On the one hand, we’re led to believe that cannabis impairs a user’s cognitive function – especially short-term memory. The other hand, we hear cannabis can act as a neuroprotectant, maybe even preventing the onset of neurodegenerative diseases.

Cannabis is a diverse, complex plant comprised of hundreds of chemicals. Two of these chemicals – THC and CBD – affect us in significantly different ways.

Cannabis contains at least 85 cannabinoids, the chemical compounds that interact with the brain’s receptors. The most-famous and well known cannabinoids are THC and CBD.

THC, as we all know, is responsible for most of cannabis’ psychoactive effects. It affects the brain by activating cannabinoids receptors, namely CB1. THC promotes creativity, amplifies your thoughts, and keeps you focuses… Until stimuli distracts you to a tangential thought.

Surprisingly, CBD, THC’s non-psychoactive sibling, shows affinity to bind to either CB1 or CB2. Instead, CBD seems to indirectly stimulate cannabinoid signaling by suppressing the enzyme that breaks down anandamide. This partially explains why CBD appears to combat some effects of THC, and why higher CBD concentrations result in fewer intoxicating effects.

The Biphasic Effect: Why Proper THC Dosage is Important

The effect of cannabis vary by individual and are highly dependent on dosing and the form of preparation. It’s important to note that many cannabinoids – THC in particular – have a biphasic effect. This means that low and high doses can have opposite effect in users. This partly explains why many users feel relaxed with low doses and paranoid under high doses. Most medical practitioners advise patients to start off with a low dosage and gradually increase it as the patient determines how their body reacts. This process is known as “self-titration.”

Another way to to think of the biphasic effect is a therapeutic window. Cannabis has a narrow therapeutic range. The difference between the optimal dosage that gives the effect you want versus a dosage that creates adverse effects can be very subtle. Chronic pain is one such example where low to medium dosages relieve it, while high dosages amplifies it.

Further complicating the issue is that THC and CBD levels – as well as the ratios between them – can vary dramatically from strain to strain. It’s important for people to be conscious of these levels as they find the most appropriate dosage to treat their condition.

The same applies to lifestyle users who may find they have a preference for a particular strain. One strain may make them feel extremely sleepy or paranoid, while another might make them feel relaxed and euphoric. Everyone’s body chemistry is different, hence, cannabis will affect each one differently.

Optimal Dosing: Low to Moderate

• Elevated mood, feelings of euphoria, and relaxation.
• Sleepiness (higher CBD concentrations can counteract it).
• Increase in creativity
• Pain Relief
• Alleviating nausea
• Appetite stimulation

Suboptimal Dosing: High

• Hallucinations varying from mild to moderate
• Paranoia
• Anxiety
• Disorientation
• Heightened pain sensitivity

Refocusing on the topic of this article, why is there so much contradictory or paradoxical evidence on how marijuana affects the brain?

Dr. Mike Hart, head physician at Marijuana for Trauma, offers an explanation:

“Frustratingly, we have very few high-quality human studies that examine the potential long-term benefits or negative effects of cannabis consumption on the brain. But, just like cannabis has biphasic acute effects, the same may hold true in long-term usage,” says Dr. Hart. “Too much, too often, over a long period of time, could cause negative effects like diminished verbal memory recall; while the right amount and right frequency could elicit the benefits we’ve found in early studies on animal models, such as neuroprotection and the slowing or prevention of neurodegenerative disease.”

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Legal cannabinoids and THC alternative medicines have been approved for medicinal use. Other medicines that mimic the properties of marijuana are currently undergoing clinical trials before FDA approval. The FDA can allow companies to conduct clinical trials of drugs that are intended to treat disorders, even if they’re marijuana-based drugs.

Epidiolex

Not yet fully approved by the FDA, Epidiolex is currently in its clinical trails. GW Pharmaceuticals has been developing and testing multiple cannabinoid drugs. It contains a highly purified, plant-derived form of cannabidoil (CBD), which is the non-psychoactive compound present in marijuana plants.

The “high” from ingesting marijuana comes from THC, the main psychoactive ingredient in THC. Epidiolex utilized CBD instead of THC. CBD has been known to treat Dravet syndrome, a rare and sever form of epilepsy in children. Epidiolex has been found to be beneficial in the treatment of Dravet and Lennox-Gastaut Syndrome, another uncommon form of childhood epilepsy.

Syndros

Syndros is just the generic version of Marinol that was recently approved by the FDA. The active ingredient in Syndros is also Dronabinol and the drug is being used to treat the same ailments as Marinol.

Both drugs have been found useful in treating anorexia associated with weight loss in patients suffering from AIDS. Patients going through chemotherapy hve found the drug to relieve their weight loss, nausea, and vomiting associated with the chemotherapy.

Sativex

Sativex is another drug not approved by the FDA currently undergoing clinical trials. GW Pharmaceuticals is also in charge of developing and testing Sativex. It is being used to treat spasticity due to multiple sclerosis in 25 countries.

Cesamet

Cesamet is a FDA-approved medicine which is a schedule II drug that is only available through prescription. It has already undergone its clinical trials and has been found to help cancer patients dealing with loss of appetite, nausea, and vomiting. It is meant to be orally administered.

The active ingredient in Cesamet is called Nabilone, which is similar to the active ingredient in Cannabis, THC. The active synthetic cannabinoid nabilone has complex effects on the central nervous system. It interacts with the cannabinoid receptor system in the same way THC and other legal cannabinoids would.

Marinol

Marinol is a THC-based drug that received FDA approval in 1985. The synthetic form of THC has made a return in liquid form recently. Dronabinol is the active ingredient in Marinol. It is taken in capsule form and it is a light yellow resinous oil that is sticky at room temperatures and hardens upon refrigeration much like hash oil.

The Next Steps

Opponents of legalized marijuana believe there are enough FDA-approved alternatives to prevent the legalization of marijuana in its plant form. However, these opponents are disregarding the benefits of the entourage effect. The entourage effect provides additional medical benefits when the various components of marijuana combine. When cannabinoids and THC are separated, they may not be as helpful to certain patients. More research needs to be done on these legal alternatives if they are going to replace actual marijuana as medicine.

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What are cannabinoid receptors?

THE CB receptors can be found throughout the body, and there are two main kinds: CB1 and CB2 receptors. CB1 receptors are mostly found in the brain with some present in the lung, kidney, liver, fat, heart, muscle and bone. CB2 receptors are primarily found in the immune system, and blood cells but both can be found in the same tissues providing different functions. CB1 receptors are mostly responsible for the psychoactive and euphoric effects of THC. On the other hand, CB2 receptors mostly work in the immune system, but they are also present in the liver, gut, muscle and bone.

Generally speaking the CB1 and CB2 receptors cause healing properties when activated within the areas of the body they are located. Receptors are similar to lucks, and the cannabinoids are the keys. The activity of CB1 and twp receptors usually reverses the damage done to the body, returning it to homeostasis. This also applies to mental health damage because endocannabinoids can aid in balancing mood and creating euphoria.

The balance between CB1 and CB2 inhibition and activation by cannabinoids is important. Heavy CB1 inhibition may lead to an increased risk of depression, mood disturbance, and immunosuppression. However, if CB1 over-activates there is an increased risk of psychoactivity, systemic inflammation, cardiovascular risk, diabetes, and obesity.

What does the endocannabinoid system do?

The primary job of the endocannabinoids system is to promote homeostasis, which maintains a stable internal environment despite changes in the external environment. The fact that the endocannabinoid system is connected with most of our basic functions may reveal why cannabis has been found useful in treating many medical conditions.

According to one study, the endocannabinoid system is nothing less a naturally evolved harm reduction system. Endocannabinoid levels naturally increase after a head injury is sustained, illustrating the body’s awareness of the sudden lack in homeostasis and the use of endocannabinoids as a remedy.

The Effects of Cannabis on the Endocannabinoid System

Research has shown that taking small amounts of cannabinoids from cannabis can signal the body to make more endocannabinoids and build more receptors than there already are inside the body. This may be part of why users do not get high immediately, but after a few smokes enough receptors have been made to respond, then you can feel it.

Cannabinoids and Cancer

Cannabinoids have been found to be useful chemotherapeutic agents. In fact, cannabinoids have been found to kill cancer cells. This and the pain relief canabinoids provide are the main reasons chemo patients turn to smoking weed to get through their therapy.

In Conclusion

Endocannabinoids have been assigned to fix biochemical imbalances that come in damaged or diseased states. From birth, cannabinoids are presented to us within our mother’s milk. The endocannabinoid system remains an important aspect of the way our bodies can heal and function, ingesting cannabinoids are a supplement to our natural healing process. Further research on endocannabinoids and the endocannabinoid system can help elaborate more ways in which we can use cannabinoids to heal our bodies and minds.

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There are five major cannainoids with some variants in medical marijuana that are particularly effective for relieving symptoms of illness, and each one produces different physiological and psychological effects. This is one of the main reasons why certain strains of medical marijuana are bred to have different amounts of each cannabinoid and are recommended for different conditions.

Major cannabinoids in medical marijuana

What is THC and its effects?

THC stands for delta-9-teetrahydrocannabinol. It is probably the best known cannabinoid present in medical and recreational marijuana. Physically it acts as a muscle relaxant and anti-inflammatory and psychologically it acts as a stimulant. This makes medical marijuana strains high in THC a good choice for patients who need relief while also to remain alert and active.

THC in medical marijuana acts in the following ways:

• anti-epileptic
• anti-inflammatory
• anti-depressant
• stimulates appetite
• lowers blood pressure
• apoptosis (self induced cell death)

What is CBD and its effects?

CBD stands for cannabidiol and it actually reduces the psycholigal effects of medical marijuana. For most patients, a strain that has high THC and high cannabidiol will not have a great psychological impact but the physical ones are more. Medical marijuana strains high in cannabidiol, like Blueberry and Harlequin, are especially effective for illnesses with strong physical symptoms.

Cannabidiol’s effects include:

• reduced pain
• reduced anxiety
• reduced nausea
• sedative effects
• anti-convulsive
• anti-schizophrenic
• slows the spread of cancer

What CBN is and its effects?

CBN stands for cannabinol, not to be confused with Cannabidiol. Cannabinol is very similar to THC, but it has less psychological effects. It is produces as THC breaks down within the medical marijuana plant. High THC will make cannabinol’s effects stronger, and very high cannabinol concentrations can produce undesirable strong head highs.

Strains like Strawberry Haze and Blue Rhino, which can be particularly helpful for:

• lowering pressure in the eye (such as with glaucoma)
• analgesic
• anti-seizure

What is CBD and its effects?

Cannabichromene enhances the effects of THC. High cannabichromene levels will make a high-THC medical marijuana strain more potent.

Cannabichromene working together with THC is known to be a:

• sedative
• analgesic
• anti-inflammatory

What is CBG and its effects?

CBG is an abbreviation for cannabigerol. It has no psychological effects on its own, and is not usually found in high amounts in most medical marijuana. Scientists believe that cannabigerol is actually one of the oldest forms of cannabinoids, meaning it works in conjunction with the rest of the cannabinoids. It also have anti-microbial properties. CBG has physical effects such as:

• lowering pressure in the eye
• anti-inflammatory
• sedative
• sleep assistance

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Cannabinoids are also separated into subclasses. These are as follows:

• Cannabigerols (CBG).
• Canabichromenes (CBS).
• Cannabidoils (CBD).
• Tetrahydrocannabinols.
• Cannabinol CBN and Cannabinodiol (CBDL).
• Other cannabinoids such as cannabicyclol (CBL),cannabielson(CBE), cannabitriol (CBT) and other miscellaneous types.

What do cannabinoids do?

Like opiates, cannabinoids affect the user by interacting with specific receptors, located within different parts of the central nervous system. There are only two kinds of cannabinoid receptors that have have been found to do and are termed CB1 and CB2. A substance that occurs naturally in the brain and binds to CB1 receptors was discovered in 1992 and termed “anandamide.”

Additinally natural occuring substances that bind CB1 have since been discovered, and these, together with the receptors are termed the “endogenous cannabinoid system.”

The actual effects that the cannabinoids have reflect the areas of the brain thet interact with. These interactions tend to occur in our limbic syste (the part of the brain that affects memory, cognitions and psychomotor performance) and mesolimbic pathway (activity in this region is associated with feelings of reward) and there are also widely distributed in areas of pain perception.

Many researchers are still learning about the endogenous cannabinoid system. Much of the research however, has focused on the many potential medical uses of man-made cannabioids, refereed to as “synthetic analogues.”

The difference between cannabinoids

The major difference between the cannabinoids are determined by the extent to which they are psychologically active. Three classes of cannabinoids; the CBG, CBC and CBD are not known to have such an effects/ THC, CBN, CBDL and some cannabinoids on the other hand are known to be psychologically active to varying degrees.

CBS is considered tp be the most abundant cannabinoid, contributing up to 40% of cannabis resin. Interestingly, CBD may actually have anti-anxiety effects and lessen the psychoactive effects of THC. This means that a plant with a greater percentage of CBD may reduce the intensity of the effects of the THC, which in effect lowers the potency of the plant. This means that a plant containing less CBD might have an increased psychological impact and result in unwanted effects such as anxiety.

When THC is exposed to air, it oxidizes and forms CBN. CBN is a very weak psychoactive and not unlike CBD interacts with THC to reduce its effects.

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Cannabinol (CBN) comes from cannabigerolic acid (CBGA) in cannabis. The plant naturally produces enzymes that converts the CBGA into three major cannabinoids:

• cannabichromene carboxylic acid (CBCA)
• cannaidiol carboxylic acid
• tetrahydrocannabinol carboxylic acid

When the develops THCA, it is generally converted into THC as a result of heat or UV light. With that in mind, THCA can be converted to CBNA over time as well. When THCA is exposed to air over a long period of time, it loses hydrogen molecules and oxidizes, turning it into CBNA. As with the rest of the acidic cannabinoids, CBNA will convert into cannabinol(CBN) when it is exposed to heat or UV light.

Therapeutic uses of Cannabinol:

• Analgesic: Relieves pain.
• Antibacterial: Slows bacterial growth.
• Anti-Emetic: Reduces vomiting and nausea.
• Anti-Epileptic: Reduces seizures and convulsions.
• Anti-inflammatory: Reduces inflammation systemically.
• Anti-Insomnia: Aids with sleep.
• Anti-Proliferative: Inhibits cancer cell growth.
• Appetite Stimulant: cannabinol appears to be a mild appetite stimulant.
• Bone Stimulant: Promotes bone growth by stimulating osteocytes.

Current ongoing studies:

Analgesic: Both THC and CBN have been identified as pain relievers, but THC is far more powerful. A 2002 study identifies that both THC and CNB can cause a release of certain gene-related peptides from sensory nerves and are the only identified cannabinoids to use this mechanism.

Appetite Stimulant: THC stimulates the appetite, giving users the “munchies” that many people would describe. In was only in 2012, that is was discovered that CBN actually also stimulates the appetite, though this effect appears to be weaker than THC.

Cancer Growth Inhibitor: A 2006 study revealed that CBN joins THC and numerous other cannabinoids in having the ability to control the growth of cancer cells. CBN was specifically found to control a type of lung tumor known as a Lewis carcinoma.

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Given that Epidiolex’s clinical trial success may mark the biggest advance for medical marijuana, we will have a better look about the study from GW Pharmaceuticals and its results.

A little background:

Americans attitude towards marijuana have been steadily improving over the course of the past twenty years. According to Gallup, 58% of Americans support marijuana legalization, up from 25% in 1995, and as a result, 23 states, including the District of Columbia (D.C.) have passed medical marijuana laws.

In those states, patients with a doctor’s approval, can be prescribed marijuana to treat various ailments, such as chronic pain and glaucoma.

Marijuana has long been touted by marijuana supporters as an effective medicine for these indications, however, placebo controlled, FDA-worthy studies that support marijuana’s benefits are hard to come by.

An important breakthrough:

GW Pharmaceuticals has been researching the use of medicine that is derived from the chemicals that are found in marijuana since the 1990s. Despite the company’s efforts spanning decades, the company has won regulatory approval for only one marijuana drug so far: Sativex.

Although Sativex is used to treat muscle spams in patients suffering from multiple sclerosis, it has arguably failed to become a commercial success. The company continues to spend millions researching the various chemical cannabinoids found in marijuana. As part of that research, GW discovered that CBD, a non-psychoactive chemical cannabinoid, may be effective in epileptics.

That discovery led to the creation of Epidiolex, a purified formulation of CBD extract, and the launch of studies in Dravet syndrome and Lennox-Gastaut syndrome patients. Dravet syndrome and Lennox-Gastaut syndrome are two forms of childhood epilepsy that is tough-to-treat and don’t respond well to current therapies, including anti-convulsants.

This week GW Parmaceuticals reported data from the first two Dravet syndrome studies, and the findings are very remarkable. Epidiolex reduced the number of monthly seizures in 120 randomized Dravet syndrome patients by 39%. For comparison, patients receiving a placebo only saw an 11% improvement in the number of seizures.

Moving forward

In the second half of 2016, the results of the second Dravet syndrome trial should be available. If that trial also succeeds, then an FDA filing for approval could come shortly thereafter.

Epidiolex has previously been granted FDA fast-track status, as such, a decision from the FDA would be expected to come six months after Epidiolex’s application for approval is accepted by the agency.

Without a doubt, an Epidiolex approval would be a big victory for patients struggling with this form of epilepsy. It would also be an achievement for the company and its investors, especially if results in Lennox-Gastaut syndrome patients are as successful. GW expects to report results from its Lennox-Gastaut studies later this year.

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Scientific research on THC began decades ago in Israel, and has since spread to many countries across the globe. Due to its status as an illegal drug, information about this cannabis compound is hard to come by.

Its discovery in 1964

THC was first isolated and synthesized from the cannabis plant by a scientist called Dr. Raphael Mechoulam in Israel.

As a postdoctoral student in the early 60s, Dr. Mechoulam noticed that the active compounds in morphine and cocaine had been isolated, but no one had isolated the active ingredient in marijuana.

He was in such a rush to conduct his research that he actually broke the law by obtaining marijuana from his friends in the police department. Even with all the hardships, the scientist managed to isolate THC is 1964, marking the start of a long career dedicated to cannabis research.

The discovery of THC paved the way for later discovered and earned Dr. Mechoulam numerous honors, including a NIDA Discovery Award in 2011.

THC is part of more than 60 active ingredients in cannabis

Despite THC being the most recognized ingredients in marijuana, it is just one of many compounds in the plant with known medical uses.

It belongs to a unique class of compounds called cannabinoids. Since Dr. Mecholam’s discovery, more than 60 other cannabinoids in cannabis have been identified.

THC is used in FDA-approved pharmaceuticals

While THC is still illegal in the U.S. and most countries around the world, synthetic versions of the chemical have been legally prescribed for decades.

The first THC-based pharmaceutical, called a Marinol, was developed by a company called Unimed Pharmaceuticals with funding from the National Cancer Institute. In 1985, Marinol received FDA approval as a treatment for chemotherapy-related nausea and vomiting.

Since then, other pharmaceuticals containing THC have been developed. These include Cesament, a synthetic form of THC, and Sativex, a whole cannabis extract administered as an oral spray.

THC can protect brain cells and stimulate their growth

Contrary to the age old story that THC destroys your brain cells, it has been proven to have a number of positive effects on them. Whereas most recreational drugs are neurotoxic, THC is considered to be a “neuroprotectant,” meaning it can protect brain cells from damage caused by things like inflammation and oxidative stress.

Scientists have even shown that THC can promote the growth of new brain cells through a process known as neurogenesis. This effect was first discovered in 2005 by researchers at the University of Saskatchewan.

Dr. Xia Zhang, the study’s lead author, noted in an interview with Science Daily: “Most drugs of abuse suppress neurogenesis. Only marijuana promotes neurogenesis”.

Chemicals like THC are found in the body

Following the discovery of THC, scientists went on a decades long search for similar chemicals in humans that might explain its effects. In 1992, Dr. Mechoulam and his team made another breakthrough when they discovered a molecule called anandamide.

Anandamide is one of the few cannabinoids produced in various parts of the body, including the brain. Similar to the way opioids work by mimicking their natural counterparts, chemicals in marijuana mimic naturally occurring cannabinoids called endocannabinoids.

Both anandamide and THC act on pathways in the body called cannabinoid receptors. In the brain, anandamide works to regulate mood, sleep, memory and appetite.

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