Marijuana: Its effects and mechanisms of action

\"\"Dr. Darryl Inaba is Director of Clinical and Behavioral Health Services for the Addictions Recovery Center and Director of Research and Education of CNS Productions in Medford, Oregon. He is an associate Clinical Professor at the University of California in San Francisco, CA., Special Consultant, Instructor, at the University of Utah School on Alcohol and Other Drug Dependencies in Salt Lake City, UT and a Lifetime Fellow at Haight Ashbury Free Clinics, Inc., in San Francisco, CA. Dr. Inaba has authored several papers, award winning educational films and is co-author of Uppers, Downers, All Arounders a text on addiction and related disorders that is used in more than 400 colleges and universities. He has been honored with over 90 individual awards for his work in the areas of prevention and treatment of substance abuse problems. In March 2015, interviewed Dr. Inaba on what is the current knowledge of marijuana’s effects and mechanisms of action in the human body.

RV:  Why is there so much continued controversy about the effects and even the existence of Cannabis Use Disorder in both the Science and general communities?

Dr. Inaba: Cannabis is indeed one of the oldest psychoactive substance that has been in continuous use in the world, it was used in Chinese medicine thousands of years ago and archeologists have even found still active molecules of its chemicals in Egyptian mummies.  The funny thing about its long history of use is that we still barely how it works and what it does to the brain. The most curious thing for me as an addiction treatment provider is that regular marijuana users continue an ardent denial about it even being a drug. They think of marijuana as an herb, a food, an economic entrepreneurial opportunity, or even as a political constitutional right. Almost no one thinks of marijuana as being a drug.  Opium, cocaine, alcohol, LSD all come from botanical sources and no one has any problems thinking of them as drugs, so why isn’t marijuana respected as a drug as well?  As an addiction treatment professional and a clinical pharmacist, I know that the most psychoactive cannabinoid in marijuana is tetrahydrocannabinol (THC). This chemical, this drug, and many of the other cannabinoids in marijuana does cross the blood brain barrier to produce a long list of psychoactive effects: it impairs driving and tracking abilities and is an abusable/addictive substance and should not be used by adolescents, pregnant women, people with a history of addiction, or people who have mental health problems. Despite these issues and many scientifically validated studies about adverse mental and physical effects of cannabinoids, many people do not believe that there are any negative problems associated with the use of marijuana or its primary psychoactive substance, THC.

RV: So how do chemicals produced by the cannabis plant have so many different effects on the body and brain?

Dr. Inaba: Let’s look at what we know about marijuana and its cannabinoids from a neuropharmacological perspective.  It has only been about 25 years since research scientists first discovered the biological receptor sites that interact with the chemicals produced by the Cannabis plant, the phytocannabinoids in marijuana. It turns out that our brain and body cells have unique receptor sites known as G protein-coupled receptors that are on the pre-synaptic axons fibers of neurons.  Through further research scientists then discovered anandamide which is our natural biologically produced brain communication neurotransmitter. So, all of us already have a natural chemical in our brains that produce the same effects as THC.  A few years later scientists started finding a whole set of neurotransmitters that act like the various chemicals in marijuana.  It turns out that THC and the other phytocannabinoids activate these same receptors artificially through the use of this drug. Once the researchers found the first naturally occurring neurotransmitter that produced the same effects as cannabis (anadamide), they kept looking for others and soon found a second one 2AG, and then a third AGE, a fourth NADA, a fifth OAE. Perhaps more will even be discovered in the future but now we know of two major types of cannabinoids: those produced by plants, phytocannabinoids and those produced naturally in the body, the endocannabinoids. Along with the discovery of endocannabinoids, scientists have found a slough of receptors for them throughout the human body, not just in the brain. The G protein-coupled cannabinoid receptors are actually the most abundant receptors in the human body even more so then the opiate endorphin/enkephalin/dynorphin receptors. This partially explains why marijuana has so many different effects, both positive and negative, on the human body.

RV: What is the other reason for marijuana having so many different and sometimes very controversial effects on the brain and body.

Dr. Inaba: The other reason is that there are an almost infinite number of marijuana strains each with varying levels of different phytocannabinoids that can further be influenced by different growing techniques, storage, use, and even how long they have been harvested before they are consumed. There are some 480 or so biologically active chemicals, 66 of which are cannabinoids, 80 to 100 psychoactive chemicals, greater than 100 psychoactive metabolites produced from their use, and additionally 2,000 or so chemicals produced when pot is combusted for inhalation processes. This not only explains why there are so many different effects one gets from using pot but also why the use of it produces tremendous controversy about its effects. This also complicates doing definitive research on what marijuana does in the body. We can more easily say what THC or CBD does in the body but marijuana has just too many chemicals and variables to keep on top of. Then, we have identified two main types of receptors for the cannabinoids: CB1 and CB2.  CB1 receptor sites are responsible for the feelings of euphoria when marijuana is used. These are located the cortex and sub cortical areas of the brain but there are no cannabinoid receptors in brain stem, the part of the brain that controls heart rate and breathing.  Other psychoactive drugs like opiates and cocaine have major receptors in brain stem but not cannabis which is why an overdose from marijuana does not usually result in death.  I say usually because marijuana is now being increasingly linked to suicides, accidents, homicides, drowning and other then a physical shut down or hyperactivity resulting in death. CB1 Receptors in addition to producing euphoric feelings are also responsible for marijuana’s addictive properties.  CB2 receptors are mainly outside of the brain and are primarily activated by cannabidiol (CBD) that is also found in most strains of marijuana. CBD interacts with the CB2 and other receptors to produce many health beneficial effects and actually opposes THC euphoric effects.  CBD interacts with the immune system, has anti-seizure, pain relief and many other positive medical effects.  I think that there is a future for medical marijuana because of CBD and other unique chemicals in cannabis but in my opinion that does not include rolling up “shake” in a Zig Zag and smoking it as medical marijuana.

RV:  How does marijuana produce addiction or bring about severe cannabis-use disorder as specified in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5)?

Dr. Inaba: When marijuana is abused for its euphoric effects, the brain mistakes the infusion of artificial phytocannabinoids as a excessive release of its natural endocannabinoids and progressively shuts down production, storage and release of its natural endocannabinoids in an effort to maintain its normal neurochemical balance or homeostasis. It also shuts down its cannabinoid receptors through a process called “down regulation.”  Thus, a pot user has to use more and more marijuana just to retain some functionality as their natural brain chemical has been depleted. Phytocannabinoids in marijuana causes an imbalance of dopamine another neurotransmitter. Dopamine in the brain’s addiction pathway is imbalanced by all addictive drugs. Marijuana first exaggerates dopamine release to hijack the brain’s reward and survival instincts resulting in compulsion to keep using pot. Then it is depleted causing craving and obsession to start using again. Addictive use of marijuana produces tolerance, physical dependence and even withdrawal symptoms. Current research documents that 8-9 percent of the people who expose themselves to marijuana will become addicted to it but most people deny that it does that.  We treat several cannabis use disorder clients at my program in Oregon, and most are self-admitted to treatment complaining that they can’t stop using it. Our current waiting list is 4 months long for residential treatment.

RV:  Are there any other consequences from heavy use of marijuana?

Dr. Inaba: Marijuana interferes with a person’s ability to complete tasks requiring multiple steps to achieve a goal. It impairs depth perception, can suppresses short term memory ability, and has many other detrimental mental effects.  Regular heavy use of marijuana has recently been shown to produce and 8 point drop in IQ- that is the same IQ drop experienced from exposure to lead poisoning! That is significant and as a health professional, I am very concerned about the drug being used by young people.  Adolescents that start using marijuana at an early age are 5 to 6 times more liable to go onto to become addicts than others who delay their first use of the drug until they at least graduated from high school. The deluge of current laws permitting medical and recreational marijuana use has decreased the perception that marijuana has any harmful effects.  This has open the door to increase abuse of it especially in the population most vulnerable to its adverse consequences, our youth. 

RV:  Are there any other major concerns that you have about the current use of marijuana?

Dr. Inaba: I am very concerned about the rapid increase in the concentration of THC and the potency of marijuana and its products on our streets.  Back in the 1960s, the marijuana samples I tested were 1-2 % THC. By the 1980s ,with genetic manipulation, sinsemilla, and other enhanced growing processes, a 8-9 % THC range was common.  Currently the Marijuana Potency Monitoring Project at the University of Mississippi report an average THC concentration of about 15% in hundreds of samples confiscated by law enforcement throughout the U.S.  A recent report of 700 pot samples sold in Colorado outlets found an the average THC concentration of 20-30%.  In this analysis researchers also found toxins, rodenticides, and even heavy metals contaminants from the chemicals and fertilizers used to increase THC potency via genetically modifications. Then, there is the increasing problem of extracts with extremely high concentrations of THC know as dabs, BHO, honey oil or wax.  Dabbing is a process of extracting and concentrating THC using butane. This results in a oil or wax-like substance that contains 90% or greater concentration of THC. I have treated clients with terrible and long-lasting psychological and traumatic effects from it.  Some have experienced a heart attack or feel like they will have a heart attack. One client had 6 emergency room visits in a two month period suffering from a very painful and scary cannabis hyperemesis syndrome, uncontrollable vomiting, from its use. Pot “Edibles,” THC extract infused candies, cookies, soft drinks, energy drinks, etc. has also exploded across the country. These products often contain much more THC per candy bar, gummy bear, or bottle than is usually available in a marijuana cigarette or “joint.” Then there is the problem of synthetic cannabinoids, potentially an infinite number of designer chemicals currently made from 9 different chemical families that act like super-potent THC at cannabinoid brain receptors.  Sold as incense, potpourri, aromatherapy, and even as e-cigarettes these chemicals have been tested to be anywhere from 5 to 800 times more potent than THC.

We are definitely in a new era of marijuana or cannabinoid abuse and the future doesn’t look too good. Why society continues to ignore the science and the pharmacology of marijuana as being a drug is completely baffling to me. Maybe it’s all part of the addictive process that Bill W of AA once accurately described as: Cunning, Baffling, and Powerful.

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