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An interview with Vincenzo Di Marzo, the man who named the Endocannabinoid System

Professor Di Marzo is one of the world’s leading cannabinoid scientists, co-author of more than 460 peer-reviewed publications, and in 2010 was recognised as Thompson Reuters ‘top scientist of the decade’ for pharmacology and toxicology. He has previously served as President of the International Cannabinoid Research Society (ICRS) and is a recipient of ICRS’s Mechoulam Award for “outstanding contributions to cannabinoid research”.
In this Video Vincenzo Di Marzo gets interviewed in Tucson, Arizona at the 2012 National Clinical Conference on Cannabis Therapeutics. The 2012 conference focused on The Endocannabinoid System: Clinical Implications for Health Care.

Run From the Cure – The Rick Simpson Story

A Film By Christian Laurette – After a serious head injury in 1997, Rick Simpson sought relief from his medical condition through the use of medicinal hemp oil. When Rick discovered that the hemp oil (with its high concentration of T.H.C.) cured cancers and other illnesses, he tried to share it with as many people as he could free of charge – curing and controlling literally hundreds of people’s illnesses… but when the story went public, the long arm of the law snatched the medicine – leaving potentially thousands of people without their cancer treatments – and leaving Rick with unconstitutional charges of possessing and trafficking cannabis!

Uploaded on YouTube by Strain Spot | For more information please visit: http://phoenixtears.ca/

Triggering flowering in cannabis: a consequence of photoperiodism

The practice of indoor cultivation of cannabis is advantageous for accelerating the growth of the plant. Annual harvest capability can be maximized by increasing the annual production cycles of cannabis production. The phenomenon which is exploited to artificially flower the cannabis plant is the photoperiodic control: the innate biological light sensory system.

Many flowering plants sense seasonal changes, particularly the changes in night length, as signals to initiate flowering. Some plants flower when the night length starts to decrease and fall below their critical photoperiod, and these plants are classified as long day plants. Long day plants initiate their flowering during late spring or early summer. Examples of long day plants include oat (Avena), pea (Pisum sativum) and barley (Hordeum vulgare).

Other plants work in an entirely opposite manner. They initiate flowering when the night length starts to increase, and they are classified as short-day plants. A period of undisturbed darkness, above the critical photoperiod, is required for floral development. Examples of short-day plants include cotton (Gossypium), rice (Oryza), soybeans (Glycine max) and cannabis (Cannabis sativa and Cannabis indica).

There are some plants which are classified as day-neutral plants, in which floral development is independent of the photoperiod. Plants such as cucumbers (Cucumis sativus), corn (Z. mays subsp. mays) and tomatoes (Solanum lycopersicum) are examples of day neutral plants.

The Phytochrome light sensors

Phytochromes are proteins which are present in the cannabis plant and sensitive to light in the red and far-red region of the visible spectrum. Phytochromes exist in either the ground (Pr) or excited state (Pfr). In the Pr state, phytochromes can absorb red light (wavelength of 650–670 nm)  and consequently transform into the excited state Pfr. The excited state only absorbs light near the infra-red region (wavelength 705–740 nm), converting it back to the ground state. Infra-red light is commonly used in production facilities to promote the flowering of cannabis.


Phytochromes have two photo-inter convertible forms: Pr and Pfr

Since Pfr reverts to Pr during darkness, there will be no Pfr remaining at sunrise if the night is long (winter) and some Pfr remaining if the night is short (summer). The amount of Pfr present controls flowering, setting of winter buds, and vegetative growth according to the seasons. Consequently the phytochrome system acts as a biological light switch, as it is involved in the regulation of the circadian clock of the plant.

Signalling Cascade to trigger flowering

The phytochrome system is interlined to a downstream signalling cascade which leads to the production of flowering hormones or “florigens”. There is currently a large absence of knowledge of the molecular biology and genetic control of flowering in cannabis plants.  The photoperiodic genetic interplay of Arabidopsis thaliana, the model organism in the plant world, has been studied in depth. However, as it is a long day plant, it would have a considerably different molecular interplay of flowering as compared to cannabis.

Rice is a more accurate model for analogy as it is a short day plant (henceforth would exhibit more homology with cannabis), and has been studied extensively. In rice, the phytochrome system plays an important role in day-length recognition, partly through the control of transcriptional factors which influence the production of flowering hormones. One example is the transcriptional factor SE1, and interaction between activated phytochromes (Pfr) and SE1 repressed the activation of flowering genes. A key protein involved in the flowering of rice, Hd3a, has it expression decreased by red light, and reversed by far red light. This emphasizes the involvement of the phytochrome system in the production of flowering hormones.

In indoor cultivation practices of cannabis, the plant is exposed to extended periods of artificial light in the vegetative state (first 8 weeks) expedites growth, particularly height. However in the subsequent four weeks (the flowering state), equal periods of light and darkness are important for the plant to flower.  It is hypothesized that the period of darkness is required to inactivate phytochromes, and inhibit any repression of flowering genes caused by activated phytochromes.

Autoflowering genetics

Cannabis ruderalis is a species of cannabis present Eastern Europe, Russia, China and elsewhere in central and northern Asia. Typically it is present as a wild cannabis plant outdoors in these regions. This species of cannabis is day neutral or ‘auto-flowering’, and can begin flowering within three weeks of germination.

ruderalis

Given that the day-neutral or auto-flowering genetic characteristic is href=”http://www.ismokemag.co.uk/cannabis-seeds-basic-breeding/”>recessiveit indicates that the genes involved have a loss of function mutation. Due to a lack of genetic research, it is unknown which pinpointed genes are responsible for lack of photoperiodism in Cannabis ruderalis.  Studies from Arabidopsis thaliana showed that LHY and CCA1 are critical for day-length sensitive flowering, and loss of function of these genes caused the plant to attain day-neutral characteristics. A similar consequence could be occurring in Cannabis ruderalis, where critical interacting genes are mutated.

Harnessing the flowering mechanism

Through various breeding exercises, the auto-flowering genetics of Cannabis ruderalis have been used to create auto-flowering strains of the plant. These strains switch from the vegetative stage to the flowering stage of the lifecycle with age, independent of the photoperiod. These plants can be grown outdoors without the need for close control of lighting periods, while maintaining a short harvest period. This is one example of how the flowering mechanism has been harnessed for commercial production.

There is a need to understand the genetic mechanisms which are involved in the flowering process of cannabis, and to pinpoint the key genes which are responsible. This can lead to the better selection of genetics strains for auto-flowering plants – looking for target genes through the analysis of DNA. The flowering molecular biology and the genetics controlling it, could be targeted with various transcription factors. This could be done so to accelerate production time of cannabis and be influenced to flower earlier, consequently increasing the number of production cycles in a year and maximising yield.

The proposed mechanism of action of cannabidiol (CBD) and cannabidiolic acid (CBDA)

Playing a role in almost every physiological system in the body, the endocannabinoid system is a key homeostatic regulator. Historically it has been overlooked as a possible therapeutic target, as there was not much known about disease implications of the system. However with the incredible success stories reported from the use of cannabidiol (CBD) and cannabidiolic acid (CBDA), the endocannabinoid system is increasingly gathering interest in the medical community.

The theory of clinical endocannabinoid deficiency is progressively gathering supportive evidence for it’s involvement in migraine, fibromyalgia and irritable bowel syndrome. Some diseases have shown endocannabinoid abnormalities such as epilepsy, cancer and a wide array of neurodegenerative diseases.

CBD and CBDA have shown to be very effective at treating a variety of conditions, and their therapeutic evidence and value is growing daily. The precise mechanism of action for both of these compounds is still debated. However by inferring from their pharmacological characteristics, conclusions can be drawn on the diseases which would benefit the most from these compounds.

Cannabidiol: how does it work?

CBD has very little action at the CB1 and CB2 receptors. It is able to block the actions of compounds which activate these receptors, such as THC. Consequently it can suppress that psychoactivity of THC, and can be effective to reduce it’s side effects.

CBD also inhibits the enzyme which degrades anandamide, fatty acid amide hydrolase (FAAH), and can consequently restore anandamide levels in diseases which have shown clinical endocannabinoid deficiency. A clinical study using CBD for schizophrenia brought about a significant increase in serum anandamide levels, consequently bringing about a marked clinical improvement.

cannabidiol

As CBD is an enantiomeric compound, it’s different enantiomers can have varying effects. A study has shown that the (−)-enantiomer was better at inhibiting FAAH as compared to the (+)-enantiomer. In contrast, the (+)-enantiomer showed more affinity for the CB1 and CB2 receptors and would probably be a better compound to be given in combination with THC.

CBD also has affinity at certain Transient receptor potential (TRP) cation channels, which are implicated in many diseases. CBD desensitizes (dampen the receptor’s activity) TRPV1, TRPV2, TRPV3, TRPV4 and TRPA1 channels which are highly active in pain states in many diseases. CBD is also an antagonist of the TRPM8 receptor, which heavily implicated in allodynia. CBD also targets key neural signalling receptors such as 5-HT1a and 5-HT3a, which are useful targets for diseases such as epilepsy and numerous anxiety disorders.

Cannabidiolic acid: the precursor with an important role

A heat activated reaction causes the removal of the carboxyl group on CBDA, and leads to the formation of CBD. CBDA’s interaction with the endocannabinoid system is & minimal, but it has other interesting target receptors.& CBDA desensitizes the TRPV1, TRPV3, TRPV4 and TRPA1 receptors. CBDA also & inhibits key inflammatory mediators such as COX-1 and COX-2.

The COX-1 & enzyme is a promising target for reducing seizures, and the use of CBDA in the treatment of epilepsy has been patented by British company GW Pharmaceuticals. COX-2 is responsible for a wide range of inflammatory processes in the body. Other well known COX-2 inhibitors include & acetylsalicylic acid (Aspirin), naproxen, ibuprofen and tolmetin. CBDA could mimic the effects of these drugs in treating inflammation.

Working in synergy

Diseases are often caused by the misregulation of multiple physiological systems in the body. As suggested by anecdotes, the combination of CBD and CBDA could be much more effective than the single compounds, especially for diseases such as epilepsy. By & complementing each other’s properties, they could work very effectively. Recently published data has revealed that acidic cannabinoids (such as CBDA) can help the uptake and metabolism of CBD or other phytocannabinoids. Administering CBDA with CBD could decrease the amount of CBD needed to be effective.

5 Ways Cannabis Affects Your Sleep

Article by LS

Besides easing insomnia, cannabis seems to have a wide range of effects on sleep.

This is because chemicals in cannabis, known as cannabinoids, actually mimic the activity of chemicals found naturally in the brain.

These chemicals and their biological pathways make up the body’s endocannabinoid system, which is responsible for regulating sleep, among other things.

Likewise, research shows that cannabis can also have a direct impact on sleep. Here’s 5 of the most important effects that studies have identified so far.

1. Easier Falling Asleep

(Photo: clinicaomegazeta.com)

Some of the earliest research on marijuana and sleep shows that cannabis’s main ingredient, THC, can significantly reduce the time it takes for both insomniacs and healthy people to fall asleep.

In a small study published in 1973, THC reduced the time it took for 9 subjects with insomnia to fall asleep by over an hour on average. However, the researchers noted that too high of a dose could counteract the effect.

THC was also found to ease falling asleep in a 2013 study involving healthy subjects.

2. Longer Sleep

(Photo: WikiHow)

Early studies also revealed that taking either THC or CBD before bed could lead to an increase in overall sleep. In one study, increasing the dose of THC also increased the amount of time spent sleeping.

However, higher doses of THC also caused a “hang over” feeling in some subjects when they woke up, while the feeling was not present at lower doses.

3. More Deep Sleep

(Photo: cobalt123/Flickr)

Some of the more interesting effects of marijuana on sleep involve its impact on the sleep cycle. Studies show that THC can increase the amount of slow-wave sleep, also known as deep sleep, that an user experiences during their slumber.

This is likely a good thing, since deep sleep is believed to play a major role in the restoration process that occurs during sleep.

What’s more, experts believe that the most damaging effects of sleep deprivation result from a lack of slow-wave sleep. For example, research has shown that reduced slow-wave sleep can be a strong predictor of high blood pressure in older men.

4. Shorter REM Sleep

(Photo: uhdwallpapers.org)

Another way cannabis affects the sleep cycle is a reduction in REM sleep. Many people who smoke before bed report a lack of dreaming, which only occurs during REM sleep.

While less REM sleep could be seen as a negative effect of marijuana use, scientists are still not sure what purpose REM sleep actually serves.

However, people who quit after using cannabis on a frequent basis often experience an increase in REM sleep, also known as the “REM rebound” effect, which is accompanied by an increase in dreaming and restlessness during sleep. But this effect tends to wear off within days or weeks, depending on the individual.

5. Better Breathing

(Photo: Huffington Post/Getty)

When it comes to medical use, marijuana could offer an incredible benefit to the approximately 25% of men and 9% of women who suffer from a disorder called sleep apnea.

Sleep apnea is characterized by disrupted breathing during sleep, and has been linked to a number of serious conditions, including diabetes and heart problems. Unfortunately, the vast majority of sleep apnea sufferers remain undiagnosed and untreated.

Even of those who seek treatment, many eventually give up on wearing a CPAP mask every night.

But that’s where marijuana may help, as researchers are currently trialing THC as an alternative, with early results already showing promise. If clinical trials are successful, sleep apnea patients may one day have the option of swapping a bulky sleep mask for popping a few pills before bed.

Cannabis and Spinal Cord Injuries

Spinal cord injuries (SCI) are uncommon but can have permanent and devastating effects on one’s daily life and well-being. Still, research has a long way to go in developing effective SCI medications without side effects or addictive potential. As early as the 1970s, studies began documenting cannabis’ ability to fight pain and spasticity in patients with spinal cord injury. Today medical marijuana offers patients an alternative regimen that treats these relentless and unpleasant symptoms that can take such a toll on life quality.

Spinal Cord Injury Causes and Symptoms

Severe pain, stiffness, blood clots, insomnia, uncontrollable bladder and bowel, sexual dysfunction, anxiety, and depression are just some of the symptoms that plague the day-to-day of SCI patients. Spinal cord injuries are divided into two categories: complete and incomplete. At the “complete” level, the patient experiences total function loss below the location of injury. “Incomplete” refers to a partial loss of function with varying degrees of severity between patients.

Spinal cord injuries are caused by trauma to the spine, when dislodged bone fragment, ligaments, or disc material damage the spinal tissue on impact. Unlike back injuries, spinal cord injuries affect motor functions because axons (or extensions of nerve cells that carry messages to the brain) are destroyed by the fractured or compressed vertebrae.

Living with a Spinal Cord Injury

Stuart Parsons, a military veteran of 10 years, suffers from a spinal condition called Diffuse Idiopathic Skeletal Hyperostosis (DISH). Though typically developed over time, Parsons’ DISH was caused by trauma when he was hit hard from behind in a military accident. Four of the spinal discs in his neck became fused together and pushed forward, creating pressure on the esophagus. As a result, Parsons experiences chronic pain, nausea, and eating and breathing difficulties.

The Department of Veteran Affairs (VA) urged Parsons to manage his pain using opiates, but as a recovering drug addict, Parsons adamantly refused. After some deliberation, he decided to instead try the legal medical cannabis Washington state had to offer.

“I cannot tell you how happy I am with it,” Parsons said. “I have learned so much about CBD and its painkilling properties.”

How Cannabis Can Help Treat Spinal Cord Injuries

Many more people are becoming aware of cannabis’ painkilling superpowers, but why it works so well is a story largely left untold. Research has helped piece together an understanding, but despite crystal clear results, development of cannabinoid-based medications for spinal cord injuries remains halted at the political gate.

Studies have confirmed cannabis’ ability to treat many signature symptoms of SCI including pain, spasticity, insomnia, and depression. Some improvement in bladder and bowel control has also been noted. Cannabinoids, the medicinal compounds found in cannabis, are what offer this amazing diversity of symptom relief to SCI patients.

Cannabidiol (CBD), the compound mentioned by Parsons, is slowly but surely becoming a name in the arena of pain relievers. Studies have not only demonstrated CBD’s remarkable painkilling properties, but also its ability to reduce spasticity and improved motor function in SCI patients.

Tetrahydrocannabinol (THC), though stereotyped as marijuana’s “psychoactive stoner” compound, carries its own medical value in treating spinal cord injuries. Various studies show that THC improves many SCI symptoms including pain, spasticity, bladder control, and insomnia.

It’s clear that cannabis, even in its raw form, is providing patients with safe relief of SCI symptoms. Other research monitoring the restoration of nerve function and growth of new cells by cannabis compounds is further brightening futures for people living with chronic pain and other conditions. How long patients will be waiting for factual information and improved cannabis policy, however, is unknown.

Cannabinoids in the Treatment of Epilepsy – A Literature Review

A Schwarz (a,b), AR Mohammad (b), S Pagliazzi (b)
a) Monash University, Melbourne, Australia; b) Under The Tree BioPharmaceuticals Pty Ltd, Australia
Abstract:

This summary aims to provide information about the potential use of cannabinoids in the treatment of epilepsy. Background information about the disease and the extent of epilepsy as a health problem is illustrated. The proposed mechanisms behind seizures are discussed, alongside a basic anatomy and physiology of the central nervous system. Finally, the current body of evidence on how cannabinoids could be a valuable addition and/or alternative to current treatments is examined. Cannabidiol has shown to have profound anticonvulsive effects in both animal and human trials, and has a favorable side effect profile. Large scale and multi-disciplinary research is required to validate the use of cannabidiol as an anticonvulsant and to further define its pharmacological action.

Keywords: epilepsy, seizure, epileptogenesis, anticonvulsant, cannabinoids, Cannabidiol

Introduction:

Definition of Epilepsy

Epilepsy as a term, describes the enduring predisposition of the brain to generate epileptic seizures. The international league against epilepsy (ILAE) added to this conceptual definition in 2014 (Fisher et al., 2014), stating that to be diagnosed with epilepsy, a patient must fit at least one of three categories;

  • A patient must have experienced two unprovoked seizures, at least 24 hours apart
  • A patient has experienced one unprovoked seizure, however there is a high chance of recurrence – this allows patients who have been put on treatment after a single seizure to fit the diagnostic criteria
  • A patient is diagnosed with an epilepsy syndrome

A seizure is the clinical manifestation of excessive and synchronous electrical activity within the brain. The presentation of seizures can vary greatly depending on the specificity of the areas of the brain that are affected, as well as the number of brain regions affected (Fisher et al., 2014).

Epileptogenesis is the process whereby the neuronal network in the brain changes over time to promote the development of seizures (Fisher et al., 2014).

Epidemiology & Impact

Current figures estimate that there are over 2.5 million people in Europe living with active epilepsy, defined by at least one seizure occurrence during […]