Adverse Health Effects Of Recreational Cannabis Use

Background: Cannabis plants produce a unique family of terpeno-phenolic compounds called cannabinoids, which produce the "high" one experiences from consuming marijuana. Cannabis is usually smoked in a ‘joint’ or with a water pipe (sometimes with tobacco added) because smoking is the most efficient way to achieve the desired psychoactive effects.

Two Major Constituents of Cannabis. THC is psychoactive.

A quick summary for all:

1. There are 483 identifiable chemical constituents known to exist in the cannabis plant, and at least 85 different cannabinoids have been isolated from the plant.

2. The two cannabinoids usually produced in greatest abundance are cannabidiol (CBD) and/or delta-9-tetrahydrocannabinol (THC), but only THC is psychoactive or gives “high”.

3. Since the early 1970s, Cannabis plants have been categorized by their chemical phenotype or "chemotype", based on the overall amount of THC produced, and on the ratio of THC to CBD. Although overall cannabinoid production is influenced by environmental factors, the THC/CBD ratio is genetically determined and remains fixed throughout the life of a plant.

4. Non-drug plants produce relatively low levels of THC and high levels of CBD, while drug plants produce high levels of THC and low levels of CBD. When plants of these two chemotypes cross-pollinate, the plants in the first filial (F1) generation have an intermediate chemotype and produce similar amounts of CBD and THC. Female plants of this chemotype may produce enough THC to be utilized for drug production.

Recreational Use:

Cannabis is used for a wide variety of purposes including recreational use, medical use and as hemp fibre. Many human culture including Chinese, Indian and Greek, etc., have records of cannabis use in various social and religious activities. Cannabis is a popular recreational drug around the world, only behind alcohol, caffeine and tobacco, and it is also available as baked product and as a tea!!!

Summary: The article reports analysis of various “side-effects” that have been associated with ‘heavy’ or ‘regular’ cannabis, which for the study purpose is defined as daily or near-daily use. Starting from year 1993 till year 2013, a comparison of the evidence in 1993 with the evidence and interpretation of the same health outcomes in 2013 is attempted. Various fallouts including health, social behaviors, education, etc. are evaluated for regular user vis-à-vis a non-regular/non-user.

Results: The key conclusions are:

Adverse Effects of Acute Cannabis Use

1. Cannabis does not produce fatal overdoses.

2. Driving while cannabis-intoxicated doubles the risk of a car crash; this risk increases substantially if users are also alcohol-intoxicated.

3. Cannabis use during pregnancy slightly reduces birth weight of the baby.

Adverse Effects of Chronic Cannabis Use

1. Regular cannabis users can develop a dependence syndrome, the risks of which are around 1 in 10 of all cannabis users and 1 in 6 among those who start in adolescence.

2. Regular cannabis users double their risks of experiencing psychotic symptoms and disorders, especially if they have a personal or family history of psychotic disorders, and if they start using cannabis in their mid-teens.

3. Regular adolescent cannabis users have lower educational attainment than non-using peers but researchers don't know whether the link is causal.

4. Regular adolescent cannabis users are more likely to use other illicit drugs, but researchers don't know whether the link is causal.

5. Regular cannabis use that begins in adolescence and continues throughout young adulthood appears to produce intellectual impairment, but the mechanism and reversibility of the impairment is unclear.

6. Regular cannabis use in adolescence approximately doubles the risk of being diagnosed with schizophrenia or reporting psychotic symptoms in adulthood.

7. Regular cannabis smokers have a higher risk of developing chronic bronchitis.

8. Cannabis smoking by middle aged adults probably increases the risk of myocardial infarction.

Article Citation: Hall, W. What has research over the past two decades revealed about the adverse health effects of recreational cannabis use? Addiction 2015, 110(1), 19-35. (free copy)

Cannabis Addicts Have Reduced Dopamine Release in Brain

Summary: Various reported studies have shown that addiction to drugs of abuse such as cocaine and heroin, have serious effects on dopamine release in human brain, but such evidence for cannabis was missing until now. A latest publication in the journal Molecular Psychiatry provides evidence of a compromised dopamine system in heavy users of marijuana. Lower dopamine release was found in the striatum - a region of the brain that is involved in working memory, impulsive behavior, and attention.

Whether Dark or Light: It Doesnt Make You BRIGHT!!!!!!!

Study: The study was carried involving 11 adults between the ages of 21 and 40 who were severely dependent on cannabis (CD) and 12 matched healthy controls (HC). On average, the cannabis group started using at age 16, became dependent on cannabis by age 20, and have been dependent for the past 7 years. In the month prior to the study, nearly all users in this study smoked marijuana daily. Moreover, during the study period the heavy marijuana users stayed in the hospital for a week, during which they abstained from using it. This was to ensure that the experiments (scans) were not measuring the drug's effects.

Experimental Details: The researchers used positron emission tomography (PET) scans to track a radio-tracing molecule that binds to the brain's dopamine receptors. In scientific terminology, 11 CD and 12 HC completed two positron emission tomography scans with [¹¹C]-(+)-PHNO, before and after oral administration of d-amphetamine. Magnetic resonance spectroscopy (MRS) measures of glutamate in the striatum and hippocampus were obtained in the same subjects. Percent change in [¹¹C]-(+)-PHNO-binding potential (delta-BP_ND) was compared between groups and correlations with MRS glutamate, subclinical psychopathological and neurocognitive parameters were examined.

From this, they were able to measure the release of dopamine in the striatum, which is a brain region involved in memory, impulsive behavior and attention. Additionally, the team was able to track dopamine release in other brain regions, including the thalamus, midbrain and globus pallidus.

Participants were scanned before and after being given oral amphetamine to elicit dopamine release. The percent change in the binding of the radiotracer was taken as an indicator of capacity for dopamine release.

Results: Compared with the controls, the cannabis users had significantly lower dopamine release in the striatum, including subregions involved in associative and sensorimotor learning, and in the globus pallidus.

On further investigating the link between dopamine release in the striatum and cognitive performance on learning and working memory tasks, the researchers did not observe a difference in performance between the two groups. However, they do note that among all participants, those who had lower dopamine release performed worse on both tasks.

Conclusions: The researchers conclude their study by noting that the lower dopamine release is linked with inattention and negative symptoms in marijuana users, and with "poorer working memory and probabilistic category learning performance" in both groups. 

Article citation: Abi-Dargham, A.; et. al. Deficits in striatal dopamine release in cannabis dependence. Molecular Psychiatry 2016 | doi:10.1038/mp.2016.21

Cannabidiol in Asthma Treatment: Now Mice Later Men?

Cannabinoids are components of the Cannabis sativa (marijuana) plant and are known to exert potent anti-inflammatory, immunomodulatory, and analgesic effects through activation of cannabinoid-1 and cannabinoid-2 (CB1 and CB2) receptors located in the central nervous system (CNS) and immune cells, respectively. Cannabidiol (CBD) is the main nonpsychotropic cannabinoid and reported to have beneficial effects in many pathological conditions, including neuropsychiatric disorders and brain inflammatory diseases, without having significant activity on CB1 and CB2 receptors.

Asthma is a disorder of the conducting airways, which contract too much and too easily both spontaneously and in response to a wide range of exogenous and endogenous stimuli. This airway hyper-responsiveness is accompanied by enhanced sensory irritability of airways and increased mucus secretion. Classically, asthma is characterized by chronic airway inflammation and remodeling, hyper-responsiveness, and increase of T-helper cell 2 levels- (Th2-) related cytokines.

Taking a clue form various published results that CBD was shown to have potent immunosuppressive and anti-inflammatory properties, researchers developed a mouse model where they were able to prove protective effect of CBD upon inflammatory response in an animal model of asthma. Researchers determined the levels of 6 cytokines implicated in asthma, which can be divided by the response profiles Th1 (TNF-α and IL-6) and Th2 (IL-4, IL-13, IL-10, and IL-5). Asthma induction resulted in an increase in all cytokines levels when compared to control animals. CBD treatment was able to decrease both Th1 and Th2 cytokines.

Study Design: Rats were immunized by an i.p. injection of 10 µg of chicken ovalbumin (OVA) in 100 µL of aluminum hydroxide (alum) or alum alone. After 14 days, rats were boosted with OVA or alum. Seven days later, rats received aerosol challenges (30 min/for 3 days) with 1% OVA or saline. CBD was suspended in 2% of polyoxyethylenesorbitan monooleate (Tween 80). The solutions were prepared immediately before use and were protected from light during the experimental session. CBD was administered i.p. once a day during the last two days of the OVA challenge at the dose of 5 mg/kg.

All treatments were administered in a volume of 1 mL/kg of CBD or vehicle. For this experiment, 21 rats were used, which were randomly divided into three groups: vehicle (control) (n = 7), OVA + vehicle (asthma control) (n = 7), and OVA + CBD (asthma + treatment) (n = 7). Blood samples were obtained 24 hours after the last challenge by decapitation to determine the levels of cytokines.

Important clinical findings using a mice model:

1. CBD treatment significantly decreased the levels of cytokines involved in the immune response to an allergen, such as IL-4 and IL-5: IL-4 is responsible for the inhibition of Th1 cells differentiation and for Th2 cells differentiation and expansion and has an important role in IgE production. In addition, IL-4 seems to be a requisite for T lymphocytes to produce IL-5. IL-5 is essential for the maturation of eosinophils, and it accumulates in the lung during the inflammatory process of asthma.

2. IL-13 was reduced by CBD administration: IL-13 is considered a major stimulus for mucus hypersecretion, an important characteristic of asthma, which contributes to the exacerbation of symptoms.

3. CBD is able to decrease IL-6 levels: IL-6 levels are increased in sputum and systemic circulation in severe asthmatic patients, which can be responsible for the raise of C-reactive protein circulation in these patients.

4. CBD reduced the levels of TNF-α: TNF-α is a major mediator of severe asthma.

The authors were also candid is pointing outs some limitations on their part in not been able to measure lung function and the effect of CBD in bronchoalveolar lavage fluid cytokines, but they are sure that these results can act as a guide for future experiments.

Article citation: Dal-Pizzol, F.; et. al. Evaluation of Serum Cytokines Levels and the Role of Cannabidiol Treatment in Animal Model of Asthma. Mediators Inflamm 2015, 538670.

Drugs in Clinical Pipeline: Resunab

Resunab [1',1'-dimethylheptyl- Δ⁸-tetrahydrocannabinol-11-oic acid] is developed to achieve the goal of providing a synthetic Cannabis-derived drug that would show analgesic efficacy and have a low potential for abuse. This idea is proven through various experiments where there is no evidence that Resunab produces psychotropic actions when given at therapeutic doses. In a variety of animal assays, Resunab shows efficacy in models for pain and inflammation. Furthermore, in the rat adjuvant arthritis model, Resunab displayed a remarkable action in preventing the destruction of inflamed joints.

Resunab as a novel synthetic oral drug has the potential to treat chronic inflammation and fibrosis. Pre-clinical and Phase 1 studies have shown Resunab to have a favourable safety, tolerability and pharmacokinetic profile. Resunab is designed to trigger the resolution of chronic inflammation by binding to and activating the CB2 receptor on immune cells (in effect, turning inflammation "off"). Resunab holds the potential to be a safe and potent anti-inflammatory drug with a unique mechanism of action to treat a range of chronic inflammatory diseases.

In June 2015, Corbus Pharma announced that the U.S. Food and Drug Administration (US-FDA) has granted Corbus' lead drug candidate Resunab, Orphan Drug Designation for the treatment of systemic sclerosis. Systemic sclerosis is a chronic, serious, life-threatening inflammatory disease causing fibrosis of skin and internal organs, affecting predominately women in mid-life. Systemic sclerosis is associated with severe morbidity and high mortality. There are currently no FDA-approved drug therapies for systemic sclerosis.

The FDA has already cleared the Corbus' investigational new drug application (IND) for systemic sclerosis and the company is preparing to commence Phase 2 studies.

Common Name: Resunab

Synonyms:  Ajulemic acid; AJA; CT-3; IP-751; AB-III-56; HU-239; CPL 7075

IUPAC Name: (6aR,10aR)-3-(1,1-dimethylheptyl)-6a,7,10,10a-tetrahydro-1-hydroxy-6,6-dimethyl-6H-Dibenzo(b,d)pyran-9-carboxylic acid

CAS Number: 137945-48-3

SMILES: CC(C)(CCCCCC)c2cc1OC(C)(C)[C@@H]3/C=C\C(C[C@H]3c1c(O)c2)C(O)=O

Mechanism of Action: 

Indication: Anti-inflammatory Drugs; Analgesic Drugs; Treatment of Systemic Sclerosis

Development Stage: Phase II

Company: Corbus Pharma

The studies into mechanism of Resunab have produced some contradictory questions.  On the one hand, modest binding to the known cannabinoid receptors, CB1 and CB2 has been reported, and effects by receptor specific antagonists as well as stereospecificity has been observed suggesting a possible role for these receptors in the actions of Resunab. On the other hand, the fact that Resunab does not produce psychoactivity, a process that is believed to require the activation of CB1, appears to be a contradiction. A possible explanation is that Resunab, in addition to activating the receptor, selectively antagonizes a downstream event that is required for psychotropic activity but is not needed for anti-inflammatory actions [1].

References:
1. Burstein, S. Ajulemic acid (IP-751): synthesis, proof of principle, toxicity studies, and clinical trials. AAPS J 2005, 7(1), E143-8.

Cannabis-Based Medicine As Potential Therapy For Alzheimer's Disease

Alzheimer is an age-dependent neurodegenerative process distinct from normal aging and characterized morphologically by the presence of senile plaques, mainly composed of different species of fibrillar β-amyloid (Aβ) produced by the cleavage of the Aβ precursor protein (APP) due to ß- and γ-secretases, and by the presence of neurofibrillary tangles, mostly composed of various isoforms of hyper-phosphorylated and nitrated tau protein. One tendency of opinion proposes that Aβ triggers plaque formation, tau hyper-phosphorylation, and disease progression. This may happens in a percentage of familial Alzheimer’s disease (AD) cases linked to mutations in genes encoding APP, and presenilin 1 and presenilin 2 which are enzymes involved in the cleavage of APP, or in Down syndrome. However, tau hyper-phosphorylation precedes Aβ deposition in many cerebral regions in sporadic cases of AD.

Recent studies have shown that Aβ acts as a seed of new Aβ production and deposition under appropriate conditions and that abnormal tau promotes the production and deposition of hyper-phosphorylated tau under determinate experimental conditions. Therefore, Aβ and hyper-phosphorylated tau promote the progression of the pathological process in an exponential way once these abnormal proteins are accumulated in the brain.

During the last few years, targeting the endogenous cannabinoid system (ECS) has emerged as a potential therapeutic approach to treat Alzheimer in such first stages. The endocannabinoid system is composed by a number of cannabinoid receptors, including the well-characterized central and peripheral neurons (CB1) and immune cells (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 ß-amyloid peptide action and tau phosphorylation, as well as by promoting the brain’s intrinsic repair mechanisms. Endocannabinoid signaling has been demonstrated to modulate the main pathological processes occurring during the silent period of the neurodegenerative process, including protein misfolding, neuroinflammation, excitotoxicity, mitochondrial dysfunction, and oxidative stress.

Here are summarized two studies where Cannabis has successfully stopped Aβ production.

Study 1 [1]

Since the characterization of the Cannabis sativa-produced cannabinoid, Delta-9-tetrahydrocannabinol (THC), in the 1960's, this natural product has been widely explored as an anti-emetic, anti-convulsive, anti-inflammatory, and analgesic. In contexts to Alzheimer, efficacy results from THC binding to the family of cannabinoid receptors found primarily on central and peripheral neurons (CB1) or immune cells (CB2). The active component of marijuana, Delta-9-tetrahydrocannabinol (THC), competitively inhibits the enzyme acetylcholinesterase (AChE) as well as prevents AChE-induced amyloid beta-peptide (Aβ) 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 Aβ aggregation, and study provides a previously unrecognized molecular mechanism through which cannabinoid molecules may directly impact the progression of this debilitating disease.

Study 2 [2]

This study demonstrated that delta-9-tetrahydrocannabinol (THC) or cannabidiol (CBD) botanical extracts, as well as the combination of both natural cannabinoids, which are the components of an already approved cannabis-based medicine, preserved memory in AβPP/PS1 transgenic mice when chronically administered during the early symptomatic stage. Moreover, THC + CBD reduced learning impairment in AβPP/PS1 mice. A significant decrease in soluble Aβ42 peptide levels and a change in plaques composition were also observed in THC + CBD-treated AβPP/PS1 mice, suggesting a cannabinoid-induced reduction in the harmful effect of the most toxic form of the Aβ peptide. Among the mechanisms related with these positive cognitive effects, the anti-inflammatory properties of cannabinoids may also play a relevant role. Researchers observed reduced astrogliosis, microgliosis, and inflammatory-related molecules in treated AβPP/PS1 mice, which were more marked after treatment with THC + CBD than with either THC or CBD. Moreover, other cannabinoid-induced effects were uncovered by a genome-wide gene expression study. Researchers also identified the redox protein thioredoxin 2 and the signaling protein Wnt16 as significant substrates for the THC + CBD-induced effects in our AD model. The present findings show that the combination of THC and CBD exhibits a better therapeutic profile than each cannabis component alone and support the consideration of a cannabis-based medicine as potential therapy against AD.

These studies have demonstrated the ability of cannabinoids to provide neuroprotection against β-amyloid peptide (Aβ) toxicity. Yet, it is important to note that in these reports, cannabinoids serve as signaling molecules which regulate downstream events implicated in Alzheimer's disease pathology and are not directly implicated as effecting Aβ at a molecular level.

References:

1. Eubanks, L. M.; et. al. A molecular link between the active component of marijuana and Alzheimer's disease pathology. Mol Pharm 2006, 3(6), 773-777.
2. Ester, A.; et. al. Cannabis-Based Medicine Reduces Multiple Pathological Processes in AßPP/PS1 Mice. Journal of Alzheimer's Disease 2015, 43(3). DOI: 10.3233/JAD-141014

Cannabis-Based Epilepsy Drug (Epidiolex) has Positive News

Epidiolex, is a liquid formulation of highly purified Cannabidiol (CBD) extract which is under trials as a treatment for various orphan pediatric epilepsy syndromes. It has been granted Orphan Drug Designation for the treatment of Dravet syndrome and  Lennox-Gastaut syndrome by US-FDA. 

Epidiolex also known as (GWP42003 oral solution) is as an oily solution containing 100 mg/mL of cannabidiol (CBD) dissolved in excipients, sesame oil, ethanol, sucralose and strawberry flavouring.

GW Pharmaceuticals is developing Epidiolex. 

In a Phase III study, the in-development epilepsy drug slashed rates of seizures by more than 50%, a hopeful sign for the cannabis-derived treatment. In a presentation with American Academy of Neurology, Epidiolex was credited with 54% reduction in number of seizures among patients with severe and/or treatment-resistant epilepsy. 

The study was conducted through an expanded access program, which allows drugmakers to make unapproved products available to patients who have life-threatening diseases with no therapeutic alternatives, and its results by no means stand in for placebo-controlled efficacy data. The study enrolled 213 people from toddlers to adults and dosed them with Epidiolex twice daily. Among the 137 patients who stayed on the drug for 12 weeks, the drug led to a 54% mean reduction in seizures, including a 53% average cut in those with Dravet syndrome and a 55% reduction in sufferers with Lennox-Gastaut syndrome. 

GW Pharma, which is working on Phase III trials studying Epidiolex in Dravet and is planning a late-stage Lennox-Gastaut study in 2015 is very upbeat with these findings. The drug is already enrolled in the FDA's fast-track program, guaranteeing a speedy regulatory review. GW Pharma too plans to conducts a separate late-stage program and investigators believe the open-label study points to potential success for the cannabis-based therapy.

References:
1. ClinicalTrials.gov Epidiolex and Drug Resistant Epilepsy in Children (CBD). NCT02397863 (retrieved 30-05-2015)
2. ClinicalTrials.gov A Study of GWP42003 as Adjunctive Therapy in the First Line Treatment of Schizophrenia or Related Psychotic Disorder. NCT02006628 (retrieved 30-05-2015)