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Endocannabinoid system in neurodegenerative disorders.

By | Neurodegenerative

Authors:

Balapal S. Basavarajappa, Madhu Shivakumar, Vikram Joshi, Shivakumar Subbanna


Published in Journal of Neurochemistry

September 2017

 

Abstract

Most neurodegenerative disorders (NDDs) are characterized by cognitive impairment and other neurological defects. The definite cause of and pathways underlying the progression of these NDDs are not well-defined. Several mechanisms have been proposed to contribute to the development of NDDs. These mechanisms may proceed concurrently or successively, and they differ among cell types at different developmental stages in distinct brain regions. The endocannabinoid system, which involves cannabinoid receptors type 1 (CB1R) and type 2 (CB2R), endogenous cannabinoids and the enzymes that catabolize these compounds, has been shown to contribute to the development of NDDs in several animal models and human studies. In this review, we discuss the functions of the endocannabinoid system in NDDs and converse the therapeutic efficacy of targeting the endocannabinoid system to rescue NDDs.

 

DOI: 10.1111/jnc.14098

Full Text

Citation:

Basavarajappa BS, Shivakumar M, Joshi V, Subbanna S. Endocannabinoid system in neurodegenerative disorders. Journal of Neurochemistry. 2017;142(5):624-648. doi:10.1111/jnc.14098.

Natural Phytochemicals in the Treatment and Prevention of Dementia: An Overview.

By | Dementia

Authors:

Rosaliana Libro, Sabrina Giacoppo, Thangavelu Soundara Rajan, Placido Bramanti, Emanuela Mazzon


Published in Molecules

21 April 2016

 

Abstract

The word dementia describes a class of heterogeneous diseases which etiopathogenetic mechanisms are not well understood. There are different types of dementia, among which, Alzheimer’s disease (AD), vascular dementia (VaD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD) are the more common. Currently approved pharmacological treatments for most forms of dementia seem to act only on symptoms without having profound disease-modifying effects. Thus, alternative strategies capable of preventing the progressive loss of specific neuronal populations are urgently required. In particular, the attention of researchers has been focused on phytochemical compounds that have shown antioxidative, anti-amyloidogenic, anti-inflammatory and anti-apoptotic properties and that could represent important resources in the discovery of drug candidates against dementia. In this review, we summarize the neuroprotective effects of the main phytochemicals belonging to the polyphenol, isothiocyanate, alkaloid and cannabinoid families in the prevention and treatment of the most common kinds of dementia. We believe that natural phytochemicals may represent a promising sources of alternative medicine, at least in association with therapies approved to date for dementia.

 

 

DOI: 10.3390/molecules21040518

Full Text

Citation:

Libro R, Giacoppo S, Rajan TS, Bramanti P, Mazzon E. Natural Phytochemicals in the Treatment and Prevention of Dementia: An Overview. Molecules. 2016;21(4):518. doi:10.3390/molecules21040518.

Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic.

By | Alzheimer's Disease

Authors:

Ester Aso, Isidre Ferrer


Published in Frontiers in Pharmacology

5 March 2014

 

Abstract

The limited effectiveness of current therapies against Alzheimer’s disease (AD) highlights the need for intensifying research efforts devoted to developing new agents for preventing or retarding the disease process. During the last few years, targeting the endogenous cannabinoid system has emerged as a potential therapeutic approach to treat Alzheimer. The endocannabinoid system is composed by a number of cannabinoid receptors, including the well-characterized CB1 and CB2 receptors, with their endogenous ligands and the enzymes related to the synthesis and degradation of these endocannabinoid compounds. Several findings indicate that the activation of both CB1 and CB2 receptors by natural or synthetic agonists, at non-psychoactive doses, have beneficial effects in Alzheimer experimental models by reducing the harmful β-amyloid peptide action and tau phosphorylation, as well as by promoting the brain’s intrinsic repair mechanisms. Moreover, endocannabinoid signaling has been demonstrated to modulate numerous concomitant pathological processes, including neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress. The present paper summarizes the main experimental studies demonstrating the polyvalent properties of cannabinoid compounds for the treatment of AD, which together encourage progress toward a clinical trial.

 

DOI: 10.3389/fphar.2014.00037

Full Text

Citation:

Aso E, Ferrer I. Cannabinoids for treatment of Alzheimer’s disease: moving toward the clinic. Frontiers in Pharmacology. 2014;5(37). doi:10.3389/fphar.2014.00037.

A molecular link between the active component of marijuana and Alzheimer’s disease pathology.

By | Alzheimer's Disease

Authors:

Lisa M. Eubanks, Claude J. Rogers, George F. Koob, Arthur J. Olson, Tobin J. Dickerson, Kim D. Janda


Published in Molecular Pharmaceutics

2006

 

Abstract

Alzheimer’s disease is the leading cause of dementia among the elderly, and with the ever-increasing size of this population, cases of Alzheimer’s disease are expected to triple over the next 50 years. Consequently, the development of treatments that slow or halt the disease progression have become imperative to both improve the quality of life for patients and reduce the health care costs attributable to Alzheimer’s disease. Here, we demonstrate that the active component of marijuana, Delta9-tetrahydrocannabinol (THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid beta-peptide (Abeta) aggregation, the key pathological marker of Alzheimer’s disease. Computational modeling of the THC-AChE interaction revealed that THC binds in the peripheral anionic site of AChE, the critical region involved in amyloidgenesis. Compared to currently approved drugs prescribed for the treatment of Alzheimer’s disease, THC is a considerably superior inhibitor of Abeta aggregation, and this study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease.

 

DOI: 10.1021/mp060066m

Author Manuscript

Citation:

Eubanks LM, Rogers CJ, Beuscher, et al. A Molecular Link between the Active Component of Marijuana and Alzheimers Disease Pathology. Molecular Pharmaceutics. 2006;3(6):773-777. doi:10.1021/mp060066m.

Cannabis sativa: the unconventional “weed” allergen.

By | Allergy

Authors:

Thad L. Ocampo, Tonya S. Rans


Published in Annals of Allergy, Asthma & Immunology

March 2015

 

Abstract

Introduction

Passage of legislation in Washington, Colorado, Oregon, Alaska, and the District of Columbia allowing recreational use of marijuana, despite federal regulation to the contrary, highlights the continued debate surrounding this unconventional plant. Allergies to marijuana are not commonly reported in the medical literature despite being the most widely used illicit drug in the world. However, especially in the setting of an evolving legal status, marijuana might become an increasingly relevant “weed” for the allergist. This article aims to review the literature pertaining to Cannabis sativa in the context of allergic disease and its potential clinical implications.

 

 

DOI: 10.1016/j.anai.2015.01.004

Full Text

Citation:

Ocampo TL, Rans TS. Cannabis sativa: the unconventional “weed” allergen. Annals of Allergy, Asthma & Immunology2015;114(3):187-192. doi:10.1016/j.anai.2015.01.004.

Cannabinoids in attention-deficit/hyperactivity disorder: A randomised-controlled trial.

By | ADHD

Abstract

Adults with ADHD describe self-medicating with cannabis, with some reporting a preference for cannabis over ADHD medications. A small number of psychiatrists in the US prescribe cannabis medication for ADHD, despite there being no evidence from randomised controlled studies. The EMA-C trial (Experimental Medicine in ADHD-Cannabinoids) was a pilot randomised placebo-controlled experimental study of a cannabinoid medication, Sativex Oromucosal Spray, in 30 adults with ADHD. The primary outcome was cognitive performance and activity level using the QbTest. Secondary outcomes included ADHD and emotional lability (EL) symptoms. From 17.07.14 to 18.06.15, 30 participants were randomly assigned to the active (n=15) or placebo (n=15) group. For the primary outcome, no significant difference was found in the ITT analysis although the overall pattern of scores was such that the active group usually had scores that were better than the placebo group (Est=-0.17, 95%CI-0.40 to 0.07, p=0.16, n=15/11 active/placebo). For secondary outcomes Sativex was associated with a nominally significant improvement in hyperactivity/impulsivity (p=0.03) and a cognitive measure of inhibition (p=0.05), and a trend towards improvement for inattention (p=0.10) and EL (p=0.11). Per-protocol effects were higher. Results did not meet significance following adjustment for multiple testing. One serious (muscular seizures/spasms) and three mild adverse events occurred in the active group and one serious (cardiovascular problems) adverse event in the placebo group. Adults with ADHD may represent a subgroup of individuals who experience a reduction of symptoms and no cognitive impairments following cannabinoid use. While not definitive, this study provides preliminary evidence supporting the self-medication theory of cannabis use in ADHD and the need for further studies of the endocannabinoid system in ADHD.

Authors:

Ruth E. Cooper, Emma Williams, Seth Seegobin, Charlotte Tye, Jonna Kuntsi, Philip Asherson


Published in European Neuropsychopharmacology

August 2017


 

DOI: 10.1016/j.euroneuro.2017.05.005

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Citation:

Cooper RE, Williams E, Seegobin S, Tye C, Kuntsi J, Asherson P. Cannabinoids in attention-deficit/hyperactivity disorder: A randomised-controlled trial. European Neuropsychopharmacology. 2017;27(8):795-808. doi:10.1016/j.euroneuro.2017.05.005.

Targeting the Endocannabinoid System in Psychiatric Illness.

By | Psychiatric Problems

Authors:

Martin A. Katzman, Melissa Furtado, Leena Anand


Published in Journal of Clinical Psychopharmacology

December 2016

 

Abstract

Prevalence of psychiatric disorders continues to rise globally, yet remission rates and patient outcome remain less than ideal. As a result, novel treatment approaches for these disorders are necessary to decrease societal economic burden, as well as increase individual functioning. The recent discovery of the endocannabinoid system has provided an outlet for further research into its role in psychiatric disorders, because efficacy of targeted treatments have been demonstrated in medical illnesses, including cancers, neuropathic pain, and multiple sclerosis. The present review will investigate the role of the endocannabinoid system in psychiatric disorders, specifically schizophrenia, depressive, anxiety, and posttraumatic stress disorders, as well as attention-deficit hyperactivity disorder. Controversy remains in prescribing medicinal cannabinoid treatments due to the fear of adverse effects. However, one must consider all potential limitations when determining the safety and tolerability of cannabinoid products, specifically cannabinoid content (ie, Δ-tetrahydrocannabinol vs cannabidiol) as well as study design. The potential efficacy of cannabinoid treatments in the psychiatric population is an emerging topic of interest that provides potential value going forward in medicine.

 

 

DOI: 10.1097/JCP.0000000000000581

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Citation:

Katzman MA, Furtado M, Anand L. Targeting the Endocannabinoid System in Psychiatric Illness. Journal of Clinical Psychopharmacology. 2016;36(6):691-703. doi:10.1097/jcp.0000000000000581.

The impact of ADHD persistence, recent cannabis use, and age of regular cannabis use onset on subcortical volume and cortical thickness in young adults.

By | ADHD

Authors:

Krista M. Lisdahl, Leanne Tamm, Jeffery N. Epstein, Terry Jernigan, Brooke S. G. Molina, Stephen P. Hinshaw, James M. Swanson, Erik Newman, Clare Kelly, James M. Bjork, MTA Neuroimaging Group


Published in Drug and Alcohol Dependence

1 April 2016

 

Abstract

BACKGROUND:

Both Attention Deficit Hyperactivity Disorder (ADHD) and chronic cannabis (CAN) use have been associated with brain structural abnormalities, although little is known about the effects of both in young adults.

METHODS:

Participants included: those with a childhood diagnosis of ADHD who were CAN users (ADHD_CAN; n=37) and non-users (NU) (ADHD_NU; n=44) and a local normative comparison group (LNCG) who did (LNCG_CAN; n=18) and did not (LNCG_NU; n=21) use CAN regularly. Multiple regressions and MANCOVAs were used to examine the independent and interactive effects of a childhood ADHD diagnosis and CAN group status and age of onset (CUO) on subcortical volumes and cortical thickness.

RESULTS:

After controlling for age, gender, total brain volume, nicotine use, and past-year binge drinking, childhood ADHD diagnosis did not predict brain structure; however, persistence of ADHD was associated with smaller left precentral/postcentral cortical thickness. Compared to all non-users, CAN users had decreased cortical thickness in right hemisphere superior frontal sulcus, anterior cingulate, and isthmus of cingulate gyrus regions and left hemisphere superior frontal sulcus and precentral gyrus regions. Early cannabis use age of onset (CUO) in those with ADHD predicted greater right hemisphere superior frontal and postcentral cortical thickness.

DISCUSSION:

Young adults with persistent ADHD demonstrated brain structure abnormalities in regions underlying motor control, working memory and inhibitory control. Further, CAN use was linked with abnormal brain structure in regions with high concentrations of cannabinoid receptors. Additional large-scale longitudinal studies are needed to clarify how substance use impacts neurodevelopment in youth with and without ADHD.

 

DOI: 10.1016/j.drugalcdep.2016.01.032

Author Manuscript

Citation:

Lisdahl KM, Tamm L, Epstein JN, et al. The impact of ADHD persistence, recent cannabis use, and age of regular cannabis use onset on subcortical volume and cortical thickness in young adults. Drug and Alcohol Dependence. 2016;161:135-146. doi:10.1016/j.drugalcdep.2016.01.032.

Association of the cannabinoid receptor gene (CNR1) with ADHD and post‐traumatic stress disorder.

By | ADHD

Authors:

Ake T. Lu, Matthew N. Ogdie, Marjo‐Ritta Järvelin, Irma K. Moilanen, Sandra K. Loo James T. McCracken, James J. McGough, May H. Yang, Leena Peltonen, Stanley F. Nelson Rita M. Cantor, Susan L. Smalley


Published in American Journal of Medical Genetics Part B: Neuropsychiatric Genetics

22 January 2008

 

Abstract

Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder affecting some 5-10% of children and 4-5% of adults. The cannabinoid receptor gene (CNR1) is a positional candidate gene due to its location near an identified ADHD linkage peak on chromosome 6, its role in stress and dopamine regulation, its association with other psychiatric disorders that co-occur with ADHD, and its function in learning and memory. We tested SNP variants at the CNR1 gene in two independent samples-an unselected adolescent sample from Northern Finland, and a family-based sample of trios (an ADHD child and their parents). In addition to using the trios for association study, the parents (with and without ADHD) were used as an additional case/control sample of adults for association tests. ADHD and its co-morbid psychiatric disorders were examined. A significant association was detected for a SNP haplotype (C-G) with ADHD (P = 0.008). A sex by genotype interaction was observed as well with this haplotype posing a greater risk in males than females. An association of an alternative SNP haplotype in this gene was found for post-traumatic stress disorder (PTSD) (P = 0.04 for C-A, and P = 0.01 for C-G). These observations require replication, however, they suggest that the CNR1 gene may be a risk factor for ADHD and possibly PTSD, and that this gene warrants further investigation for a role in neuropsychiatric disorders.

 

DOI: 10.1002/ajmg.b.30693

Full Text

Citation:

Lu AT, Ogdie MN, Järvelin M-R, et al. Association of the cannabinoid receptor gene (CNR1) with ADHD and post-traumatic stress disorder. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics. 2008;147B(8):1488-1494. doi:10.1002/ajmg.b.30693.

Epidiolex Weighs in at Schedule V

By | Cannabinoids, CBD, Conditions, Epilepsy, General Information, News, Research, Research Articles, Seizure Disorder
But CBD remains on Schedule I, due to its supposed abuse liability.  “DEA’s decision to move Epidiolex to Schedule V…  applies only to CBD products approved by the FDA. Other, non-FDA-approved CBD preparations remain in Schedule I,”  says GW Pharmaceuticals’ press release (excerpted below):

Product expected to be available within six weeks

GW Pharmaceuticals plc (Nasdaq: GWPH, “GW,” “the Company” or “the Group”), a biopharmaceutical company focused on discovering, developing and commercializing novel therapeutics from its proprietary cannabinoid product platform, along with its U.S. subsidiary Greenwich Biosciences, announced today that EPIDIOLEX®(cannabidiol) oral solution has been transferred to Schedule V, the lowest restriction classification, by the U.S. Drug Enforcement Administration (DEA). EPIDIOLEX, which was approved by the U.S. Food and Drug Administration (FDA) on June 25, 2018 for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS) or Dravet syndrome in patients two years of age or older, is the first prescription pharmaceutical formulation of highly-purified, plant-derived cannabidiol (CBD), a cannabinoid lacking the high associated with marijuana, and the first in a new category of anti-epileptic drugs (AEDs).

“We are pleased that the DEA has placed EPIDIOLEX in the lowest restriction Schedule, because it will help ensure that patients with LGS and Dravet syndrome, two of the most debilitating forms of epilepsy, can access this important new treatment option through their physicians,” said Justin Gover, GW’s Chief Executive Officer. “With this final step in the regulatory process completed, we are working hard to make EPIDIOLEX available within the next six weeks as we know there is excitement for a standardized version of cannabidiol that has undergone the rigor of controlled clinical trials and been approved by the FDA.”

With this decision, the product label for EPIDIOLEX will be finalized. The Company’s development program represents the only well-controlled clinical evaluation of a cannabinoid medication for patients with LGS and Dravet syndrome. Both diseases, which develop in childhood, are rare, severe forms of epilepsy that are notoriously treatment-resistant.[1],[2] Most patients with LGS and Dravet syndrome require multiple seizure medications and the majority are resistant to currently approved AEDs.2,[3],[4] The day-to-day impact of these conditions is significant with high rates of early mortality.[5],[6] The Company anticipates making EPIDIOLEX available within the next six weeks. Availability is primarily dependent on the time involved in obtaining the required Schedule V licenses for the U.S. distributor and importer.

Medicines in Schedule V have a proven medical use and low potential for abuse. DEA’s decision to move EPIDIOLEX to Schedule V was based on non-clinical and clinical data that evaluated the medicine’s potential for abuse and applies only to CBD products approved by the FDA. Other, non-FDA-approved CBD preparations remain in Schedule I. Some examples of Schedule V drugs are cough preparations such as Robitussin AC, and a number of commonly prescribed anti-epilepsy drugs such as VIMPAT (lacosamide), BRIVIACT (brivaracetam), and Lyrica (pregabalin).

The most common adverse reactions that occurred in EPIDIOLEX-treated patients were somnolence, decreased appetite, diarrhea, transaminase elevations, fatigue, malaise, and asthenia, rash, insomnia, sleep disorder and poor-quality sleep, and infections.  The medicine will be marketed in the United States by Greenwich Biosciences, the U.S. subsidiary of GW Pharmaceuticals plc. More information, including the final product label, can be found at Epidiolex.com. Read More