Medicinal Uses of Marijuana and Cannabinoids

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“In the past two decades, there has been increasing interest in the therapeutic potential of cannabis and single cannabinoids, mainly cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC). THC and cannabis products rich in THC exert their effects mainly through the activation of cannabinoid receptors (CB1 and CB2). Since 1975, 140 controlled clinical trials using different cannabinoids or whole-plant preparations for the treatment of a large number of disorders and symptoms have been conducted. Results have led to the approval of cannabis-based medicines [dronabinol, nabilone, and the cannabis extract nabiximols (Sativex®, THC:CBD = 1:1)] as well as cannabis flowers in several countries. Controlled clinical studies provide substantial evidence for the use of cannabinoid receptor agonists in cancer chemotherapy induced nausea and vomiting, appetite loss and cachexia in cancer and HIV patients, neuropathic and chronic pain, and in spasticity in multiple sclerosis. In addition, there is also some evidence suggesting a therapeutic potential of cannabis-based medicines in other indications including Tourette syndrome, spinal cord injury, Crohn’s disease, irritable bowel syndrome, and glaucoma. In several other indications, small uncontrolled and single-case studies reporting beneficial effects are available, for example in posttraumatic stress disorder, attention deficit hyperactivity disorder, and migraine. The most common side effects of THC and cannabis-based medicines rich in THC are sedation and dizziness (in more than 10% of patients), psychological effects, and dry mouth. Tolerance to these side effects nearly always develops within a short time. Withdrawal symptoms are hardly ever a problem in the therapeutic setting. In recent years there is an increasing interest in the medical use of CBD, which exerts no intoxicating side effects and is usually well-tolerated. Preliminary data suggest promising effects in the treatment of anxiety disorders, schizophrenia, dystonia, and some forms of epilepsy. This review gives an overview on clinical studies which have been published over the past 40 years.”

http://www.tandfonline.com/doi/abs/10.1080/07352689.2016.1265360?needAccess=true&journalCode=bpts20

“Review Identifies 140 Controlled Clinical Trials Related to Cannabis”  http://blog.norml.org/2017/06/04/review-identifies-140-controlled-clinical-trials-related-to-cannabis/

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

European Neuropsychopharmacology Home

“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.

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.”

https://www.ncbi.nlm.nih.gov/pubmed/28576350

http://www.europeanneuropsychopharmacology.com/article/S0924-977X(17)30237-7/fulltext

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Heterologous Regulation of the Cannabinoid Type 1 Receptor by Angiotensin II in Astrocytes of Spontaneously Hypertensive Rats.

“Brainstem and cerebellar astrocytes have critical roles to play in hypertension and attention deficit hyperactivity disorder (ADHD), respectively. Angiotensin (Ang) II, via the astroglial Ang Type 1 receptor (AT1R), has been demonstrated to elevate pro-inflammatory mediators in the brainstem and the cerebellum.

The activation of astroglial Cannabinoid Type 1 Receptor (CB1R), a master regulator of homeostasis, has been shown to neutralize inflammatory states.

Factors that drive disease physiology, are known to alter the expression of CB1Rs.

In the current study, we investigated the role of Ang II in regulating CB1R protein and mRNA expression in astrocytes isolated from the brainstem and the cerebellum of Spontaneously Hypertensive Rats (SHRs).

The results were then compared with the normotensive counterpart, Wistar rats. Not only was the basal expression of CB1R protein and mRNA significantly lower in SHR brainstem astrocytes, but treatment with Ang II resulted in lowering it further in the initial 12 hours. In the case of cerebellum, Ang II upregulated the CB1R protein and mRNA in SHR astrocytes. While the effect of Ang II on CB1R protein was predominantly mediated via the AT1R in SHR brainstem; both AT1R and AT2R mediated Ang II’s effect in the SHR cerebellum.

This data is strongly indicative of a potential new mode of cross talk between components of the renin angiotensin system and the endocannabinoid system in astrocytes. The consequence of such a crosstalk could be a potential reduced endocannabinoid tone in brainstem in hypertensive states, but not in the cerebellum under the same conditions.”

http://www.ncbi.nlm.nih.gov/pubmed/27529509

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ENDOCANNABINOID SYSTEM: A multi-facet therapeutic target.

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“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

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

“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

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

“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

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

“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

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

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“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/

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

“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

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

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 EJNCastelli 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

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