Transcription of Anandamide – S1E5 – Dr. Pritesh Kumar

Endocannabinoid System

Transcription of Anandamide – Episode 5

On the last episode of Anslinger: The untold cannabis conspiracy we investigated the Committee on Drug Addiction and their role in creating patented pharmaceuticals. We determined that alkaloid chemistry played an important role in shaping the future of pain-relieving pharmaceuticals, which provided evidence for the obsession in advancing morphine research, while disregarding cannabis research altogether.

We also found that another reason for not advancing cannabis research was simply because the technology available for isolating and elucidating complex structures like cannabis did not exist, making synthesizing and therefore patenting cannabis pharmaceuticals impossible.

In this episode we will continue to investigate the Committee on Drug Addiction, but the questions with our interviewee, Dr. Pritesh Kumar, will actually be geared towards information the Committee on Drug Addiction had not uncovered during their research days. Dr. Kumar will uncover how opioids and cannabinoids physiologically interact within the human brain’s opioid system and the human brain’s endocannabinoid system.

During Anslinger’s reign, from 1930 to 1962, Anslinger worked on the Committee on Drug Addiction with a goal of ultimately rendering morphine unnecessary, by creating a number of substitutes to replace the medicinal uses of morphine. From their archives, we can see that they thought that once they found substitutes for morphine, they could move on to synthesizing other habit-forming drugs, outlawing their natural forms along the way.

The group of men knew this would not be an easy task and they continuously would be scrutinized for their work, so to reduce social problems, they unanimously decided to keep a majority of their work out of the public’s eye. And so determined they would only make public statements if it were in the best interest of the pubic.

Regardless of the difficulty of the task, the group of men knew that IF they could find non-addictive substitutes to morphine, they would solve an enormous international problem. These synthetic substitutes would make morphine obsolete in international commerce, allowing them to outlaw morphine entirely, solving the global addiction issue.

But in reality, this vision was a pipe dream because they seemed to have forgotten the demand of the addict and the ability of a drug dealer to capitalize on situations. Outlawing morphine or mostly anything for that matter, creates a feeling of scarcity in the market leading to increased prices. This in turn creates opportunities for the black market and when drug dealers are dealing an addictive drug like morphine or other opioids, outlawing a drug will do very little to prevent sales or use AND can have severe unintended consequences.

Because the addict must have it. And in most cases, they are physically willing to risk their life to use it.

In economics, illicit opioid demand is likely considered to be price inelastic, meaning drug addicts are willing to buy the drug even with fluctuations in price. As a comparison, similar to opioids, gasoline demand is also price inelastic, because most people who drive a personal car are willing to buy the gasoline even with large fluctuations in price.

But there is always a breaking point… and at some point, gas prices get too high. So people start to substitute their purchasing decisions from gasoline-powered cars to electric vehicles. At this point, the open, legal, market intervenes and prices often reduce to counteract long-term demand of gas-powered vehicles—but that’s a different story. 😉

However, this inelastic demand phenomenon also occurs with drugs – at some point, regulation makes the price of drugs too high, so the addict will substitute the drug for a similar, but cheaper drug. This substitution occurred more recently with our current opioid epidemic. For example, in Kentucky in 2013, legislators passed House Bill 217, more commonly known as the “Pill Mill Bill.” This bill’s intentions were to combat prescription drug abuse by closing pain management clinics and implementing new standards for prescribing opioids. The bill was successful with its intention, but created horrible unintended consequences, because once again, there was no thought to the individual addicts who were prescribed the drug for pain. So when the clinics shut down, the now opioid addicted individuals not only lost their prescription for pain management, but were suffering from opioid withdrawal.

These addicts then hit the streets to find blackmarket opioids, which had become higher in value for the drug dealer. The more that this bill and similar bills swept the nation, the harder it became to find prescription drugs. Soon the price of opioids hit the peak of price inelasticity and the individual who had initially gone to the doctor for back pain, or whatever it may have been, was now an opioid addict with nowhere to feed his or her demand for pain reduction, and now withdrawal, but to seek out the illicit black market for heroin, a significantly cheaper but lower quality opioid than legal prescription drugs.

Oddly enough, the quality of heroin was once pharmaceutical grade – before it was subject to federal control, providing incentive for drug dealers to manufacture it themselves at a reduced quality, with the potential to be cut with various unknown substances.

Now during the 1930s, I don’t think the Committee on Drug Addiction had any idea that their research, policies and enforcement strategies would have the unintended consequences of a massive opioid epidemic today. But you have to wonder if their intentions were truly in the best interest of the public.

In fact, when the Committee on Drug Addiction first formed under the National Research Council, Dr. Lyndon Small, a Fellow at Harvard University, and Assistant Professor of Research Chemistry at University of Virginia and Director of Research Chemistry for the Committee on Drug Addiction, expressed pessimism towards finding non-addictive, pain-relieving substitutions for morphine through chemical manipulation. I can’t tell you his exact reasoning for his pessimism, perhaps it was because he had just returned from two-years of over-seas work in Germany researching the subject, or perhaps it was because, at the time, we didn’t really know anything about how opioids and addiction worked within our brain’s opioid system.

Because of more recent medical discoveries in the 1970s, we now know the addictive desire to crave more opioids is because of the way the human brain receives opioids. And because this conversation is so complex, today’s interview is technically a continuation of episode 4, so we will once again hear from pharmacologist and toxicologist, Dr. Pritesh Kumar.

Annie: Can you explain our bodies opioids system and its opioid receptors.

Dr. Kumar: Yeah absolutely. Opioid receptors are a group of what are known as a G-protein coupled receptors that consist of opiates and ligands which could be endogenous opiates such as enkephalins, endorphins, endomorphin and even dynorphins.

So in our body, generally speaking, there are three major classes of opiate receptors. You have your Mu receptors (Mu) which have a number of subtypes. I believe that the receptors have three subtypes M1, M2 and M3. And these receptors are actually the most when people think of morphine for example, this is the receptor that it works through, which is the Mu receptor. These are present in the brainstem, thalamus, and other areas.

These receptors are very important in that when they are activated, or let’s say when morphine binds to these receptors, this mechanism results in the pain relief, the sedation, the psychoactivity. But also, on the down side, activation of these receptors can lead to serious respiratory depression, constipation and even physical dependence and addiction. So that’s the Mu receptor.

There’s also two other receptors – the Kappa and Delta receptor. The Kappa receptor is primarily present in the limbic system, which is part of which is part of the forebrain, the brainstem and the spinal cord. And activation of this receptor also can cause pain relief, to a lesser extent and sedation and some of the side effects of this receptor activation are loss of breath and dependence and the potential addiction.

The last receptor, the Delta receptor, is widely distributed in the brain but also in the digestive and GI tract and in the spinal cord. So activation of this receptor can also lead to pain relief, but also can lead to antidepressant effects and may also cause respiratory depression.

So all three receptors share the common pain relieving properties but have slightly differing negative side effects during activation. And these three receptors are important because pharmaceutical companies they target these receptors when they’re developing new drugs for pain relief. So targeting one receptor versus the other or targeting both at the same time may have a different effect on pain relief and their side effect profiles may be different as well by selective or biased targeting.

Annie: How do the endogenous opioids work within the system?

Dr. Kumar: Endogenous really is a term that means in our body. So there are naturally occurring opiates in our body, for example, opiate receptors in our brains are activated by a family of peptides or opiates that our bodies naturally produce like enkephalin, dynorphins, and endorphins which are essentially released by the neurons. So in short endogenous opiates are those that are already present in our body that are released by the neurons and can activate the opiate receptors.

Annie: Do you know when opioid system was discovered in the body?

Dr. Kumar: I believe it was in, well so I don’t know when the system was discovered but the binding sites for opiates was really established in right around 1972 1973. And later on, so these binding sites were discovered in the 70s but it wasn’t until significantly later that they started resorting to refer to them as Mu, Delta and Kappa opioid receptors.

Annie: But we I mean clearly we knew that there was something going on with that. Considering that we’ve been using opium for centuries as with cannabis

Dr. Kumar: Absolutely it’s been used to be an ancient ancient history but it wasn’t until the 70s where you know that system was actually discovered so I’d say another no common I guess commonality between the opiate system and the cannabinoid system is that you know while the material has been used or the compounds have been used for centuries it wasn’t until the last 30 to 40 years that we actually discovered how their work

Annie: Another major breakthrough in medicine

Dr. Kumar: Right.

Annie: What about the morphine molecule. Can you explain the morphine molecule and how it functions with these opioid receptors.

Dr. Kumar: Absolutely. So as morphine binds with morphine binds to the new receptor as morphine binds to the receptor a molecular signaling actually activates these receptors to mediate certain actions, such as pain relief for example.

Annie: So it would it morphine would be an I guess a phyto-opioid or is it considered a phyto-opioid, I guess if it’s coming directly from the plant?

Dr. Kumar: You know I’ve never heard you but I really like it. But I really like it. But based on your definition, yes, you’d be correct.

Annie: So is it kind of similar with how cannabinoids work within the system when it’s like a lock and key where that morphine molecule is a similar structure as your endogenous opioids might be. So it can fit well into that opioid receptor and turn it on or off.

Now back to the story of Anslinger: The untold cannabis conspiracy.

Throughout Anslinger’s reign as Commissioner of Narcotics, the medical world knew that natural and synthetic opioids and molecules within the natural cannabis plant acted on the brain; however, they weren’t exactly sure how.

But as Dr. Kumar stated, in 1973, two years before Anslinger passed away at age 83, the binding sites of opioids were discovered in the brain. This was seen as an enormous breakthrough in the medical world, because pharmacologist could now dial in their patented prescription medicines and manufacture opioids to trigger the desired responses. This lead to an influx of research funding, unleashing the power of the pain-relieving properties of opioids.

Simultaneously, in the 1970s, as the medical world was becoming more aware of the way opioids interact with our bodies’ system, the medical and scientific world were also finally unraveling the cannabis compounds’ complexities with the isolation, elucidation and synthesis of THC and CBD.

The isolation, elucidation and synthesis of cannabis’ major active compounds CBD and THC would create a large push to study the addictive, medical, and therapeutic properties of cannabis in a scientific manner in accordance with western medicine.

This breakthrough was essential to determining if Anslinger’s argument against cannabis aligned with the actual scientific evidence. Unfortunately, by the time legitimate cannabis research was finally functional, Anslinger had retired from the Federal Bureau of Narcotics and the Bureau itself was being reorganized from the Department of Treasury to the Department of Justice to form what we know today as the Drug Enforcement Agency and the Controlled Substances Act.

Prior to and during this reorganization, the Committee on Drug Addiction’s researchers, like Dr. Lawrence Kolb, provided serious recommendation to further investigate the medical and therapeutic properties of cannabis and addressed that funding should be allocated to specifically study the plant’s properties. They also argued that cannabis should not regulated by imprisonment because this kind of regulation would destroy opportunities for young Americans who may be imprisoned for partaking in an activity that is as common as alcohol among the age group.

We will discuss this at more depth in later episodes. But for now, what is important to note is that the Department of Justice went completely against these recommendations. And instead placed what the DEA referred to as “marijuana” and “tetrahydrocannabinol” or THC in the most highly regulated drug category, as dangerous as heroin, with no medical benefit and high potential for abuse.

This resulted in a narcotic scheduling that has since been responsible for the imprisonment of millions of America’s youth, and up until more recently, a nearly complete halt on researching cannabis for medicinal or therapeutic properties. That is, up until the 1990s when researchers finally discovered the brain’s endocannabinoid system.

Like the opioid system, pinpointing this system, was monumental for the cannabis industry, and beyond the medical and therapeutic aspect of actually helping people, I believe it is one reason as to why there is such an enormous push for cannabis policy reform – because pharmaceutical powerhouses can now target specific cannabinoid receptors and can effectively formulate patented, synthesized cannabis pharmaceuticals and formulate natural cannabis derivatives with patented ingestion mechanisms.

So how do these potential pharmaceuticals and natural forms of cannabinoids react in our bodies? Let’s find out from Dr. Pritesh Kumar.

Annie: Can you explain our bodies endocannabinoid system and it’s cannabinoid receptors?

Dr. Kumar: Sure. So our body’s endocannabinoid system comprises of the endogenous cannabinoids, the enzymes, and the receptors, CB1 and CB2. So the endogenous compounds. There are two primary compounds that are found within our body. One is Anandamide and the other is called 2-AG (2-Arachidonoylglycerol). The first one was actually discovered and isolated in the 90s by a friend of mine and he named it Anandmide. Ananda‘s actually Sunskrit for “bliss,” but he named it the the blissful molecule. So that’s Anandmide. It has been investigated for a number of pharmacological things in the body for example mediating sleep, hunger, and inflammation.

The other compound 2-Arachidonoylglycerol has also been investigated for a number of things and mediates a lot of the homeostatic actions in our body. 2-AG’s heavily present in the brain in terms of concentration, while Anandmide is present in different areas of the body. So these compounds they work in a very different manner. If you think of how traditional neurotransmitters work these are the exact opposite. So the reason why I say that is you know most things in your body – most neurotransmitters – the way they work is that an event will happen and neurotransmitters are released.

Or most neurotransmitters, such as Dopamin, are you know usually fluctuating in the body at any given time, at a level of concentration.

Endocannabinoids on the other hand they are produced on an on demand fashion. So there will be an event that occurs, an insult for example, and these compounds are produced on the postsynaptic neuron and they travel in a reverse manner to the presynaptic neuron where they bind to the CB1 or CB2 receptor. So it works in reverse to traditional neurotransmitters.

Annie: What impact does that have within the body?

Dr. Kumar: So it has a tremendous impact because way that these endocannabinoids work is you know research has shown that is more of a the purpose of these and looking at them is twofold one to maintain homeostasis in the body. They’ve been shown to regulate a wide number of physiological processes. And two, it becomes very important once we understand the mechanism to develop a drug or therapeutic that that targets the system.

Annie: So is 2-AG and Anandamide those are both considered endogenous cannabinoids?

Dr. Kumar: That’s correct.

Annie: So what about the phytocannabinoids that are kind of like the phyto-opiate that I made up the term for?

Dr. Kumar: Sure. Those are exogamous plant derived.

Annie: Exogenous. That was the word I was looking for.

Dr. Kumar: Like CBD, Cannabidiol, THC, tetrahydrocannabinol. These are compounds that are not naturally present in our body that are found in the plant. And it’s the most fascinating in the 90s when it was shown that there is an endogenous cannabinoid system which is already present for these compounds in the plant to bind to, which shows there has been a long evolutionary relationship between you know cannabis for example and the endocannabinoid system and within our body.

Annie: That just kind of give me chills.

So why was this discovery of the endogenous cannabinoid system so essential for understanding exogenous cannabinoids in the cannabis plant?

Dr. Kumar: OK so you know this is there’s a detailed answer and then there’s a none-detailed answer. I’ll try to go in between.

So when you look at traditional drug development and drug targeting, it’s important to understand what’s occurring in the body with the receptor system you’re targeting. Most drugs work through a receptor. In the 90s when these receptors were discovered it became very exciting for pharmaceutical companies.

So I believe in 1990 CB1 was discovered in 1992 CB2 was discovered, along with some other compounds. So this is very exciting because now there was a system in the body that could be targeted and exploited from a pharmacological perspective.

And so I’ll give you just one example. So Anandamide – Anandamide is regulated by an enzyme called FAAH, F-A-A-H. It’s fatty acid amide hydrolase. So this enzyme regulates the concentration of Anandamide or the endogenous ligands in our bodies. So the discovery of these enzymes was very important because now you can develop a drug or a compound that can block enhance or reduce the activity of that enzyme, which will naturally modulate the concentration of Anandamide in our bodies. That’s just one example of why that discovery was important and how it can be approached from a drug development perspective.

Annie: So with the with the name of ānanda meaning “bliss” is that because the receptor has a lot to do with happiness and like a blissful state in our mind or was that just a coincidence?

Dr. Kumar: No you’re right. Yes and no. So that receptor is tied partially to the psychoactive effects of THC. So there is that blissful name to it right.

Annie: So I think you said earlier that these that these endogenous cannabinoids turn on their receptors, are the opioid receptors, are those always on?

Dr. Kumar: So they they share similar properties in that they both have endogenous ligands and the system has been elucidated; however, the opiate system, you know, has been investigated for a number of years. So we know a lot more about the opiate system than we do about the endocannabinoid system. We’re just starting to scratch the surface on endocannabinoid receptors, their mechanism, what’s going on physiologically when they’re activated, and what are the side effects.

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We can tell by Dr. Kumar’s explanation why this newly discovered endocannabinoid system was so difficult to pinpoint – basically it is counter-intuitive to the other neurotransmitters that we know play a major role in our body. And if this endocannabinoid system is responsible for maintaining homeostasis, or balance, in our body’s physiological processes, understanding this endocannabinoid system is essential for our health.

Today we are nowhere close to understanding this system like we now understand the opioid system, but the discovery of this endocannabinoid system has led to economic development for both hemp and marijuana production across the U.S. and the international world, with manufacturers creating finished cannabinoid products for nutritional, supplemental, therapeutic, and in the case of marijuana, medicinal use.

In the pharmaceutical world, it has also lead to the development of manufactured drugs, mostly using synthetic cannabinoids and some naturally occurring cannabinoids. These synthetic cannabinoids are chemically identical to the phytocannabinoid compounds mostly found in the floral material of the cannabis plant.

One example is the synthetic cannabinoid Dronabinol, more commonly known for its trade name, Marinol. Marinol was already undergoing medical trials when the endocannabinoid system was discovered. But this discovery helped drug manufacturers understand the physiological effects of Marinol, which is now an approved synthetic pharmaceutical form of THC, that helps with appetite stimulation, mostly for AIDS and cancer patients.

In addition, the discovery of the endocannabinoid system not only helped with the efficacy of Marinol, but has also paved grounds for future cannabinoid pharmaceuticals. In fact, because of the Committee on Drug Addiction’s decision in 1930 to have the US Government hold and assign pharmaceutical patents, in 2003 the U.S. Department of Health and Human Services, which houses the Food and Drug Administration, or the FDA, became an assignee to patent number 6630507 that states that cannabinoids like THC and CBD are “antioxidants and neuroprotectants.”

The patent continues to explain that cannabinoids are “useful in the treatment and prophylaxis (which means prevention) of a wide variety of oxidation associated diseases such as ischemic, age-related, inflammatory and autoimmune diseases. The cannabinoids are found to have particular application as neuroprotectants, for example in limiting neurological damage following ischemic insults, such as stroke and trauma, or in the treatment of neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease and HIV dementia. Nonpsychoactive cannabinoids, such as cannabidiol (or CBD), are particularly advantageous…”

The patent continues on, but I think you get the point – there are some major benefits of cannabinoids that we are just beginning to truly understand.
And to top it off, the World Health Organization, which operates under the United Nations, recently released a pre-review of published peer-reviewed research and concluded that Cannabidiol, or CBD, is non addictive AND possesses medical and therapeutic benefit. The World Health Organization states CBD’s medical benefit is solely for epilepsy, which we will discuss in a later episode.

It also states that CBD’s potential therapeutic benefits include a range of 18 different diseases and issues from inflammatory diseases, to Parkinson’s, to depression, to anxiety and even opioid addiction. You can find a list of all 18 on under “CBD benefits.”

But wow! When we really start to look at the research, cannabis truly could be a massively disruptive industry on many levels – pharmaceuticals, addiction, preventative care, and in turn insurance, plus the justice system and the associated arrests and prison sentences, not to mention eating hemp as a health food alternative and natural fiber source.

What else can we learn from Dr. Kumar about our body’s endocannabinoid system and our cannabinoid receptors?

Annie: So how do the opioid and endocannabinoid receptors relate?

Pritesh: They relate it to a number of ways. They relate in the areas that they are distributed within the body. For example, there is cannabinoid receptor expression in the same area where there is an opiate receptor expression, specifically the Mu receptor in the central nervous system. You know they both mediate overlapping, for example pharmacological responses, in very clinically important areas like drug abuse and pain management.

So there has been a recognized functional interaction between the compounds of these receptors. So there’s some type of cross interaction between the opiate and the endocannabinoid system. Also not only in the functional interaction side, but when it comes to mediating behavioral responses related to addiction, and you know possibly opening up new strategies for the treatment of opiate dependence.

So I guess to sum up. They relate in the sense of – they overlap in their pharmacological effects, for example, targeting the endocannabinoid system may also result in pain relief and targeting the opiate system may also result in pain relief. This is indicative that these receptors are distributed in a similar geographic area within the body.

Annie: So I think last time we were talking you had said that wherever there is an opioid receptor along your spine there’s a cannabinoid receptor.

Pritesh: It’s very close. In certain areas in the central nervous system, you’ll see a very similar geographic distribution for opiate receptors to cannabinoid receptors. It’s very very close.

Annie: And is that like that just in the central nervous system or throughout the entire body?

Pritesh: So it’s primarily in the central nervous system. There are for example in the G.I. tract there are certain cannabinoid receptors, but we also know there are opiate receptors in the GI tract and they mediate those functions that way, through that mechanism. Additionally so animal models have shown us that for example opiate induced reinforcement is mediated by not only both the opiates and cannabinoid system, but this is really because the Mu opioid receptor and, for example the cannabinoid system receptor one signaling system mediate overlapping responses in this and this pathway.

So there is quite a bit of overlap between the opiate system and endocannabinoid system. And I think only further research is going to be able to show what that really is. And this will actually improve drug targeting and therapeutics, once we fully are able to map where these sites are and where all opiate receptors are, where all the cannabinoid receptors are.

Annie: Are there just those two cannabinoid receptors that we know of at this point? Is there a potential that there might be even more in our body?

Pritesh: There’s been a debate going on in the scientific world on how many cannabinoid receptors there are. Still to date it’s widely said that are two receptors, CB1 and CB2. There have been a number of other receptors you know in the literature that have been referred to as a cannabinoid receptor. For example there is GPR119 which is a receptor involved in mediating mediating obesity. It is a high a huge target for pharmaceutical companies. However these have not been accepted by, by definition to be a cannabinoid receptor, so for now it’s widely accepted that there are two few you want to CB2 while there are a number of others being investigated as cannabinoid receptors.

Annie: And how does THC and CBD play a role in the two cannabinoid receptors?

Pritesh: So the way they play a role. So for example all answer that in a different way. So THC is the primary obviously the psychoactive ingredient in the cannabis plant. Tetrahydrocannabinol binds and activates to the CB1 receptor in the Central Nervous System, which leads to not only a lot of its pain relieving and other properties and also to its psychoactive properties. CBD on the other hand CVD has emerged not only in the recent media and in regards to epilepsy and other conditions. However the interesting thing about CBD is that it has very little binding affinity for either CB1 or CB2. So most researchers think that CBD actually works through a non-cannabinoid mechanism potentially through a Seratonin or an Adenosine receptor.

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At this point, much of the current belief is that CBD acts on body through CB2 receptors, but the theory that CBD interacts with Serotonin receptors or the Adenosine receptors is a growing opinion amongst the scientific community.

I must admit, I didn’t know much about Serotonin when Dr. Kumar told me this, so I had to do a little investigation. The basics of what I found is that Serotonin and its receptors are extremely important in regulating movements throughout the gastro-intestinal tract. In fact about 90% of the body’s serotonin is produced in the cell walls of the GI tract with about the remaining 10% found in the Central Nervous System. Serotonin is naturally synthesized in the body from an essential amino acid called tryptophan. Tryptophan is considered an essential amino acid, because our body needs it every day but can’t make it on its own. So we must ingest it through foods like dairy, fish, meats, and in one of the more efficient ways, seeds and nuts, like hemp.

Both the Serotonin and Adenosine receptors and their agonists act on physiological processes very similar to the endocannabinoid system, like mood, memory, appetite, anxiety, sleep and thermoregulation. And btw agonists is the technical term for chemicals like endogenous or exogenous cannabinoids and opioids that bind to receptors creating a biological response.

After learning more about Serotonin and Adenosine receptors, I could definitely visualize why scientists would think that something like CBD, potentially would be binding to other receptors within the peripheral and Central Nervous System. Particularly since CBD has been more commonly accepted to create positive physiological processes associated with these receptors, but seems to have a low affinity towards the endocannabinoid receptors that we currently know of.

Back in the 1930s Anslinger, along with the rest of the Committee on Drug Addiction, would have loved to know what we know now. But like cannabis and opioids, their scientific knowledge on understanding physiological responses was just beginning.

When the Committee was making their choices towards researching and synthesizing opioids, they knew that even if they couldn’t find the holy grail, they would at least improve the understanding of alkaloid chemistry, which we know from the previous episode, has been essential to understanding life and creating modern pharmaceuticals. And given the power that opioids like morphine have over the human brain, the Committee could tell there was meaningful work in their research.

During the early years of the Committee, a common conversation among these men was the need to find multiple drugs to replace the six actions that one drug had on man. The Committee referred to these actions as the six actions of morphine. Most of these actions have been elucidated through the discovery of receptors like Serotinin, but one action that is still a bit of a mystery is analgesic action, or the action of pain.

Annie: So with the from my reading I’ve found that there are six actions of morphine that include respiration and the effects on bronchial cough, intestinal and gastric action, synergistic action, analgesic action, convulsive and toxic action, and actions of morphine on the muscular system. Do the cannabinoid receptors and cannabis act on any of these actions?

Pritesh: Okay so in general there are short-term effects of cannabis that are well known in the literature, whether it’s psychoactivity, sedation or relief of pain. There are physiological effects and then there’s also functional and behavioral effects. Then theirs subjective effects. There are also your typical sematic effects and short term physical effects of cannabis use can be anywhere from an increased heart rate, dry mouth, reddening of the eyes, which is basically due to the constriction of the capillaries which leads to congestion of those blood vessels.

There could be a short-term reduction in the entire ocular pressure in your eye, muscle relaxation and maybe, generally a decrease in body temperature. Short term cannabis use however the difference is you know these peak levels really occur between 30 minutes to one hour after consumption and they last for a few hours. But that also is highly dependent on the route of administration, whether that is smoking or eating or vaporization or… it’s very dependent on the route of administration. There are documented neurological effects as well.

You know the challenge has been this substance has been illegal in the U.S. for quite some time and it still is on a federal level, so that impedes and doesn’t allow proper research to occur. So we don’t know a lot of the long term effects unfortunately because of these long term clinical trials have not being done.

So I would say in some a lot of the effects of cannabis versus opiates they are vastly different. The similarities as we know now are most likely related to the pain relieving properties. The addiction profile of cannabis has not been shown to be anywhere as drastic as what it is for for opiates. Those type of studies have simply not been done on on the cannabis side.

Annie: So the it’s more related to similarities with the analgesic action is supposed to, at least that we know of to this point, than any of the other actions.

Pritesh: That’s correct. If somebody asked me the the main similarity between opiates and cannabis it would be the pain on the properties and that’s it. As far as we know now.

Annie: What about in terms of like, is there a tolerance that builds similarly between the two with with pain actions and do you need like substantially more cannabis to feel the same analgesic action that you would with opioids.

Pritesh: So you know to compare the two there has not been a study comparing opiate threshold in terms of tolerance to let’s say THC threshold. The difference is really in the mode of consumption right. You know there are a few there are patients that consume the raw plant or they consume isolated compounds from that plant. So the potency levels are very different in both in both routes.

Generally speaking the higher the potency and this is a rule of thumb for any drug in general the higher the potency the quicker an individual will develop tolerance to that substance; however, you know there have been very minimal studies on on tolerance on them especially for cannabis in certain clinical trials.

And the reason why this occurs really is — So tolerances you know related to how many times basically that substance that receptor in your body. If you can think about it in this way the more times you hit a certain receptor, that receptor is going to become desensitized and then it will be up regulated and your body has a natural process where that receptor once has desensitized, it can be up regulated, and then it can be degraded. So the receptor amount will decrease over time if you continuously hit and hit that receptor.

Now back to Anslinger and the untold cannabis conspiracy.

There is a lot to still be learned about this endocannabinoid system, but Dr. Kumar makes an essential point about federal regulation impeding proper cannabis research. In the 1960s when the researchers of the Committee on Addiction specifically recommended resources to study cannabis and not treating possession as a felony, they also defined cannabis as a non-narcotic, habit-forming drug, but not an addictive drug.

However, the DEA decided to go against their recommendation by scheduling cannabis as a Schedule I Narcotic, accusing the plant of having no medical value and high potential for abuse. Besides making a plant highly illegal and therefore subject to incarceration for a broad population, this scheduling also stripped federal dollars from being used to study the plant and its effects on the human body.

During the 1970s, 80s and 90s, there were only two DEA permits issued to grow and conduct research on cannabis. One was given to Dr. Paul Mahlberg, a biologist who studied the lipophilic secretory glands in the plant, which is where the plant’s cannabinoids are produced. The other DEA permit was given to the University of Mississippi School of Pharmacy.

The University of Mississippi received their DEA permit under contract with the National Institute on Drug Abuse in 1968 and monopolized the growth of cannabis marijuana growers for research purposes for 48 years, or until 2016. And because the National Institute on Drug Abuse only allows for the marijuana grown to be sold for research purposes and not prescription medicine, no Phase 3 medical trials could be performed on cannabis marijuana, meaning no cannabis drug would be able to undergo clinical trials necessary for FDA approval and to prove its medical contribution. Oddly, according to the Multidisciplinary Association for Psychedelic Studies, aka MAPS, marijuana is the only Schedule I Drug where only one facility has had control over production.

This becomes very interesting when we look to recent news that suggested that the marijuana coming out of the University of Mississippi’s facility often tested under of the cannabinoid spectrum requested and commonly contained mold and bacteria. I think this negative press could have led to the National Institute of Drug Abuse releasing their cannabis cultivation monopoly.

In addition, since the US Department of Health and Human Services officially announced the value of cannabinoids as antioxidants and neuroprotectants in 2003, the DEA has also started to loosen their grip on cannabis research. Just a little bit.

Now it is commonly recognized that the DEA will allow for the study of THC on rats and mice, but grants are not normally funded unless the study supports the argument against THC having medical benefit or supports the negative effects of cannabis in some manner.

Because, after all, THC having no medical benefit is one of the DEA’s core beliefs for cannabis incarceration – I mean regulation.

In addition, when grants are finally funded, the paperwork is long and arduous to actually obtain the natural forms of THC through cannabis marijuana. So if the outcome of the test is similar, most researchers will end up switching to synthetic THC, which is often categorized as a Schedule III narcotic, meaning it has accepted medical benefit.
So this is a lot of talk about THC, but what about cannabis’ other major cannabinoid, CBD? The non-intoxicating cannabinoid?

Well, back in 1931, 3 years after Dr. Walther Straub bred Indian hemp into high quality medical cannabis and tested it on a human subject, and one year after Commissioner Harry Anslinger officially came into power, a seismic shift occurred within the cannabis industry.

So what was already known about medical cannabis and CBD? And what was the seismic shift that occurred?

You’ll find out on the next episode of Anslinger: The untold cannabis conspiracy.

**** Thank you for listening to this week’s episode. Sponsored by Natural Hemp Oil and Anavii Market.

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