These findings suggest that increasing safe access to medical cannabis may reduce the personal and social harms associated with addiction, particularly in relation to the growing problematic use of pharmaceutical opiates. Despite a lack of regulatory oversight by federal governments in North America, community-based medical cannabis dispensaries have proven successful at supplying patients with a safe source of cannabis within an environment conducive to healing, and may be reducing the problematic use of pharmaceutical opiates and other potentially harmful substances in their communities.”

http://www.ncbi.nlm.nih.gov/pubmed/22880540

Cannabidiol for the treatment of cannabis withdrawal syndrome: a case report.

Abstract

“What is known and Objective:  Cannabis withdrawal in heavy users is commonly followed by increased anxiety, insomnia, loss of appetite, migraine, irritability, restlessness and other physical and psychological signs. Tolerance to cannabis and cannabis withdrawal symptoms are believed to be the result of the desensitization of CB(1) receptors by THC. Case summary:  This report describes the case of a 19-year-old woman with cannabis withdrawal syndrome treated with cannabidiol (CBD) for 10 days. Daily symptom assessments demonstrated the absence of significant withdrawal, anxiety and dissociative symptoms during the treatment. What is new and Conclusion:  CBD can be effective for the treatment of cannabis withdrawal syndrome.”

http://www.ncbi.nlm.nih.gov/pubmed/23095052

The endocannabinoid system as a target for the treatment of cannabis dependence

“Cannabinoid replacement therapy and CB1 receptor antagonism are two potential treatments for cannabis dependence that are currently under investigation. However, abuse liability and adverse side effects may limit the scope of each of these approaches. A potential alternative stems from the recognition that (i) frequent cannabis use may cause an adaptive downregulation of brain endocannabinoid signaling, and (ii) that genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence. These findings suggest in turn that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol (2-AG), might alleviate cannabis withdrawal and dependence. One such agent, the fatty-acid amide hydrolase (FAAH) inhibitor URB597, selectively increases anandamide levels in the brain of rodents and primates. Preclinical studies show that URB597 produces analgesic, anxiolytic-like and antidepressant-like effects in rodents, which are not accompanied by overt signs of abuse liability. In this article, we review evidence suggesting that (i) cannabis influences brain endocannabinoid signaling; and (ii) FAAH inhibitors such as URB597 might offer a possible therapeutic avenue for the treatment of cannabis withdrawal.”

“Direct modulation of CB1receptors as a treatment for cannabis dependence”

“Even though, as we have seen above, direct activation of CB1 receptors may yield variable behavioral responses, low-dosage oral Δ9-THC has shown promise in the management of human cannabis withdrawal. The rationale for this approach is that controlled replacement of Δ9-THC for smoked cannabis may reduce the severity of withdrawal symptoms and allow a dependent individual to remain abstinent. Additionally, given that dependent subjects are experienced with cannabis, and Δ9-THC is administered at low doses, administration of the latter is unlikely to result in the anxiety responses observed with inexperienced users or high dosages. Consistent with this idea, two independent clinical studies have shown that low-dose oral Δ9-THC attenuates withdrawal symptom scores and is minimally intoxicating in non-treatment seeking daily cannabis users.””

“Several therapeutic modalities are currently being considered to treat cannabis dependence, including activation or deactivation of CB1receptors. While these stategies show promise in measures of cannabis withdrawal and abstinence, they may also create problems of abuse liability or adverse emotional effects. An additional approach might be to enhance endogenous anandamide signaling using agents that attenuate the deactivation of this endocannabinoid transmitter.”

“Increasing anandamide signaling with deactivation inhibitors, such as the FAAH blocker URB597, potentiates stress coping behaviors in animals, indicating a role for anandamide in physiopathological context of stress-related responses. Similarly, elevation of anandamide in specific brain regions opposes the anhedonic effects of stress and promotes normal positive responses to pleasurable stimuli in rodents. It is reasonable to hypothesize that these effects could act to blunt the negative affect and stress, which is common during cannabis withdrawal, thus allowing cannabis dependent individuals to successfully abstain from drug use.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2647947/

The endogenous cannabinoid system and the treatment of marijuana dependence.

Abstract

“The active principle of marijuana, Delta9-tetrahydrocannabinol (Delta9-THC), exerts its pharmacological effects by binding to selective receptors present on the membranes of neurons and other cells. These cannabinoid receptors are normally engaged by a family of lipid mediators, called endocannabinoids, which are thought to participate in the regulation of a diversity of brain functions, including pain, mood, appetite and memory. Marijuana use may lead to adaptive changes in endocannabinoid signaling, and these changes might contribute to effects of marijuana as well as to the establishment of marijuana dependence. In the present article, I outline current views on how endocannabinoid substances are produced, released, and deactivated in the brain. In addition, I review recent progress on the development of pharmacological agents that interfere with endocannabinoid deactivation and discuss their potential utility in the treatment of marijuana dependence and other aspects of drug abuse.”

http://www.ncbi.nlm.nih.gov/pubmed/15464150

Therapeutic aspects of cannabis and cannabinoids

The British Journal of Psychiatry

“HISTORY OF THERAPEUTIC USE

The first formal report of cannabis as a medicine appeared in China nearly 5000 years ago when it was recommended for malaria, constipation, rheumatic pains and childbirth and, mixed with wine, as a surgical analgesic. There are subsequent records of its use throughout Asia, the Middle East, Southern Africa and South America. Accounts by Pliny, Dioscorides and Galen remained influential in European medicine for 16 centuries.”

“It was not until the 19th century that cannabis became a mainstream medicine in Britain. W. B. O’Shaughnessy, an Irish scientist and physician, observed its use in India as an analgesic, anticonvulsant, anti-spasmodic, anti-emetic and hypnotic. After toxicity experiments on goats and dogs, he gave it to patients and was impressed with its muscle-relaxant, anticonvulsant and analgesic properties, and recorded its use-fulness as an anti-emetic.”

“After these observations were published in 1842, medicinal use of cannabis expanded rapidly. It soon became available ‘over the counter’ in pharmacies and by 1854 it had found its way into the United States Dispensatory. The American market became flooded with dozens of cannabis-containing home remedies.”

“Cannabis was outlawed in 1928 by ratification of the 1925 Geneva Convention on the manufacture, sale and movement of dangerous drugs. Prescription remained possible until final prohibition under the 1971 Misuse of Drugs Act, against the advice of the Advisory Committee on Drug Dependence.”

“In the USA, medical use was effectively ruled out by the Marijuana Tax Act 1937. This ruling has been under almost constant legal challenge and many special dispensations were made between 1976 and 1992 for individuals to receive ‘compassionate reefers’. Although this loophole has been closed, a 1996 California state law permits cultivation or consumption of cannabis for medical purposes, if a doctor provides a written endorsement. Similar arrangements apply in Italy and Canberra, Australia.”

“Results and Conclusions Cannabis and some cannabinoids are effective anti-emetics and analgesics and reduce intra-ocular pressure. There is evidence of symptom relief and improved well-being in selected neurological conditions, AIDS and certain cancers. Cannabinoids may reduce anxiety and improve sleep. Anticonvulsant activity requires clarification. Other properties identified by basic research await evaluation. Standard treatments for many relevant disorders are unsatisfactory. Cannabis is safe in overdose but often produces unwanted effects, typically sedation, intoxication, clumsiness, dizziness, dry mouth, lowered blood pressure or increased heart rate. The discovery of specific receptors and natural ligands may lead to drug developments. Research is needed to optimise dose and route of administration, quantify therapeutic and adverse effects, and examine interactions.”

http://bjp.rcpsych.org/content/178/2/107.long

The therapeutic potential of novel cannabinoid receptors.

Cover image

“Cannabinoids produce a plethora of biological effects, including the modulation of neuronal activity through the activation of CB(1) receptors and of immune responses through the activation of CB(2) receptors. The selective targeting of either of these two receptor subtypes has clear therapeutic value. Recent evidence indicates that some of the cannabinomimetic effects previously thought to be produced through CB(1) and/or CB(2) receptors, be they on neuronal activity, on the vasculature tone or immune responses, still persist despite the pharmacological blockade or genetic ablation of CB(1) and/or CB(2) receptors. This suggests that additional cannabinoid and cannabinoid-like receptors exist. Here we will review this evidence in the context of their therapeutic value and discuss their true belonging to the endocannabinoid signaling system.”  http://www.ncbi.nlm.nih.gov/pubmed/19248809

“The therapeutic potential of novel cannabinoid receptors”  http://www.sciencedirect.com/science/article/pii/S0163725809000266

Cannabinoid receptors in brain: pharmacogenetics, neuropharmacology, neurotoxicology, and potential therapeutic applications.

“Much progress has been achieved in cannabinoid research. A major breakthrough in marijuana-cannabinoid research has been the discovery of a previously unknown but elaborate endogenous endocannabinoid system (ECS), complete with endocannabinoids and enzymes for their biosynthesis and degradation with genes encoding two distinct cannabinoid (CB1 and CB2) receptors (CBRs) that are activated by endocannabinoids, cannabinoids, and marijuana use.

Physical and genetic localization of the CBR genes CNR1 and CNR2 have been mapped to chromosome 6 and 1, respectively. A number of variations in CBR genes have been associated with human disorders including osteoporosis, attention deficit hyperactivity disorder (ADHD), posttraumatic stress disorder (PTSD), drug dependency, obesity, and depression. Other family of lipid receptors including vanilloid (VR1) and lysophosphatidic acid (LPA) receptors appear to be related to the CBRs at the phylogenetic level. The ubiquitous abundance and differential distribution of the ECS in the human body and brain along with the coupling to many signal transduction pathways may explain the effects in most biological system and the myriad behavioral effects associated with smoking marijuana. The neuropharmacological and neuroprotective features of phytocannabinoids and endocannabinoid associated neurogenesis have revealed roles for the use of cannabinoids in neurodegenerative pathologies with less neurotoxicity. The remarkable progress in understanding the biological actions of marijuana and cannabinoids have provided much richer results than previously appreciated cannabinoid genomics and raised a number of critical issues on the molecular mechanisms of cannabinoid induced behavioral and biochemical alterations. These advances will allow specific therapeutic targeting of the different components of the ECS in health and disease.

 This review focuses on these recent advances in cannabinoid genomics and the surprising new fundamental roles that the ECS plays in the retrograde signaling associated with cannabinoid inhibition of neurotransmitter release to the genetic basis of the effects of marijuana use and pharmacotherpeutic applications and limitations. Much evidence is provided for the complex CNR1 and CNR2 gene structures and their associated regulatory elements. Thus, understanding the ECS in the human body and brain will contribute to elucidating this natural regulatory mechanism in health and disease.”

http://www.ncbi.nlm.nih.gov/pubmed/19897083

Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis.

Abstract

“The endogenous cannabinoid (CB) (endocannabinoid) signaling system is involved in a variety of (patho)physiological processes, primarily by virtue of natural, arachidonic acid-derived lipids (endocannabinoids) that activate G protein-coupled CB1 and CB2 receptors. A hyperactive endocannabinoid system appears to contribute to the etiology of several disease states that constitute significant global threats to human health. Consequently, mounting interest surrounds the design and profiling of receptor-targeted CB antagonists as pharmacotherapeutics that attenuate endocannabinoid transmission for salutary gain. Experimental and clinical evidence supports the therapeutic potential of CB1 receptor antagonists to treat overweight/obesity, obesity-related cardiometabolic disorders, and substance abuse. Laboratory data suggest that CB2 receptor antagonists might be effective immunomodulatory and, perhaps, anti-inflammatory drugs. One CB1 receptor antagonist/inverse agonist, rimonabant, has emerged as the first-in-class drug approved outside the United States for weight control. Select follow-on agents (taranabant, otenabant, surinabant, rosonabant, SLV-319, AVE1625, V24343) have also been studied in the clinic. However, rimonabant’s market withdrawal in the European Union and suspension of rimonabant’s, taranabant’s, and otenabant’s ongoing development programs have highlighted some adverse clinical side effects (especially nausea and psychiatric disturbances) of CB1 receptor antagonists/inverse agonists. Novel CB1 receptor ligands that are peripherally directed and/or exhibit neutral antagonism (the latter not affecting constitutive CB1 receptor signaling) may optimize the benefits of CB1 receptor antagonists while minimizing any risk. Indeed, CB1 receptor-neutral antagonists appear from preclinical data to offer efficacy comparable to or better than that of prototype CB1 receptor antagonists/inverse agonists, with less propensity to induce nausea. Continued pharmacological profiling, as the prelude to first-in-man testing of CB1 receptor antagonists with unique modes of targeting/pharmacological action, represents an exciting translational frontier in the critical path to CB receptor blockers as medicines.”

http://www.ncbi.nlm.nih.gov/pubmed/19249987

Targeted modulators of the endogenous cannabinoid system: future medications to treat addiction disorders and obesity.

Abstract

“The endogenous endocannabinoid system encompasses a family of natural signaling lipids (“endocannabinoids”) functionally related to (9)-tetrahydrocannabinol, the psychoactive ingredient of marijuana (cannabis), along with proteins that modulate the endocannabinoids, including enzymes, transporters, and receptors. The endocannabinoid system’s ubiquitous regulatory actions in health and disease underscore its importance to mammalian (patho)physiology and suggest discrete targets through which it may be modulated for therapeutic gain. Medications based on the endocannabinoid system are an important focus of contemporary translational research, particularly with respect to substance abuse and obesity, two prevalent disorders with a pathogenic component of endocannabinoid system hyperactivity. Pressing health care needs have made the rational design of targeted CB1 cannabinoid-receptor modulators a promising route to future medications with significant therapeutic impact against psychobehavioral and metabolic disturbances having a reward-supported appetitive component.”

http://www.ncbi.nlm.nih.gov/pubmed/17915075

The Endocannabinoid System and the Brain.

Abstract

“The psychoactive constituent in cannabis, Δ(9)-tetrahydrocannabinol (THC), was isolated in the mid-1960s, but the cannabinoid receptors, CB1 and CB2, and the major endogenous cannabinoids (anandamide and 2-arachidonoyl glycerol) were identified only 20 to 25 years later. The cannabinoid system affects both central nervous system (CNS) and peripheral processes. In this review, we have tried to summarize research-with an emphasis on recent publications-on the actions of the endocannabinoid system on anxiety, depression, neurogenesis, reward, cognition, learning, and memory. The effects are at times biphasic-lower doses causing effects opposite to those seen at high doses. Recently, numerous endocannabinoid-like compounds have been identified in the brain. Only a few have been investigated for their CNS activity, and future investigations on their action may throw light on a wide spectrum of brain functions. Expected final online publication date for the Annual Review of Psychology Volume 64 is November 30, 2012. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.”

http://www.ncbi.nlm.nih.gov/pubmed/22804774