Category Archives: Attention-Deficit/Hyperactivity Disorder (ADHD)

ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

Posted on by
Reply

Image result for Curr Clin Pharmacol.

“Cannabis sativa is also popularly known as marijuana. It is being cultivated and used by man for recreational and medicinal purposes from many centuries.

Study of cannabinoids was at bay for very long time and its therapeutic value could not be adequately harnessed due to its legal status as proscribed drug in most of the countries.

The research of drugs acting on endocannabinoid system has seen many ups and down in recent past. Presently, it is known that endocannabinoids has role in pathology of many disorders and they also serve “protective role” in many medical conditions.

Several diseases like emesis, pain, inflammation, multiple sclerosis, anorexia, epilepsy, glaucoma, schizophrenia, cardiovascular disorders, cancer, obesity, metabolic syndrome related diseases, Parkinson’s disease, Huntington’s disease, Alzheimer’s disease and Tourette’s syndrome could possibly be treated by drugs modulating endocannabinoid system.

Presently, cannabinoid receptor agonists like nabilone and dronabinol are used for reducing the chemotherapy induced vomiting. Sativex (cannabidiol and THC combination) is approved in the UK, Spain and New Zealand to treat spasticity due to multiple sclerosis. In US it is under investigation for cancer pain, another drug Epidiolex (cannabidiol) is also under investigation in US for childhood seizures. Rimonabant, CB1 receptor antagonist appeared as a promising anti-obesity drug during clinical trials but it also exhibited remarkable psychiatric side effect profile. Due to which the US Food and Drug Administration did not approve Rimonabant in US. It sale was also suspended across the EU in 2008.

Recent discontinuation of clinical trial related to FAAH inhibitor due to occurrence of serious adverse events in the participating subjects could be discouraging for the research fraternity. Despite of some mishaps in clinical trials related to drugs acting on endocannabinoid system, still lot of research is being carried out to explore and establish the therapeutic targets for both cannabinoid receptor agonists and antagonists.

One challenge is to develop drugs that target only cannabinoid receptors in a particular tissue and another is to invent drugs that acts selectively on cannabinoid receptors located outside the blood brain barrier. Besides this, development of the suitable dosage forms with maximum efficacy and minimum adverse effects is also warranted.

Another angle to be introspected for therapeutic abilities of this group of drugs is non-CB1 and non-CB2 receptor targets for cannabinoids.

In order to successfully exploit the therapeutic potential of endocannabinoid system, it is imperative to further characterize the endocannabinoid system in terms of identification of the exact cellular location of cannabinoid receptors and their role as “protective” and “disease inducing substance”, time-dependent changes in the expression of cannabinoid receptors.”

http://www.ncbi.nlm.nih.gov/pubmed/27086601

Prenatal elevation of endocannabinoids corrects the unbalance between dopamine systems and reduces activity in the Naples High Excitability rats.

Posted on by
Reply

“Several evidences suggest that endocannabinoids exert a neurotrophic effect on developing mesencephalic dopamine neurons.

Since an altered mesocorticolimbic system seems to underlie hyperactivity and attention deficit in clinical and animal studies of attention deficit hyperactivity disorder(ADHD), prenatal elevation of anandamide has been induced…

The data suggest a corrected unbalance between the two dopamine systems that apparently leads to reducedhyperactivity and modified scanning times in this animal model of ADHD.

This, in turn, might open new strategies in the treatment of a subset of ADHD cases.”

http://www.ncbi.nlm.nih.gov/pubmed/12732229

Association between cannabinoid receptor gene (CNR1) and childhood attention deficit/hyperactivity disorder in Spanish male alcoholic patients

Posted on by
Reply

“The CB1 receptor is encoded by the CNR1 gene (6q14–q15), which is known to carry a nine-allele microsatellite polymorphism containing repeats of a single trinucleotide, ATT, which localizes to the 3’UTR of the gene and has been related to drug dependency states in Caucasian populations.

Moreover, a link has been found between this polymorphism and the properties of the event-related wave p300, some studies having suggested that p300 variations might function as a marker for an underlying, hereditary, predisposition to alcoholism.

Moreover, a direct relationship has been found between p300 wave fluctuations and attention deficit/hyperactivity disorder (ADHD). In recent years, the relationship between ADHD and addictions has been stressed. ADHD has been linked to the malfunctioning of catecholaminergic systems, which also play a fundamental role in the brain’s rewarding system.

These data suggest that the link between the cannabinoid system and the p300 wave could be related to some aspects of ADHD.

In this study, we found a quantitative relationship between the largest-sized alleles of the CNR1 gene and the presence of ADHD during childhood in Spanish male alcoholic patients…

To the best of our knowledge, this is the first study relating the CNR1-gene polymorphisms with ADHD in alcoholic patients.

These data are consistent with the fact that the cannabinoid system is known to affect dopaminergic transmission, with the malfunctioning of the dopaminergic system being regarded as a potential physiopathological cause of ADHD. Further studies are needed to determine the functional basis of the observed association.”

http://www.nature.com/mp/journal/v8/n5/full/4001278a.html

Subtypes of attention deficit-hyperactivity disorder (ADHD) and cannabis use.

Posted on by
Reply

“The current study examined the association between subtypes of attention-deficit/hyperactivity disorder (ADHD) and cannabis use within a sample of 2811 current users.

When asked about the ADHD symptoms they have experienced when not using cannabis, a higher proportion of daily users met symptom criteria for an ADHD diagnoses of the subtypes that include hyperactive-impulsive symptoms than the inattentive subtype.

For nondaily users, the proportions of users meeting symptom criteria did not differ by subtype.

These results have implications for identifying which individuals with ADHD might be more likely to self-medicate using cannabis. Furthermore, these findings indirectly support research linking relevant cannabinoid receptors to regulatory control.”

http://www.ncbi.nlm.nih.gov/pubmed/24093525

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

Posted on by
Reply

Logo of wtpa

“Attention deficit hyperactivity disorder (ADHD) is a highly heritable disorder affecting some 5-10% of children and 4-5% of adults. The cannabinoidreceptor 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.

…the CNR1 gene may be a risk factor forADHD and possibly PTSD, and that this gene warrants further investigation for a role in neuropsychiatric disorders.

These data provide support for a putative role of endogenous cannabinoids in ADHD, and PTSD.

The CNR1gene may contribute to shared underlying risk continua, such as emotional dysregulation in response to stress, across these diverse diagnostic groups. Increased amygdala activity, poor stress reactivity as reflected by HPA response, and poor prefrontal cortical modulation is a plausible underlying mechanism of liability that may be shared across disorders.

Taken together with the current findings, we suggest that this gene may be an important risk variant in the emotional regulation difficulties underlying ADHD, PTSD, and possibly other co-morbid conditions (such as mood disorder); however, the role of CNR1 is likely small, particularly at the level of psychiatric diagnosis, so future work using more refined phenotypes or endophenotypes of affect regulation are necessary.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2685476/

Endocannabinoids activate transient receptor potential vanilloid 1 receptors to reduce hyperdopaminergia-related hyperactivity: therapeutic implications.

Posted on by
Reply

“Knockout (KO) mice invalidated for the dopamine transporter (DAT) constitute a powerful animal model of neurobiological alterations associated with hyperdopaminergia relevant to schizophrenia and attention-deficit/hyperactivity disorder (ADHD).

CONCLUSIONS:

These data indicate a dysregulated striatal endocannabinoid neurotransmission associated with hyperdopaminergic state.

Restoring endocannabinoid homeostasis in active synapses might constitute an alternative therapeutic strategy for disorders associated with hyperdopaminergia.

In this process, TRPV1 receptors seem to play a key role and represent a novel promising pharmacological target.”

http://www.ncbi.nlm.nih.gov/pubmed/16199010

The endocannabinoid system misfires in ADHD mice (Commentary on Castelli et al.)

Posted on by
Reply

European Journal of Neuroscience

“Attention-deficit hyperactivity disorder (ADHD) is characterized by short attention span, hyperactivity and impulsiveness and affects both children and adults. Its social and economic significance can hardly be overrated, with a recent literature review estimating a worldwide prevalence of more than 5% (Polanczyk et al., 2007). With importance comes controversy, and the biological basis of ADHD, its diagnostic criteria and its treatments continue to divide opinions.

Neuroscientists have tackled ADHD at several levels. Brain imaging has revealed abnormalities in ADHD patients, particularly in the neural networks linking the frontal cortex to the basal ganglia (Cubillo et al., 2011). The genetic factors underlying ADHD are also being unravelled. Several lines of research point to an involvement of the dopaminergic system, and the dopamine transporter (DAT) in particular. DAT polymorphism is correlated with ADHD (Gizer et al., 2009). Intriguingly, abnormalities of the DAT and its pharmacology may explain the apparent paradox that stimulants such as amphetamine and methylphenidate (Ritalin), which inhibit DAT activity and increase extracellular dopamine, are effective (and widespread) treatments for ADHD symptoms.

Given these findings, the use of animal models of ADHD carrying mutations in the DAT gene holds great promise. In a study published in this issue of EJN, Castelli et al. (2011) used a knock-in transgenic mouse in which a mutant version of the DAT gene results in a protein that becomes insensitive to cocaine, while retaining at least in part its functionality (Chen et al., 2006). These DAT mutant mice are hyperactive and respond paradoxically to both cocaine and methylphenidate: these drugs, which induce hyperlocomotor states in normal mice, reduce motor activity in the DAT mutants (Tilley & Gu, 2008).

Castelli et al. (2011) focused on the endocannabinoid system in the striatum of these DAT mutant mice. There are good reasons to investigate in this direction. Dopamine promotes endocannabinoid release in the striatum (Yin & Lovinger, 2006) and striatal dopamine levels are elevated in DAT mutant mice.

In normal animals, striatal projection neurons release endocannabinoids in response to ionotropic and metabotropic receptor activation. Endocannabinoids then act as retrograde messengers, diffusing in the extracellular space and binding presynaptic CB1 receptors located on glutamatergic and GABAergic terminals. In both cases, this decreases neurotransmitter release.

Castelli et al. (2011) found that endocannabinoid signalling is dramatically impaired in DAT mutant mice. Surprisingly, the mice present a specific deficit of the endocannabinoid-mediated control of GABA release, while control of glutamate is unaffected. The potential implications of these findings are fascinating: the striatum, whose intrinsic circuits are mostly GABAergic, is involved in the action selection process (Kimchi & Laubach, 2009). Thus, the inability of striatal projection neurons to suppress inhibition may be directly linked to abnormal action selection – a cardinal feature of ADHD.

This is one of several changes induced by the mutated DAT gene in the striatal network, including those of dopamine signalling previously described by the same group (Napolitano et al., 2010). However, this is the first indication that the endocannabinoid-mediated control of synaptic inhibition may be selectively impaired in ADHD, and raises the possibility that drugs able to restore this process may prove effective in its treatment.”

http://onlinelibrary.wiley.com/doi/10.1111/j.1460-9568.2011.07917.x/full

Loss of striatal cannabinoid CB1 receptor function in attention-deficit / hyperactivity disorder mice with point-mutation of the dopamine transporter.

Posted on by
Reply

“Abnormal dopamine (DA) transmission in the striatum plays a pivotal role in attention-deficit/hyperactivity disorder (ADHD).

As striatal DA signalling modulates the endocannabinoid system (ECS), the present study was aimed at investigating cannabinoid CB1 receptor (CB1R) function in a model of ADHD…

Our results point to CB1Rs as novel molecular players in ADHD, and suggest that therapeutic strategies aimed at interfering with the ECS might prove effective in this disorder.”

http://www.ncbi.nlm.nih.gov/pubmed/22034972

Medical Marijuana Helps Cure Chronic Disease

Posted on by
Reply

Medical Marijuana Helps Cure Chronic Disease

“The medicinal power of Marijuana is well documented throughtout history

Back in 2700 BC, According to Chinese lore, the Emperor Shen Nung, considered the Father of Chinese medicine, in 2700 BC ,discovered the healing properties of Marijuana as well as Ginseng and Ephedra.

Throughout recorded history, the use of Medical Marijuana  has been linked to the ancient Egyptians, Persians, Greek civilizations, George Washington, Queen Victoria and even mainstream medicine by the 1840s.

From the 1850s to Y 1942, Marijuana was listed in the United States Pharmacopeia, an official public standards-setting authority for all prescription and over-the counter medicines, as a treatment for tetanus, cholera, rabies, dysentery, alcoholism, opiate addiction, convulsive disorders, insanity, excessive menstrual bleeding and many other health problems. My father was a Dental doctor and had a license to dispense the drug, pharmacies carried it back then.

During that same time frame prohibition gained popularity, that along with a growing “faith” in federal government.

By Y 1937, the United States passed its 1st federal law against Marijuana despite objections by the American Medical Association (AMA).

In fact, Dr. William C. Woodward, testifying on behalf of the AMA, told the US Congress:

“The American Medical Association knows of no evidence that Marijuana is a dangerous drug.”

He warned that a prohibition “loses sight of the fact that future investigation may show that there are substantial medical uses for Cannabis.”

Today, we see a growing trend of acceptance of Marijuana for its medicinal purposes.

Dr. Sanjay Gupta, CNN’s chief medical correspondent, reversed his Y 2009 opinion against Marijuana when he said, “We have been terribly and systematically misled for nearly 70 yrs in the United States, and I apologize for my own role in that.”

Now people including lawmakers are seeing the legalization of Marijuana in states like Colorado and Washington for “recreational” purposes. Most Americans are in favor of Medical Marijuana,  and the legalization of this drug.

The Big Q: why does the federal government want to ban its usage?

The Big A: it is all about control and money, and there is a major market for it, plus it poses a major threat to the pharmaceutical industry.

Below are just a few of the many health benefits associated with Medical Marijuana:

1. It can stop HIV from spreading throughout the body.
2. It slows the progression of Alzheimer’s.
3. It slows the spread of cancer cells.
4. It is an active pain reliever.
5. It can prevent or help with opiate addiction.
6. It combats depression, anxiety and ADHD.
7. It can treat epilepsy and Tourette’s.
8. It can help with other neurological damage, such as concussions and strokes.
9. It can prevent blindness from glaucoma.
10. Its connected to lower insulin levels in diabetics.

Contrary to popular notions, many patients  experience health benefits from Medical Marijuana without “getting stoned.””

http://www.livetradingnews.com/medical-marijuana-helps-cure-chronic-disease-55569.htm#.U6VjgZRX-uY

Therapeutic potential of cannabinoid medicines.

Posted on by
Reply

Drug Testing and Analysis

“Cannabis was extensively used as a medicine throughout the developed world in the nineteenth century but went into decline early in the twentieth century ahead of its emergence as the most widely used illicit recreational drug later that century. Recent advances in cannabinoid pharmacology alongside the discovery of the endocannabinoid system (ECS) have re-ignited interest in cannabis-based medicines.

The ECS has emerged as an important physiological system and plausible target for new medicines. Its receptors and endogenous ligands play a vital modulatory role in diverse functions including immune response, food intake, cognition, emotion, perception, behavioural reinforcement, motor co-ordination, body temperature, wake/sleep cycle, bone formation and resorption, and various aspects of hormonal control. In disease it may act as part of the physiological response or as a component of the underlying pathology.

In the forefront of clinical research are the cannabinoids delta-9-tetrahydrocannabinol and cannabidiol, and their contrasting pharmacology will be briefly outlined. The therapeutic potential and possible risks of drugs that inhibit the ECS will also be considered. This paper will then go on to review clinical research exploring the potential of cannabinoid medicines in the following indications: symptomatic relief in multiple sclerosis, chronic neuropathic pain, intractable nausea and vomiting, loss of appetite and weight in the context of cancer or AIDS, psychosis, epilepsy, addiction, and metabolic disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/24006213

http://onlinelibrary.wiley.com/doi/10.1002/dta.1529/abstract