Potholes…

Warning: This is a long article so if you have ingested cannabis recently you may not make it through to the end. 😉 Come back after you sustain for at least 24 hours.  Reference: “Attention, memory and learning are impaired among heavy marijuana users, even after users discontinued its use for at least 24 hours”- “The Residual Cognitive Effects of Heavy Marijuana Use in College Students,” Pope, HG Jr., Yurgelun-Todd, D., Biological Psychiatry Laboratory, McLean Hospital, Belmont, MA

I put these notes together because the topic of cannabis is coming up at holiday parties and in discussions with friends and family.  I personally want to be knowledgeable on the subject because we live in Washington DC where cannabis use has been decriminalized.  I walk in the morning each day and see many people openly using it as I stroll along the waterfront–I have no issue with this, but I do take issue with users NOT having all the information about the impact of cannabis on their health (especially people under 25–more below).  I also think that there is a lot of confirmation bias occurring as I discuss the subject with others.

Let’s start with the confirmation bias by reviewing something similar from 1991 when 60 Minutes ran a story about the potential benefits Americans could potentially get from drinking more red wine.  Morley Safer stated that “the (French) farmers have been eating a very high-fat diet, it seems, and yet they don’t get heart disease,” “the explanation of the paradox, may lie in this inviting glass” – and demand for red wine spiked!  –what did I do?  I loaded up on red wine.   Yet the American Heart Association reported that many of red wine’s benefits, including antioxidants and HDL, can be obtained through other fruits and vegetables and no “direct comparison trials” had been conducted “to determine the specific effect of wine or other alcohol on the risk of developing heart disease or stroke.”  Why do I bring this up? Simply to help you understand ‘confirmation bias’– the tendency to search for, interpret, favor, and recall information in a way that confirms one’s preexisting beliefs or hypotheses.  People tend to interpret ambiguous evidence as supporting their existing position.  The effect is stronger for emotionally charged issues (politics, alcohol, and weed) and for deeply entrenched beliefs especially if you are personally involved.  I believe this same thing is happening with cannabis and many people are ignoring the issues and, more importantly, the ‘known’ unknowns!

So what facts do most people know… what facts may they not know… and what is currently unknown (or what do we know that we don’t know–the ‘known’ unknowns)?

Let’s review the facts that most people DO know

The main psychoactive part of cannabis is tetrahydrocannabinol (THC), a chemical compound known as a cannabinoid, which is one of 483 known compounds in the plant, including at least 65 other known cannabinoids (but there might be up to 113). Cannabidiol (CBD) is the second most referred to cannabinoid.  CBD is generally known as the cannabinoid that does not have intoxicating effects like those caused by THC and may have an opposing effect on disordered thinking and anxiety produced by THC.  

There are 3 species of cannabis: Sativa, Indica, and Ruderalis. Sativa is widely accepted as being indigenous to Central Asia, Indica may have originated from the Hindu Kush mountain range and Ruderalis is native to central and Eastern Europe and Russia. Indica strains generally provide a sense of deep body relaxation. Sativa strains tend to provide a more energizing experience and the effects of Ruderalis are minimized by its naturally low concentrations of THC.  Note that how Indica & Sativa make users feel has not been scientifically proven. Ruderalis is attractive to breeders because of its auto-flowering trait.  When medical cannabis dispensaries promote their products, they will report both the amount of THC/CBD and the strain I=Indica, S=Sativa and H=Hybrid of the 2 other strains. Usually, they will also report the symptoms and conditions as seen in the figure.

Beyond cannabinoids, cannabis also contains “Terpenes” the fragrant oils that give cannabis its aromatic diversity (berries, fuel, Lavender etc.). These oils are secreted in the flower’s sticky resin glands. Terpenes are by no means unique to cannabis; they can be found in many other herbs, fruits, and plants as well. Like cannabinoids, terpenes bind to receptors in the brain and give rise to various effects. Different harvests may demonstrate dramatically different terpenoid profiles due to variances in growing and curing techniques. Myrcene is the most abundant terpene in cannabis, which is where it’s mostly found in nature. It can make up as much as 65% of total terpene profile in some strains. Limonene is the second most abundant terpene in all cannabis strains, but not all strains necessarily have it. Linalool is the most responsible for the recognizable cannabis smell with its spicy and floral notes. Caryophyllene has a spicy and peppery note. Alpha-pinene and Beta-pinene smell like pine trees. Alpha-bisabolol has a pleasant floral aroma. … and there are many more Eucalyptol, Trans-nerolido, Humulene, Delta 3 Carene, Camphene, Borneol, Terpineol, Valencene, and Geraniol.

As of November 2018, 33 states and the District of Columbia have broadly legalized cannabis for recreational (The District of Columbia, California, Colorado, Maine, Massachusetts, Michigan, Nevada, Oregon, Vermont, and Washington) or medical use under certain circumstances.

Many state politicians are moving to legalize cannabis because:

• Their constituents (funders and voters) are pushing for it (62% of voters want Cannabis legalized)
• The tax revenues are sorely needed by the state governments (Study: Legal cannabis could generate more than $132 billion in federal tax revenue and  1 million jobs)
• There are too many people incarcerated for cannabis possession costing taxpayers a fortune (Stats: Number of people arrested in the USA for a cannabis law violation in 2017: 659,700; Number of those charged with cannabis law violations who were arrested for possession only: 599,282 (90.8%); Cost’s taxpayer ~$15.9 Billion/year).
• Having a safe source of cannabis that’s not contaminated with pesticides or laced potentially with other drugs will save lives.

Several medical benefits have been proven:

• In June 2018, the food and Drug Administration (FDA) approved the use of a medication containing cannabidiol (CBD) to treat two rare, severe, and specific types of epilepsy — called Lennox-Gastaut syndrome and Dravet syndrome — that are difficult to control with other types of medication. This CBD-based drug is known as Epidiolex. A study published in 2017 found that the use of CBD resulted in far fewer seizures among children with Dravet syndrome, compared with a placebo.
• Evidence suggests that oral cannabinoids are effective against nausea and vomiting caused by chemotherapy, and some small studies have found that smoked cannabis may also help to alleviate these symptoms.
• Evidence to date suggests that cannabis could help to treat some mental health conditions. Its authors found some evidence supporting the use of cannabis to relieve depression and post-traumatic stress disorder symptoms. That being said, they caution that cannabis is not an appropriate treatment for some other mental health conditions, such as bipolar disorder and psychosis.
• Another comprehensive review of the evidence, published last year in the journal Clinical Psychology Review, revealed that using cannabis may help people with alcohol or opioid dependencies to fight their addictions. But this finding may be contentious; the National Academies of Sciences review suggests that cannabis use actually drives increased risk for abuse, and becoming dependent on, other substances.
• A review from the National Academies of Sciences, Engineering, and Medicine assessed more than 10,000 scientific studies on the medical benefits and adverse effects of cannabis. One area that the report looked closely at was the use of medical cannabis to treat chronic pain.

A lot of people with “Doctor” in their titles say there is “evidence” that cannabis has a lot of positive medical benefits.   Websites are reporting benefits such as weight loss, prevent diabetes, fight cancer, treat autism, heal broken bones, treat ADHD, slow Alzheimer’s disease, treat STDs, help OCD, improve skin, replace viagra, lower blood pressure etc…  I’m not saying these items are not true–they are just NOT proven like Safer’s red wine story above.

And finally, many people are medicating, self-medicating or just enjoying cannabis.  (USA: 22.2 million, International: 158.8 million)

What most people DON’T know?

There has NOT been a lot of research—Why? We know a lot about how alcohol impacts the body because researchers have been doing studies for years (more).  But we don’t know more about the impact of cannabis on the body primarily because the U.S. Drug Enforcement Administration (DEA) considers cannabis a Schedule I drug, the same as heroin, LSD, and ecstasy, and likely to be abused and lacking in medical value. Because of that, researchers need a special license to study it.   Hopefully, this turns around soon given Sen. Chuck Grassley (R-IA), a longtime ardent cannabis legalization opponent, is stepping down as chair of the Senate Judiciary Committee potentially paving a path forward for cannabis legislation in the 116th Congress and Sen. Lindsey Graham (R-SC) is taking over.  Graham is significantly more open-minded about medical cannabis and other common-sense reform measures than the current chairman is. Grassley refused to let any cannabis bills come to a vote as Judiciary chairman, Graham has cosponsored of legislation to protect legal medical states from federal interference, supported the reschedule of cannabis and supported the removal of cannabidiol (CBD) from the list of federally banned substances.

How cannabis impacts the brain. Cannabis acts on the body’s endocannabinoid system. Great video here. A great scientific description of cannabinoids here and here. We have cannabinoid receptors all over the brain and endocannabinoids are released naturally by the body to perform certain functions. For example, the hypothalamus releases them to stimulate appetite.  Guess what?  THC (tetrahydrocannabinol) also binds to these receptors—ever hear of the ‘munchies’?  The cannabinoid receptors are special receptors within the endocannabinoid system in the brain. The cannabinoid THC molecule activates particular cannabinoid receptors. These receptors, called CB1 and CB2 (there may be many others found in the future), work like a lock and key when flooded with cannabinoids after a user ingests cannabis.  CB1 receptors are found primarily in the brain, more specifically in the basal ganglia and in the limbic system, including the hippocampus and the striatum. They are also found in the cerebellum and in both male and female reproductive systems. CB1 receptors are absent in the medulla oblongata, the part of the brainstem responsible for respiratory and cardiovascular functions (likely why you can’t overdose easily on cannabis). CB1 is also found in the human anterior eye and retina. CB2 receptors are predominantly found in the immune system or immune-derived cells with the greatest density in the spleen. While found only in the peripheral nervous system, a report does indicate that CB2 is expressed by a subpopulation of microglia in the human cerebellum. CB2 receptors appear to be responsible for the anti-inflammatory and possibly other therapeutic effects of cannabis.  Cannabinoid receptors are activated by three major groups of ligands (a molecule that binds to another molecule) endocannabinoids, produced from within the body, synthetic cannabinoids (such as HU-210),  and plant cannabinoids (such as CBD & THC).

There are potentially big negative impacts

• Cannabis can be addictive to some people  The ‘dependence’ scenario is known as a Cannabis Use Disorder. The definition is that you’ve become dependent on it psychologically, or physiologically. About 9% of cannabis users become addicted to it. Cannabis Use Disorder in school often causes a dramatic drop in grades, truancy, and reduced interest in sports and other school activities. In adults, this disorder often is associated with work impairment, unemployment, lower income, welfare dependence, and impaired social functioning. Higher executive functioning is impaired in Cannabis Use Disorder which contributes to school and work impairment. This disorder also significantly decreases motivation at school or work. There is an increased risk of accidents while driving, at sports or at work.
• Overdose is not likely but you can end up in the hospital… Cannabis is not in the same category as opioids that cause respiratory depression and stop breathing but it can cause hyperemesis (continuous vomiting) and increase a user’s blood pressure significantly. It can cause a user to feel paranoid and get acute psychosis and a small percentage of people may develop a long-term illness but much more research is needed.
• It has a bigger impact on a young persons (under 25) brain. Jodi Gilman published research on 18-to-25-year-olds that showed differences in the brain’s reward system between users and non-users.  Gilman has also concluded (research) there is evidence that cannabis use, especially when initiated at a young age, (perhaps due to the effects of delta-9- tetrahydrocannabinol on cannabinoid (CB1) receptors in the brain) may be associated with worse verbal memory and altered neural development. Gilman is also reported that young adults with early-onset cannabis use had learning weaknesses and delayed recall.
• Chronic bronchitis. There is substantial evidence of an association between long-term cannabis smoking and an increase in the frequency of episodes of chronic bronchitis. (see NASEM report referenced below)
• Vehicle crashes. There is substantial evidence of an association between smoking cannabis and an increased risk of motor vehicle crashes. (see NASEM report referenced below)
• Low birth rate. There is substantial evidence of an association between maternal cannabis smoking and low birth weight. (see NASEM report referenced below)
• Schizophrenia and other psychoses. There is substantial evidence of an association between smoking cannabis and developing schizophrenia and other psychoses. The most frequent users are at the highest risk. (see NASEM report referenced below)

What is yet to be known?

We don’t fully understand the endocannabinoid system and how it is involved in certain functions (like psychosis, schizophrenia, and anxiety).  We don’t know why the response to cannabis varies so much across people. For example, some people report getting paranoid when they use cannabis and others report that it helps with anxiety.  Why?  We do know that some people have imbalances in their endocannabinoid system (under/overproduction of natural cannabinoids) in certain conditions but we don’t know exactly why.

We don’t understand what makes one user feel one way or another.  Just saying Indica is relaxing and Sativa is a stimulant is not accurate and has never been scientifically proven.  Many researchers believe that the different and diverse effects of cannabis are derived not from the genus, but from the Cannabinoids and Terpenoids produced by the plant as it grows as well as the user’s specific endocannabinoid system at the time of use.

We don’t know how to dose cannabis or how best to ingest the drug. We don’t know the appropriate doses for an individual’s physiology, or how best to take it (smoke it or use an edible).  Most medical cannabis prescriptions just get users into the dispensary but don’t say exactly what to buy and how much to take–try that at the CVS pharmacy…

We don’t know if cannabis impacts a users’ short-term memory, mood control, attention, and motivation. We know cannabis affects the hippocampus (the part of the brain that stores memories) and empirical evidence show that it may impact the ability to recall and retain information in the short term and it makes it hard to remember things, but this research is just starting.

We don’t know a lot about the impact of cannabis on the young brain. The brain is more susceptible to permanent effects of drugs if you’re younger (under 25) but in regard to cannabis is it how early it started, how frequently it’s used, the higher the dose and how bad is the impact? Unknown…  According to Krista Lisdahl, an associate professor of psychology and director of the Brain Imaging and Neuropsychology Lab at the University of Wisconsin at Milwaukee–In studies of those chronic, heavy users, “we see cannabis users have slower processing speed, worse memory and learning scores on certain tests, poorer sustained attention,”. There are also links to depression and sleep problems in some of those users, and some heavy users show brain changes linked to poorer emotional control or memory. These changes have been particularly observed in people who began using cannabis before ages 16 or 17. (more here).

We don’t know how genes play a role Scientists have identified genes that increase susceptibility, but there may be others and we are just at the beginning of understanding that.     

We know very little about the interaction of cannabis with other drugs. The Mayo Clinic lists the following ‘possible’ drug interactions: Alcohol, Anticoagulants and anti-platelet drugs, herbs and supplements. CNS depressants, Protease inhibitors, Selective serotonin reuptake inhibitors… However very little is known.

We don’t know much about each of the cannabinoids (see appendix). Per Ryan Vandrey, an associate professor of psychiatry who researches cannabis at Johns Hopkins Medicine “We know a lot about THC and we’re starting to learn about CBD”  “Out of about 400 [compounds] we know a decent amount about two.” The unknowns about what various cannabinoids do and how they interact with each other create plenty of questions about the best ways to use medical cannabis. That means there’s a lot to learn about which compounds might contribute to psychoactive effects and which might potentially have medical uses.

The National Academies of Sciences, Engineering, and Medicine (NASEM) has released a thorough report that answers what claims are well-grounded and what claims are not. The report is based on more than 10,700 abstracts of papers published in peer-reviewed journals since 1999. Download here.

These notes are not about legalization—in fact, legalization is good (especially at the federal level) if it allows scientists to better understand cannabis and its impact on the brain.  These notes are about understanding what is known and what is unknown so you can make a reasonable decision on your own personal use now that cannabis is being decriminalized across the country. You don’t want to be one of those people that said—no one told me that smoking tobacco caused cancer.  Especially when scientists suspected it as far back as 1898.  Remember science blunted the power of the tobacco industry and prevented nearly 800,000 cancer deaths in the United States between 1975 and 2000. 

Please keep in mind that there are a number of moving parts in the cannabis equation.  There are the cannabis cannabinoids (science has only really studied 2 out of the >100 that may exist), the cannabis terpenes (>100 most not studied in regards to impact on health), how the cannabis is ingested (smoked, edible), how much cannabis is ingested (mg), your cannabinoid receptors (we know of 2 but think there are more), your endocannabinoid system (not well understood by science yet it is believed to regulate and balance things like nerve functions, stress recovery, inflammation levels, immune function, energy intake and storage, cell life and the circulatory system), and your specific DNA–not to mention interaction with other things you have taken.  So don’t say “people have been smoking it for 100’s of years”, “I like to get high and it’s not having an impact on me”, “It’s healthier than drinking” without understanding that you are getting involved with a very complex drug that is not well understood.

If you are going to use cannabis know your facts and stay up on the science or risk being one of the “No one told me cannabis caused…” of the future.

Stay up to date on cannabis research by leveraging the NIH.gov site.

  

  

  

Appendix 1: Here is a list of the most well known cannabinoids:

Cannabichromenes

Cannabichromene (CBC) – non-psychoactive and does not affect the psychoactivity of THC. CBC has shown antitumor effects in breast cancer xenoplants in mice. More common in tropical cannabis varieties.

Cannabichromenic acid (CBCA)

Cannabichromevarin (CBCV)

Cannabichromevarinic acid (CBCVA)

Cannabicyclols

Cannabicyclol (CBL)

Cannabicyclolic acid (CBLA)

Cannabicyclovarin (CBLV)

Cannabidiols

Cannabidiol (CBD) – CBD does not have intoxicating effects like those caused by THC, and may have an opposing effect on disordered thinking and anxiety produced by THC. Cannabidiol has very low affinity for the cannabinoid CB1 and CB2 receptors but is said to act as an indirect antagonist (blocks or dampens a biological response) of these receptors. At the same time, it may potentiate the effects of THC by increasing CB1 receptor density or through another CB1 receptor-related mechanism.

Cannabidiol monomethylether (CBDM)

Cannabidiolic acid (CBDA)

Cannabidiorcol (CBD-C1)

Cannabidivarin (CBDV) – usually a minor constituent of the cannabinoid profile, enhanced levels of CBDV have been reported in feral cannabis plants from the northwest Himalayas, and in hashish from Nepal.

Cannabidivarinic acid (CBDVA)

Cannabielsoins

Cannabielsoic acid B (CBEA-B)

Cannabielsoin (CBE)

Cannabielsoin acid A (CBEA-A)

Cannabigerols

Cannabigerol (CBG) – is non-psychoactive but still contributes to the overall effects of Cannabis. CBG has been shown to promote apoptosis in cancer cells and inhibit tumor growth in mice. It acts as an α2-adrenergic receptor agonist, 5-HT1A receptor antagonist, and CB1 receptor antagonist. It also binds to the CB2 receptor.

Cannabigerol monomethylether (CBGM)

Cannabigerolic acid (CBGA)

Cannabigerolic acid monomethylether (CBGAM)

Cannabigerovarin (CBGV)

Cannabigerovarinic acid (CBGVA)

Cannabinols and cannabinodiols

Cannabinodiol (CBND)

Cannabinodivarin (CBVD)

Cannabinol (CBN) – the primary product of THC degradation, and there is usually little of it in a fresh plant. CBN content increases as THC degrades in storage, and with exposure to light and air. It is only mildly psychoactive. Its affinity to the CB2 receptor is higher than for the CB1 receptor.

Cannabinol methylether (CBNM)

Cannabinol-C2 (CBN-C2)

Cannabinol-C4 (CBN-C4)

Cannabinolic acid (CBNA)

Cannabiorcool (CBN-C1)

Cannabivarin (CBV)

Cannabitriols

10-Ethoxy-9-hydroxy-delta-6a-tetrahydrocannabinol

8,9-Dihydroxy-delta-6a-tetrahydrocannabinol

Cannabitriol (CBT)

Cannabitriolvarin (CBTV)

Delta-8-tetrahydrocannabinols

Delta-8-tetrahydrocannabinol (Δ8-THC) – The principal psychoactive constituent of cannabis

Delta-8-tetrahydrocannabinolic acid (Δ8-THCA)

Delta-9-tetrahydrocannabinols

Delta-9-tetrahydrocannabinol (THC)

Delta-9-tetrahydrocannabinol-C4 (THC-C4)

Delta-9-tetrahydrocannabinolic acid A (THCA-A)

Delta-9-tetrahydrocannabinolic acid B (THCA-B)

Delta-9-tetrahydrocannabinolic acid-C4 (THCA-C4)

Delta-9-tetrahydrocannabiorcol (THC-C1)

Delta-9-tetrahydrocannabiorcolic acid (THCA-C1)

Delta-9-tetrahydrocannabivarin (THCV) – prevalent in certain central Asian and southern African strains of Cannabis. It is an antagonist of THC at CB1 receptors and lessens the psychoactive effects of THC.

Delta-9-tetrahydrocannabivarinic acid (THCVA)

Miscellaneous cannabinoids

10-Oxo-delta-6a-tetrahydrocannabinol (OTHC)

Cannabichromanon (CBCF)

Cannabifuran (CBF)

Cannabiglendol

Cannabiripsol (CBR)

Cannbicitran (CBT)

Dehydrocannabifuran (DCBF)

Delta-9-cis-tetrahydrocannabinol (cis-THC)

Tryhydroxy-delta-9-tetrahydrocannabinol (triOH-THC)

3,4,5,6-Tetrahydro-7-hydroxy-alpha-alpha-2-trimethyl-9-n-propyl-2,6-methano-2H-1-benzoxocin-5-methanol