In 2022 something very special happened in the world of cannabis science. But while the politicians are entrenched in the battle for cannabis legalization, this high-impact discovery largely remained confined to the social consciousness of the cardiovascular field. Yet, it is profound work and really ought to be included in the public conversation around cannabis. Earlier this year, a research group from the Stanford Cardiovascular Institute published an incredible cannabis paper in the scientific journal CELL. I would like to highlight this work which deepens our understanding of how cannabis affects the heart and blood vessels while also providing us with a solution to mitigate some of its negative effects.
To that end I interviewed Joseph Wu MD, PhD, whose team did the research, and who graciously took the time to answer a variety of questions.
Why is this special?
Before we go any further, let me tell you why this study is so special. It is a cannabis paper in CELL. This is very unusual, because CELL is one of the most prestigious and high-impact scientific journals in the world. In order to publish in CELL the work needs to be exceptional. You have to have an important study target; a huge amount of data, both in vitro (in petri dish) and in vivo (in animal models and clinical data); need to have figured out the biochemical mechanisms involved; and shown your result using several independently designed, overlapping experiments from a multitude of directions. Furthermore, if your discovery highlights a problem, then you better come with a solution to that problem.
Very few cannabis papers make it into a high-impact journal like CELL, which has some of the most competitive and strictest peer-review.
In other words, placing a study in a journal like CELL is incredibly difficult to achieve, takes deep funding pockets, an exceptional team as well as a healthy portion of determination and luck. That means it is usually reserved to groups with a track record of exceptional work and often means the paper will be a landmark that many future studies will reference and build upon.
In this particular case it is clear that the study will change the way companies will supplement their cannabis products. Think about how "omega-3" became the must have hottness in the food industry. Well, It looks like the cannabis space may have found its own must have supplement—Genistein.
Shouldn't the world of cannabis talk about this more?
One of the most frustrating things about the public conversations on cannabis science is how distorted and biased the conversation around the medical merits and/or risks of cannabis consumption has become. Everything is political and if you believe the media, cannabis either cures anything from cancer to mental illness or is worse than smoking and a traffic catastrophe just waiting to happen. It is all so very contentious and frustratingly dishonest. Often those articles cite studies and boldly take everything the scientists discovered out of context. “Who reads past the title anyway, right?”
So who can you believe? Certainly not the influencer that tries to tell you about the healing properties of cannabis with one hand while selling you product with the other, right? Who do you ask about what information is reliable? Well, at this point the best approach is to talk directly to the scientists that did the work and let them tell you, unedited, what they discovered in their own words. So, let me introduce you to Joseph Wu MD, PhD, director of Stanford's Cardiovascular Institute who talked to us about his team's paper with the title:
Cannabinoid receptor 1 antagonist genistein attenuates marijuana-induced vascular inflammation.
Wei, T. T., Chandy, M., Nishiga, M., ... Wu, J. C. (2022).
Cell, 185 (13), 2387–2389. https://doi.org/10.1016/j.cell.2022.06.006
Note: For laymen this very loosely translates to: “Soybean compound blocks cannabis-induced negative effects on the heart and blood vessels”.
If you think I was exaggerating about how exceptional the authors of CELL papers tend to be, then one look at Dr. Wu’s prior accomplishments should convince you otherwise. Joseph Wu, MD, PhD, is a board-certified cardiologist. He is also the Simon H. Stertzer Professor of Medicine & Radiology at Stanford University. Furthermore, he is the Director of the Stanford Cardiovascular Institute and Co-Founder and Member of the Board of Directors of Khloris Biosciences, Inc, a spin-off start up company whose mission it is to fight cancer with modern cancer vaccines. Naturally, he has published hundreds of peer-reviewed articles and received many, many, prestigious awards, like for example a host of awards from NIH and AHA as well as the Presidential Early Career Award for Scientists and Engineers (PECASE) from the Obama administration and was elected to the National Academy of Medicine. As far as credentials go, I would say, yeah, it is pretty exceptional.
So first, we’ll summarize the findings of the paper and then move on to questions from the general public, a number of questions about the team and lastly a couple of scientific questions I couldn’t resist asking.
The discovery in a nutshell
Here are the core findings of the study condensed down to the most central ideas.
For laymen in plain language:
- The research demonstrates a higher risk of heart attacks in people who use cannabis.—While there were previous studies that suggested this, this study here does so in a very large human data set, which makes it statistically very robust (500k people) and clinically directly applicable.
- Furthermore, the group also identified the mechanism of how cannabis use leads to this increased risk.—In essence, when cannabis interacts with the body important immune system compounds are released and over time this damages the blood vessels and leads to chronic diseases of the circulatory system, including heart attack.
- Excitingly, the research group also discovered that genistein, a compound that is abundant in soybeans, can block these negative effects of cannabis on the circulatory system, while leaving its psychoactive properties on the brain intact.
Of course, this is a gross simplification of the actual findings and so what follows is the scientifically more accurate version of the key discoveries (reviewed by Prof. Wu.)
In slightly less plain english:
- The study confirmed a higher risk of myocardial infarction (heart attack) among people who use cannabis. While previously established, this study is doing so in a very large data set (500k people genetic/phenotypic data set/UK Biobank)
- The group identified that the mechanism includes CB1 dependent upregulation of well established key inflammatory cytokines and oxidative stress that cause vascular inflammation and atherosclerosis.
- The researchers also identified a soybean derived compound, genistein, that can be used as a neutral CB1 antagonist and blocks the action of THC on the cardiovascular system, but not the brain.
Part I: Questions for our general audience
Alexander Schering, PhD:
What got you interested in investigating cannabis?
Joseph Wu, MD PhD:
Thomas initially began the cannabis and cardiovascular disease project in 2016. California legalized cannabis for recreational use in 2016 and we anticipated that there would be an increase in cannabis use because it was legal. However, because it is a schedule 1 drug, we had very little information on its long-term cardiovascular effects. We, therefore, started by testing the effects of THC, the psychedelic component of marijuana, using iPSC-derived endothelial cells. Thomas found that it caused increased inflammation and oxidative stress in vitro.
You and your team are doing experiments on cannabis—have you "tested" some yourself?
Which do you think you would prefer, smoking cannabis or eating an edible?
This is a very interesting question. Because edibles are absorbed in the stomach and are also subjected to first pass through the liver for metabolism, the concentration of THC would be lower than smoking a marijuana cigarette or vaping. In addition, edibles do not have other adverse compounds associated with smoking such as particulate matter 2.5 micron (PM2.5) and heavy metals. Therefore, cannabis administered orally might have a lower effective concentration of THC and not have other adverse compounds from smoking. Thus, we would hypothesize that orally administered cannabis would have fewer adverse side effects.
Do you know if any of your students use cannabis recreationally?
To my knowledge, my undergraduate students, graduate students, postdoctoral fellows, and employees do not use cannabis.
What do you feel about cigarettes and alcohol being legal and yet there's such a struggle for cannabis to be legal?
Alcohol and traditional tobacco cigarettes cause adverse effects on the body and cardiovascular system. The effects of alcohol and tobacco are determined by the amount and duration of exposure. Both these compounds are regulated by the government and have limits on its use in young people. We are learning that cannabis might also have adverse effects on the body and in particular the cardiovascular system in large doses. Like alcohol and tobacco, I believe the government should regulate the sale and distribution of cannabis and study its potential benefit and harm to the body.
There is a big chasm between what average physicians know and the state of cutting edge scientific research. This appears to be particularly true for the state of knowledge on cannabis—how can we improve this?
We must work hard to disseminate our findings to health care providers and public policymakers. By presenting our findings in publications, conferences, and medical and scientific meetings we might help inform these individuals of the benefits and harm caused by cannabis.
Similarly, the majority of cannabis consumers don’t read research papers, but the information in them could help them consume more safely—how do we bridge the gap?
By informing healthcare providers and policymakers, I anticipate that healthcare providers might change their practice and the government will revise laws accordingly. It might take time for new information to be disseminated to the public, especially cannabis users who are at risk for adverse cardiovascular events. Therefore, I also believe it is important to disseminate our findings to the public via trusted media entities that can responsibly communicate our findings.
Part II: Community Questions
Does the research in your paper only apply to smoked cannabis or can edibles also cause similar cardiovascular disease?
The UK Biobank data was collected from participants that use cannabis. This could include smoking, vaping, or edibles. The concentration that we studied in vitro and in vivo corresponds to a concentration in the blood that has been observed when smoking marijuana. Therefore, we would need to do additional studies to test the effect of edibles. However, there is evidence in the literature that even edibles or pill forms of cannabis can cause cardiovascular disease.
Does that mean we should all run out and buy soymilk, if we are cannabis consumers?
In our study, we found that THC causes inflammation, oxidative stress, and atherosclerosis in the cardiovascular system. More importantly, genistein, a soybean derivative, could block these effects. However, there are over 100 cannabinoids in cannabis and those that smoke a marijuana joint are also combining these with particulate matter and atmospheric pollution. We do not fully understand the long-term effects of cannabinoids on the body and the cardiovascular system. A soy beverage might attenuate the effects of THC, but we cannot speculate on whether it will completely protect someone from all the compounds in cannabis.
Are consumers from geographic regions with traditionally more soybean consumption more likely to be protected from THC-induced cardiovascular disease?
In the context of individuals that use THC, we would expect that soybeans would attenuate THC-induced cardiovascular disease.
Soybeans don’t taste good. Can I eat edamame and miso soup with my joint?
Genistein is the soybean derivative that blocks the adverse effects of THC on the cardiovascular system. Genistein can be found in a variety of soy-based products including soy beverages and foods. Attached below is a link to a website from the USDA that details the genistein content in a variety of foods:
USDA Database for the Isoflavone Content of Selected Foods
As a scientist and clinician what is one piece of advice you would want to give the world of recreational cannabis users?
I would urge the public to be cautious about using cannabis. With a lack of research, we do not have information on the long-term consequences of cannabis use.
PART III: Questions about the Team
Science is of course a team effort. Can you tell us a little bit about yours and the people spearheading the project?
The scientific team is large and composed of individuals with complementary expertise in molecular biology, molecular modeling, statistical analysis, small animal studies, and molecular imaging. The three co-first authors are Tzu-Tang “Thomas” Wei, Mark Chandy, and Masataka Nishiga. Thomas was a former postdoc in the lab that started the project and did much of the in vitro and in vivo work. Mark is also a former Instructor in the lab who helped provide the clinical data for the manuscript. Masa is currently an Instructor in my laboratory and helped with doing the experiments showing that THC exacerbates atherosclerosis in mouse models.
A lot of principal investigators have studied in your lab. Which one of your current graduate students do you think is the closest to graduating next and can you tell us a few words about them?
Dr. Masataka Nishiga is a current Instructor in the laboratory. He was a key contributor to finishing the Cell paper on the effects of THC on the cardiovascular system. Masa drove the atherosclerosis projects in my laboratory that were essential to satisfying the Reviewers about the link between THC and heart disease. Masa has published perhaps the most highly cited review on COVID-19 and cardiovascular disease in Nature Cardiology Reviews:
Nishiga, Masataka et al. “COVID-19 and cardiovascular disease: from basic mechanisms to clinical perspectives.” Nature reviews. Cardiology vol. 17,9 (2020): 543-558. doi:10.1038/s41569-020-0413-9
In addition, Masa is doing cutting edge research using genomic editing tools and stem cell biology to understand the mechanisms of congenital heart disease. I anticipate that he will publish this in another high impact paper and transition to his own laboratory in the near future.
If you have to pick, what is the 2nd biggest factor that you feel would accelerate your research the most? I am asking for the 2nd biggest, because in my experience researchers often like to answer that question with “More funding of course!”
We have found a link between cannabis and cardiovascular disease. There are over 100 different components in cannabis. The effects of these components on the body are not fully understood. With additional research funding, I would like to explore the mechanisms of how these cannabinoids affect the body and human health.
Did the COVID-19 pandemic affect the project?
The COVID-19 pandemic delayed the project. There were several administrative delays related to obtaining approval from Stanford and UCSF for doing the Olink experiment. In addition, there was a period of 3 months when we could not do experiments and another 6 months when we had limited laboratory activities due to the pandemic. Lastly, there were ongoing supply shortages which delayed the delivery of important reagents needed for the project.
Part IV: Scientific Questions (expert level)
For the Olink Proteomic Analysis of plasma from recreational smokers, you provided the test subject with a joint. How did you quantify the amount of THC in the marijuana cigarettes? And did you use a specific cannabis strain? Did you consider using an electronic vaping device using THC extract?
The Olink analysis was done on plasma from subjects who provided and smoked their own marijuana cigarette. The blood samples were analyzed by mass spectroscopy to determine the amount of THC. We could have used either traditional marijuana cigarettes or vaping systems. In vaping juice, the content of THC can be higher than a marijuana cigarette, so we might see a more pronounced effect.
In the scientific literature on THC there is some evidence to suggest that THC has biphasic effects. Do you think this may be what we are seeing in your HUVEC cell viability assay in the samples treated with 0.1-0.5 µM Δ9 THC?
From our experiments in HUVEC, we observe a linear relationship between the concentration and Δ9-THC and inflammation (Figure 4B). While there is a slight increase in viability of HUVEC at 0.5 µM, we do not see a consistent pattern when observing HCAEC and iPSC-EC. This may be due to chance (Figure 3A and S1C). So, I do not think we have data to support the idea of a biphasic response to THC.
The Uk Biobank contains data from people between the ages of 40-69. Previous work on THC like for example the 2017 Nature Medicine paper by Prof. Andreas Zimmer’s group suggests that THC can have opposite effects on cognition in very young and very old mice. Do you think the same applies to the cardiovascular system?
The UK biobank data found cannabis to be a risk factor for cardiovascular disease that was independent of age.
Lastly, every big paper has that one experiment that is particularly difficult to get right and the most contested during the review process. Which one do you think was the most challenging for your team?
Because of the variation in the literature, the UK Biobank data showing the link between cardiovascular disease and cannabis was initially met with skepticism. Over time, other manuscripts emerged supporting our claim. To support our claims, we performed an Olink analysis of plasma after acute marijuana smoking. The research was difficult because cannabis is a restricted substance. The Olink study was done in collaboration with UCSF. Due to the pandemic, there were administrative delays in receiving approval. However, the Olink data was important for convincing the reviewers of the association between heart disease and cannabis. We also performed experiments in mouse models to show that THC exacerbated atherosclerosis in mice on high-fat diets and genistein could block these effects. Taken together, these experiments helped convince the Reviewers that THC is associated with heart disease and genistein could block these adverse effects.
Is cannabis safe?
This question is at the heart of the debate around cannabis legalization, pun intended. However, I think it is the wrong question. The human body is a carefully balanced ecosystem of cells that cooperate in order to keep you and your species alive. At the wrong dose everything can kill you. Even two of the arguably most important substances facilitating life on earth, oxygen and water, can kill you at the wrong dosage. So the question for legalization shouldn't be "is cannabis safe?", but rather under what circumstances is it not safe.
Work like this demonstrates one thing very clearly. When it comes to health, cause and effect is not always immediately apparent. It is easy when the timeframe between cause and effect is short, like when you consume too much fentanyl you will very quickly enter life-threatening circumstances. Thus, coming to the conclusion that fentanyl threatened your life is straight forward.
But when you have a heart attack at a curiously young age of 35, and the doctors identify that clogged arteries are to blame, then figuring out that why your arteries are clogged is much less straight forward. It takes research like this to connect the dots between consuming a seemingly harmless substance which gradually upsets the balance of your body's ecosystem until it tips over and ends in a heart attack years later. With this much time and so many layers between cause and effect you really need very large data sets in order to identify the causal relationships. By and large clinical cannabis data is still quite limited. The idea that cannabis might be causing cardiovascular issues has been around for a while. But until now there never has been enough data to nail it down.
Supplementing cannabis with genistein is a gamechanger
However, being able to reverse those negative effects with a food supplement like genistein is of course a complete gamechanger. I can see a future where genistein will become the "omega-3" of cannabis products.
I think it is important that we honestly and carefully untangle the conditions and context in which cannabis acts therapeutic, from the habitual recreational use and its long-term effects. If we can do that, then I am convinced that we can make educated, adult decisions that help us enjoy cannabis safely. And discoveries like this CELL paper pave the way.
Finally, I would like to thank Prof. Wu for taking the time to answer our questions. It was incredibly interesting for us and we wish you and your team much continued success!