Medicinal and Synthetic Cannabinoids for Pediatric Patients: A Review of Clinical Effectiveness and Guidelines [Internet].

Cover of Medicinal and Synthetic Cannabinoids for Pediatric Patients: A Review of Clinical Effectiveness and Guidelines“Cannabinoids are pharmacologically active agents extracted from the cannabis plant. Cannabidiol and tetrahydrocannabinol (THC) are the most studied cannabinoids and both interact with endocannabinoid receptors in various human tissues. The endocannabinoid system moderates physiological functions, such as neurodevelopment, cognition, and motor control.

The products naturally derived from cannabis include marijuana (dried leaves and flowers, mostly for smoking) and oral cannabinoid extracts with varying concentrations of cannabinoids, including cannabidiol and THC. THC is the main psychoactive constituent and cannabidiol seems to have no psychoactive properties. In addition, there are two synthetical cannabinoids approved by the Food and Drug Administration (FDA) in the United States, dronabinol and nabilone, which are molecules similar to a type of THC (δ-9-THC)1 Nabilone is also approved in Canada. Dronabinol is indicated for chemotherapy-induced nausea and vomiting in children. The use of nabilone in children is not recommended.

In Canada, the minimum age for cannabis consumption varies by provinces and territories, and is either 18 or 19 years. A prescription is required to administer cannabinoids among children. Clinically, cannabis has been used to treat children with epilepsy, cancer palliation and primary treatment, chronic pain, and Parkinson disease.

The adverse events that clinicians need to monitor for include negative psychoactive sequelae and development of tolerance. Psychoactive sequelae may be positive, such as relaxation and euphoria, or negative, such as anxiety and irritability. In 2016, CADTH completed a Summary of Abstracts report on the use of cannabis in children with medical conditions such as attention deficit hyperactivity disorder, autism spectrum disorder, Tourette syndrome, epilepsy, posttraumatic stress disorder, or neurodegenerative diseases, and five non-randomized studies were identified. However, there were no control groups in the five studies included in the report.

It is unclear whether there is new evidence or clinical guidance for the use of medical cannabis in children with mental health conditions, neurodegenerative diseases, or pain disorders, particularly in comparison with other possible therapies for those conditions. There is a need to review the clinical effectiveness of cannabis for pediatric care, as well as clinical guidelines.”

https://www.ncbi.nlm.nih.gov/pubmed/31873990

https://www.ncbi.nlm.nih.gov/books/NBK551866/

Cannabis and Neuropsychiatric Disorders: An Updated Review.

 Image result for Acta Neurol Taiwan. journal“Cannabis plant has the scientific name called Cannabis sativa L. Cannabis plant has many species, but there are three main species including Cannabis sativa, Cannabis indica and Cannabis ruderalis. Over 70 compounds isolated from cannabis species are called cannabinoids (CBN).

Cannabinoids produce over 100 naturally occurring chemicals. The most abundant chemicals are delta-9-tetrahydrocannabinol (THC) and Cannabidiol (CBD). THC is psychotropic chemical that makes people feel “high” while CBD is nonpsychotropic chemical. However, cannabinoid chemicals are not found only in the cannabis plant, they are also produced by the mammalian body, called endocannabinoids and in the laboratory, called synthesized cannabinoids.

Endocannabinoids are endogenous lipid-based retrograde neurotransmitters that bind to cannabinoid receptors, and cannabinoid receptor proteins that are expressed throughout the mammalian central nervous system including brain and peripheral nervous system. There are at least two types of endocannabinoid receptors (CB1 and CB2) which are G-protein coupled receptors.

CB1 receptors are particularly abundant in the frontal cortex, hippocampus, basal ganglia, hypothalamus and cerebellum, spinal cord and peripheral nervous system. They are present in inhibitory GABA-ergic neurons and excitatory glutamatergic neurons. CB2 receptor is most abundantly found on cells of the immune system, hematopoietic cells and glia cells. CB2 is mainly expressed in the periphery under normal healthy condition, but in conditions of disease or injury, this upregulation occurs within the brain, and CB2 is therefore expressed in the brain in unhealthy states.

Cannabis and cannabinoid are studied in different medical conditions. The therapeutic potentials of both cannabis and cannabinoid are related to the effects of THC, CBD and other cannabinoid compounds. However, the “high” effect of THC in cannabis and cannabinoid may limit the clinical use, particularly, the study on the therapeutic potential of THC alone is more limited.

This review emphasizes the therapeutic potential of CBD and CBD with THC. CBD has shown to have benefit in a variety of neuropsychiatric disorders including autism spectrum disorder, anxiety, psychosis, neuropathic pain, cancer pain, HIV, migraine, multiple sclerosis, Alzheimer disease, Parkinson disease, Huntington disease, hypoxic-ischemic injury and epilepsy. CBD is generally well tolerated. Most common adverse events are diarrhea and somnolence. CBD also shows significantly low abuse potential.”

https://www.ncbi.nlm.nih.gov/pubmed/31867704

THC exposure during adolescence does not modify nicotine reinforcing effects and relapse in adult male mice.

 This study investigated the effects of adolescent exposure to the main psychoactive component of cannabis, ∆9-tetrahydrocannabinol (THC), in the reinforcing properties of nicotine in adult male mice. Possible alterations in relapse to nicotine-seeking behaviour in adult animals due to THC adolescent exposure were also evaluated.

RESULTS:

Adolescent THC treatment did not modify acquisition and extinction of nicotine self-administration in adulthood. Moreover, THC exposure did not alter relapse to nicotine seeking induced by stress or nicotine-associated cues.

CONCLUSIONS:

These results suggest that a history of exposure to THC during adolescence under these particular conditions does not modify the reinforcing effects and seeking behaviour of nicotine in the adult period.”

https://www.ncbi.nlm.nih.gov/pubmed/31858159

https://link.springer.com/article/10.1007%2Fs00213-019-05416-8

Cannabinoids and the expanded endocannabinoid system in neurological disorders.

 Related image“Anecdotal evidence that cannabis preparations have medical benefits together with the discovery of the psychotropic plant cannabinoid Δ9-tetrahydrocannabinol (THC) initiated efforts to develop cannabinoid-based therapeutics.

These efforts have been marked by disappointment, especially in relation to the unwanted central effects that result from activation of cannabinoid receptor 1 (CB1), which have limited the therapeutic use of drugs that activate or inactivate this receptor.

The discovery of CB2 and of endogenous cannabinoid receptor ligands (endocannabinoids) raised new possibilities for safe targeting of this endocannabinoid system. However, clinical success has been limited, complicated by the discovery of an expanded endocannabinoid system – known as the endocannabinoidome – that includes several mediators that are biochemically related to the endocannabinoids, and their receptors and metabolic enzymes.

The approvals of nabiximols, a mixture of THC and the non-psychotropic cannabinoid cannabidiol, for the treatment of spasticity and neuropathic pain in multiple sclerosis, and of purified botanical cannabidiol for the treatment of otherwise untreatable forms of paediatric epilepsy, have brought the therapeutic use of cannabinoids and endocannabinoids in neurological diseases into the limelight.

In this Review, we provide an overview of the endocannabinoid system and the endocannabinoidome before discussing their involvement in and clinical relevance to a variety of neurological disorders, including Parkinson disease, Alzheimer disease, Huntington disease, multiple sclerosis, amyotrophic lateral sclerosis, traumatic brain injury, stroke, epilepsy and glioblastoma.”

https://www.ncbi.nlm.nih.gov/pubmed/31831863

“The existence of the endocannabinoidome explains in part why some non-euphoric cannabinoids, which affect several endocannabinoidome proteins, are useful for the treatment of neurological disorders, such as multiple sclerosis and epilepsy.”

https://www.nature.com/articles/s41582-019-0284-z

Missing Pieces to the Endocannabinoid Puzzle.

Image result for trends in molecular medicine“The most bioactive ingredient of cannabis (Cannabis sativa or indica) extracts, Δ9-tetrahydrocannabinol (THC), was identified in the 1960s as one of more than 110 phytocannabinoids. It activates receptors of chemically different endogenous ligands (endocannabinoids) that, unlike THC, are metabolized by several enzymes of the endocannabinoid system. Here, the complexity of the plant-derived and endogenous cannabinoids (eCBs) is discussed, to better appreciate the challenge of: (i) dissecting their mutual interactions; (ii) understanding their impact on human pathophysiology; and (iii) exploiting them for human disease. To this aim, missing pieces to the eCB puzzle must be urgently found, by solving the 3D structures of key components, and interrogating noncanonical modes of regulation and trafficking of these lipid signals.”

https://www.ncbi.nlm.nih.gov/pubmed/31822395

https://www.cell.com/trends/molecular-medicine/fulltext/S1471-4914(19)30293-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS147149141930293X%3Fshowall%3Dtrue

Cannabis Use in Children With Pantothenate Kinase-Associated Neurodegeneration.

 SAGE Journals“Pantothenate kinase-associated neurodegeneration is characterized by severe, progressive dystonia. This study aims to describe the reported usage of cannabis products among children with pantothenate kinase-associated neurodegeneration.

METHODS:

A cross-sectional, 37-item survey was distributed in April 2019 to the families of 44 children who participate in a clinical registry of individuals with pantothenate kinase-associated neurodegeneration.

RESULTS:

We received 18 responses (40.9% response rate). Children were a mean of 11.0 (SD 4.3) years old. The 15 respondents with dystonia or spasticity were on a median of 2 tone medications (range 0-9). Seven children had ever used cannabis (38.9%). The most common source of information about cannabis was other parents. Children who had ever used cannabis were on more tone medications, were more likely to have used opiates, were less likely to be able to roll, and less likely to sit comfortably, than children who had never used cannabis. Four children reported moderate or significant improvement in dystonia with cannabis. Other areas reported to be moderate or significantly improved were pain (n = 3), sleep (n = 4), anxiety (n = 3), and behavior (n = 2). Adverse effects included sadness (n = 1), agitation/behavior change (n = 1), and tiredness (n = 1).

CONCLUSION:

Cannabis use was commonly reported among children with pantothenate kinase-associated neurodegeneration whose parents responded to a survey, particularly when many other dystonia treatments had been tried. Physicians should be aware that parents may treat their child with severe, painful dystonia with cannabis. Placebo-controlled studies of products containing cannabidiol and 9-tetrahydrocannabinol are needed for pediatric tone disorders.”

https://www.ncbi.nlm.nih.gov/pubmed/31823681

https://journals.sagepub.com/doi/abs/10.1177/0883073819890516?journalCode=jcna

Orally consumed cannabinoids provide long-lasting relief of allodynia in a mouse model of chronic neuropathic pain.

 

Image result for neuropsychopharmacology“Chronic pain affects a significant percentage of the United States population, and available pain medications like opioids have drawbacks that make long-term use untenable.

Cannabinoids show promise in the management of pain, but long-term treatment of pain with cannabinoids has been challenging to implement in preclinical models. We developed a voluntary, gelatin oral self-administration paradigm that allowed male and female mice to consume ∆9-tetrahydrocannabinol, cannabidiol, or morphine ad libitum.

Mice stably consumed these gelatins over 3 weeks, with detectable serum levels. Using a real-time gelatin measurement system, we observed that mice consumed gelatin throughout the light and dark cycles, with animals consuming less THC-gelatin than the other gelatin groups.

Consumption of all three gelatins reduced measures of allodynia in a chronic, neuropathic sciatic nerve injury model, but tolerance to morphine developed after 1 week while THC or CBD reduced allodynia over three weeks. Hyperalgesia gradually developed after sciatic nerve injury, and by the last day of testing, THC significantly reduced hyperalgesia, with a trend effect of CBD, and no effect of morphine. Mouse vocalizations were recorded throughout the experiment, and mice showed a large increase in ultrasonic, broadband clicks after sciatic nerve injury, which was reversed by THC, CBD, and morphine.

This study demonstrates that mice voluntarily consume both cannabinoids and opioids via gelatin, and that cannabinoids provide long-term relief of chronic pain states. In addition, ultrasonic clicks may objectively represent mouse pain status and could be integrated into future pain models.”

https://www.ncbi.nlm.nih.gov/pubmed/31812152

https://www.nature.com/articles/s41386-019-0585-3

An Open-Label Pilot Study Testing the Feasibility of Assessing Total Symptom Burden in Trials of Cannabinoid Medications in Palliative Care.

View details for Journal of Palliative Medicine cover image“There is considerable interest in the use of cannabinoids for symptom control in palliative care, but there is little high-quality evidence to guide clinical practice.

Objectives: Assess the feasibility of using global symptom burden measures to assess response to medicinal cannabis, to determine median tolerated doses of cannabidiol (CBD) and tetrahydrocannabinol (THC), and to document adverse events (AEs).

Design: Prospective two-arm open-label pilot trial of escalating doses of CBD and THC oil.

Setting/Subjects: Participants had advanced cancer and cancer-related symptoms in a palliative and supportive care service in an Australian cancer center.

Measurements: The main outcome measures were the number of participants screened and randomized over the time frame, the number of participants completing days 14 and 28 and providing total symptom distress scores (TSDSs) (measured using the Edmonton Symptom Assessment Scale), and the change from baseline of the TSDS at day 14.

Results: Of the 21 participants enrolled (CBD, n = 16; THC, n = 5), 18 (86%) completed the primary outcome measure at day 14 and 8 completed at day 28. The median maximum tolerated doses were CBD, 300 mg/day (range 100-600 mg); THC, 10 mg/day (range 5-30 mg). Nine of 21 patients (43%) met the definition of response (≥6 point reduction in TSDS). Drowsiness was the most common AE.

Conclusions: Trials of medicinal cannabis in advanced cancer patients undergoing palliative care are feasible. The doses of THC and CBD used in this study were generally well tolerated and the outcome measure of total symptom distress is promising as a measure of overall symptom benefit.”

https://www.ncbi.nlm.nih.gov/pubmed/31800354

https://www.liebertpub.com/doi/10.1089/jpm.2019.0540

Long-term benefit from immune modulation and anti-inflammatory treatment in metastatic mesothelioma.

Respiratory Medicine Case Reports“A 64 year old male heating engineer was investigated for a persistent cough and found to have epithelioid mesothelioma with pleural effusion, lung nodules and increased thoracic lymph nodes. He declined standard of care treatment following his own research and he was enrolled in a named patient programme of IMM-101. He was advised to correct his low vitamin D3 level and to start using anti-inflammatories such as aspirin, bromelain and low dose Naltrexone. At review one year later a CT scan showed no change and he continued on the regimen. Four years after the diagnosis a CT scan showed that there was a modest but definite progression of the left malignant pleural thickening, and a new right-sided effusion, enlargement of several intrathoracic nodes which had been noted on the early scans. The chest wall lump eventually broke down and required local radiotherapy. He then developed abdominal pain and found to have peritoneal disease. Last year he obtained the cannabinoids CBD and THC which slowed down the disease and a CT scan after he had been on this for six months, showed that his disease was fairly stable with marginal progression.”

https://www.ncbi.nlm.nih.gov/pubmed/31788420

“The patient gave his full written consent for this report and is keen that others can benefit from this treatment.”

https://www.sciencedirect.com/science/article/pii/S2213007119303168?via%3Dihub

Short-term effects of cannabis consumption on cognitive performance in medical cannabis patients.

Publication Cover “This observational study examined the acute cognitive effects of cannabis.

We hypothesized that cognitive performance would be negatively affected by acute cannabis intoxication.

Contrary to expectations, performance on neuropsychological tests remained stable or even improved during the acute intoxication stage (THC; d: .49-.65, medium effect), and continued to increase during Recovery (d: .45-.77, medium-large effect).

Contrary to our hypothesis, there was no psychometric evidence for a decline in cognitive ability following THC intoxication.”

https://www.ncbi.nlm.nih.gov/pubmed/31790276

https://www.tandfonline.com/doi/abs/10.1080/23279095.2019.1681424?journalCode=hapn21