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

Cannabis for the Treatment of Attention Deficit Hyperactivity Disorder: A Report of 3 Cases

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Abstract of Case Report

“Attention deficit hyperactivity disorder (ADHD) is a chronic neurobehavioral disorder that is highly prevalent in children and adults. An increasing number of patients with ADHD are self-medicating with cannabis, despite a lack of evidence on efficacy and safety. This case report describes 3 males (ages 18, 22, and 23) who have integrated cannabis into their treatment regimen with positive results. Semistructured interviews conducted with the patients describe subjective improvements in symptoms and on quality of life. Improvements on validated rating scales conducted post-cannabis initiation, compared to pre-cannabis initiation obtained from the medical chart, corroborated their personal accounts. Scores on the PHQ-9 (measuring depression) improved by 8-22 points (30-81%), and the SCARED (measuring anxiety) ranged from 0 to 27 points (up to 33%). Improvements on the CEER-9 scale (measuring regulation) ranged from 2 to 7 points (22-78%), and the 9-item SNAP scale (measuring inattention) showed improvements of 2-8 points (7-30%). Mild adverse events including short-term memory problems, dry mouth, and sleepiness were reported. Blood samples were also collected from the patients to determine the plasma concentrations of the cannabinoids and relevant metabolites before and after a cannabis administration. After cannabis use, the plasma levels for CBD and THC ranged from 0 to 15.29 ng/mL and 1.32 to 13.76 ng/mL, respectively. Cannabinoids, however, were not detected prior to dosing, suggesting that cannabis played a complimentary role in the therapeutic regimen of these 3 patients. Clinical trials are recommended to confirm the efficacy of cannabis in the treatment of ADHD.”

https://pubmed.ncbi.nlm.nih.gov/35224434/

https://www.karger.com/Article/FullText/521370

The Endocannabinoid System: A Potential Target for the Treatment of Various Diseases

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ijms-logo“The Endocannabinoid System (ECS) is primarily responsible for maintaining homeostasis, a balance in internal environment (temperature, mood, and immune system) and energy input and output in living, biological systems.

In addition to regulating physiological processes, the ECS directly influences anxiety, feeding behaviour/appetite, emotional behaviour, depression, nervous functions, neurogenesis, neuroprotection, reward, cognition, learning, memory, pain sensation, fertility, pregnancy, and pre-and post-natal development.

The ECS is also involved in several pathophysiological diseases such as cancer, cardiovascular diseases, and neurodegenerative diseases. In recent years, genetic and pharmacological manipulation of the ECS has gained significant interest in medicine, research, and drug discovery and development.

The distribution of the components of the ECS system throughout the body, and the physiological/pathophysiological role of the ECS-signalling pathways in many diseases, all offer promising opportunities for the development of novel cannabinergic, cannabimimetic, and cannabinoid-based therapeutic drugs that genetically or pharmacologically modulate the ECS via inhibition of metabolic pathways and/or agonism or antagonism of the receptors of the ECS. This modulation results in the differential expression/activity of the components of the ECS that may be beneficial in the treatment of a number of diseases.

This manuscript in-depth review will investigate the potential of the ECS in the treatment of various diseases, and to put forth the suggestion that many of these secondary metabolites of Cannabis sativa L. (hereafter referred to as “C. sativa L.” or “medical cannabis”), may also have potential as lead compounds in the development of cannabinoid-based pharmaceuticals for a variety of diseases.”

https://pubmed.ncbi.nlm.nih.gov/34502379/

https://www.mdpi.com/1422-0067/22/17/9472

 

“Cannabis sativa L. as a Natural Drug Meeting the Criteria of a Multitarget Approach to Treatment”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830475/

Cannabinoid and Terpenoid Doses are Associated with Adult ADHD Status of Medical Cannabis Patients.

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Logo of rmmj “The aim of this cross-sectional questionnaire-based study was to identify associations between the doses of cannabinoids and terpenes administered, and symptoms of attention deficit hyperactivity disorder (ADHD).

CONCLUSION:

These findings reveal that the higher-dose consumption of  medical cannabis (MC) components (phyto-cannabinoids and terpenes) is associated with ADHD medication reduction.

In addition, high dosage of CBN was associated with a lower ASRS score.

However, more studies are needed in order to fully understand if cannabis and its constituents can be used for management of ADHD.”

https://www.ncbi.nlm.nih.gov/pubmed/32017685

Organophosphate agent induces ADHD-like behaviors via inhibition of brain endocannabinoid-hydrolyzing enzyme(s) in adolescent male rats.

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 Go to Volume 0, Issue ja“Anticholinergic organophosphate (OP) agents act on the diverse serine hydrolases, thereby revealing unexpected biological effects. Epidemiological studies indicate a relationship between OP exposure and development of attention-deficit/hyperactivity disorder (ADHD)-like symptoms, whereas no plausible mechanism for the OP-induced ADHD has been established.

The present investigation employs ethyl octylphosphonofluoridate (EOPF) as an OP-probe which is an extremely potent inhibitor of endocannabinoid (EC, anandamide and 2-arachidonoylglycerol)-hydrolyzing enzymes: i.e., fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL).

Ex vivo experiment shows that EOPF treatment decreases FAAH and MAGL activities and conversely increases EC levels in rat brain. Subsequently, EOPF (treated intraperitoneally once at 0, 1, 2, or 3 mg/kg) clearly induces ADHD-like behaviors (in elevated plus-maze test) in both Wistar and spontaneously hypertensive rats. The EOPF-induced behaviors are reduced by a concomitant administration of cannabinoid receptor inverse agonist SLV-319.

Accordingly, EC system is a feasible target for OP-caused ADHD-like behaviors in adolescent rats.”

https://www.ncbi.nlm.nih.gov/pubmed/31995978

https://pubs.acs.org/doi/abs/10.1021/acs.jafc.9b08195

Attenuation of Novelty-Induced Hyperactivity of Gria1-/- Mice by Cannabidiol and Hippocampal Inhibitory Chemogenetics.

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“Gene-targeted mice with deficient AMPA receptor GluA1 subunits (Gria1-/- mice) show robust hyperlocomotion in a novel environment, suggesting them to constitute a model for hyperactivity disorders such as mania, schizophrenia and attention deficit hyperactivity disorder. This behavioral alteration has been associated with increased neuronal activation in the hippocampus, and it can be attenuated by chronic treatment with antimanic drugs, such as lithium, valproic acid, and lamotrigine. Now we found that systemic cannabidiol strongly blunted the hyperactivity and the hippocampal c-Fos expression of the Gria1-/- mice, while not affecting the wild-type littermate controls. Acute bilateral intra-dorsal hippocampal infusion of cannabidiol partially blocked the hyperactivity of the Gria1-/- mice, but had no effect on wild-types. The activation of the inhibitory DREADD receptor hM4Gi in the dorsal hippocampus by clozapine-N-oxide robustly inhibited the hyperactivity of the Gria1-/- mice, but had no effect on the locomotion of wild-type mice. Our results show that enhanced neuronal excitability in the hippocampus is associated with pronounced novelty-induced hyperactivity of GluA1 subunit-deficient mice. When this enhanced response of hippocampal neurons to novel stimuli is specifically reduced in the hippocampus by pharmacological treatment or by chemogenetic inhibition, Gria1-/- mice recover from behavioral hyperactivity, suggesting a hippocampal dysfunction in hyperactive behaviors that can be treated with cannabidiol.”

https://www.ncbi.nlm.nih.gov/pubmed/30984001

https://www.frontiersin.org/articles/10.3389/fphar.2019.00309/full

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/

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

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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

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

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“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

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

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

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“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