Cannabis & Male Factor Infertility – What does the research say?

Cannabis & Male Factor Infertility – A discussion with Dr Spence Pentland & Sean Quigley about the current research

We’re going to be talking and doing a deep dive into cannabis and male factor infertility. It’s a fun episode, we’re going to give a brief introduction to the endocannabinoid system, a little bit technical, but to bear with us, then we’ll get into how cannabis affects male fertility through certain semen parameters, like concentration and fertilization capacity, and the mitochondria or the energy producing powerhouses of the sperm, DNA fragmentation, different administration roots of cannabis and its impact on IVF.

Near the end, you don’t want to miss this part where we’re also going to jump into some of the positive effects that research has shown with cannabis and reproduction. And then, we will give our conclusions.

So, it’s an episode I think you don’t want to miss. We had a lot of fun diving into the research and coming up with some basic conclusions, so that you can incorporate it into your life.

  ~~O
Spence Pentland

 

BFP Cannabis Podcast

Spence Pentland: Hello, again, everybody! Welcome to another Conception Channel, a podcast brought to you by Yinstill Reproductive Wellness and The Being Fertile Program. I’m your host, Spence Pentland, and today, I will be co-hosted by my very dear friend, Mr. Sean Quigley.

Today, we’re going to be talking and doing a deep dive into cannabis and male factor infertility. It’s a fun episode, we’re going to give a brief introduction to the endocannabinoid system, a little bit technical, but to bear with us, then we’ll get into how cannabis affects male fertility through certain semen parameters, like concentration and fertilization capacity, and the mitochondria or the energy producing powerhouses of the sperm, DNA fragmentation, different administration roots of cannabis and its impact on IVF.

Near the end, you don’t want to miss this part where we’re also going to jump into some of the positive effects that research has shown with cannabis and reproduction. And then, we will give our conclusions.

So, it’s an episode I think you don’t want to miss. We had a lot of fun diving into the research and coming up with some basic conclusions, so that you can incorporate it into your life. Without further ado – welcome to the podcast.

Let’s talk about male infertility and cannabis. My name is Spence Pentland.

Sean Quigley: I’m Sean Quigley.

Spence Pentland: We’re going to attempt to decode and find some conclusions regarding the use of cannabis and its effect on male fertility. We have a quick little bias disclaimer that we are Canadian. Cannabis is legal here recreationally, and we are practitioners of Traditional Chinese Medicine. I’m not sure about Sean, but I have tried cannabis in my past. Anyway, that’s our disclaimer – do you have anything to add to that, Sean?

Sean Quigley: Yeah. I’ve also tried cannabis in the past. I mean, it’s just getting so more acceptable to talk about it, it’s a good time for it. But I think it is really important for us to have this discussion because there hasn’t been enough research done, and there’s more and more information coming out. So, hopefully, we can tease through some of those details for people today.

Spence Pentland: It’s interesting, we’ll get to that, because research that’s been done has been done on people that are okay to say, “Yes. I’ve been committing a crime, and I think that’s kind of probably skewed some things.” Anyway, today, we’re going to review literature, we’ve done some deep diving into the literature that is out there, including articles published and research that’s been done, but for the most part, just as an intro here, male factor in fertility has been on the rise over the last number of decades. And the disruption of the delicate balance of the endocannabinoid system, which we’re going to get to here really quickly by exogenous cannabinoids, like marijuana or CBD, could very well be a contributing cause to this. So, research is showing that, at least theoretically, most definitely for some people, but as we said before.

Sean Quigley: Yeah, we’ll get to some of that, but that’s a really interesting finding I think that we’re getting to.

Spence Pentland: We’ll try and tease that out. But anyway, we’ll start with the endocannabinoid system, the ECS, which was just mentioned, because an understanding of it is essential to start here. And paper published in 2013 in Italy at the University of Rome, titled the Endocannabinoid System and Spermatogenesis. That was a chunk to chew on, but it really wrapped it up nicely. It’s regarded the ECS, or the endocannabinoid system, as possibly a master system in our bodies. It’s present in the nervous system, white blood cells – a plethora of tissues in our bodies. But most notably, and for our purposes here today, the reproductive system.

The endocannabinoid system components are found in every part of the male reproductive system, from germ cells, to sperm testicles, to the reproductive tracts and fluids, and notably the hypothalamus area, which governs GnRH regulation, or the gonadotropin-releasing hormone regulation, so that HPG, or hypothalamic-pituitary-gonadal axis, and tells the pituitary to release LH or luteinizing hormone, which tells the Leydig cells to produce testosterone in the testes, and FSH, follicle stimulating hormone, which signals the Sertoli cells to support the creation of sperm, or spermatogenesis.

That was a mouthful, but it’s obvious that anything endogenous or exogenous that affects the endocannabinoid system could have an impact on reproduction. And this theory is well-proven through a research here. Of a particular note is the negative impact that exogenous cannabinoids have on mitochondrial function and mechanisms involved in fertilization – we’ll get to that. But just to get a little bit technical here, and then we’ll kind of come back out into the real world somewhat.

AEA, which is endocannabinoid, so cannabis-like transmitter, neurotransmitter, that is produced within our bodies in the endocannabinoid system, and so AEA, and 2AG endocannabinoids affect the CB1, or cannabinoid 1, and CB2 receptors in different parts and tissues of the male reproductive system in different ways. So, it’s complicated, and not yet fully understood – that’s for sure. But what we can extrapolate is that it’s clearly an intricate system that has the potential to be disrupted with exogenous cannabinoid exposure, so smoking pot.

Sean Quigley: Right. I mean, these receptors basically get overrun with this external or endogenous cannabinoids, so our internal system maybe just doesn’t know what to do with.

Spence Pentland: Yes, and excess gets created. Disruption in the system is clear, at least in theory. So, marijuana, in all its forms, has the potential to disrupt the delicate balance of this endocannabinoid system, and negatively impact male fertility – that should be clear by now. For example, the researchers have administered AEA, so the endocannabinoid, which reacts with CB1 receptor, which decreases serum LH, due to the inhibition of the GnRH release. So, this results in reduced testosterone and reduced spermatogenesis. So, they put this endocannabinoid and testosterone, and sperm production is lowered. CB1 receptors are exogenous cannabinoids, like cannabis, and marijuana activate. AEA, this endocannabinoid also affects the FSH, and can cause Sertoli cell apoptosis – the cells that produce sperm death.

And the process of maturing of and protecting sperm is also inhibited, and maybe completely disabled here. This is neat, Sean, that sperm themselves have a complete ECS system, so include the mechanisms to actually create endocannabinoids, like AEA, and the 2AG, and the CB receptors, in the head, the mid piece and the tail of the sperm. I mean, it’s crazy, it’s intricate. The AEA binds to the CB1 receptor on the sperm, and that’s how it reduces its motility, and we’ll get into that more.

Sean Quigley: That’s also the receptor that THC binds to, the CB1 receptor.

Spence Pentland: Exactly. It also negatively impacts the acrosome reaction on the head, which is required for fertilization, we’ll get into that a little bit more. But, just about to come out of this deep dive into the endocannabinoid system, another paper published talked about AEA levels of seminal plasma and AEA levels, along the female reproductive tract, which should be noted like the female reproductive system has this full endocannabinoid system as well.

So, the levels of the seminal plasma, the endocannabinoids in that seminal plasma and the levels in the female reproductive tract seem to need to be in concert with one another, for proper timing of the acrosome reaction and fertilization. So, if, again, maybe if one partner, their levels are high – anyway, that’s a study that we should unpack at a separate time.

Sean Quigley: As if we didn’t have enough to worry about.

Spence Pentland: Exactly. Anyway, it’s a brief overview of endocannabinoid system, and it should be clear already a little bit that cannabis can affect our male fertility.

Sean Quigley: Yeah, and just to add a few details in there, interesting point too is that these endocannabinoids  aren’t stored intracellularly, but they can be synthesized, and/or inactivated and activated independently, so this sort of just increases how they affect our whole system. Like, it allows for high degree of flexibility of their actions, and again just making the whole ECS system just really complex and difficult to understand.

Spence Pentland: Absolutely. We noted here that, I’m just skipping down our notes here a little bit, but in 2006 that paper from Spain published in the journal of neuropharmacology talked about the vanilloid systems, as cannabinoids may also interact with these receptors in this system, which is what they believed to play a role in the pain relief mechanism that cannabis might have. Just, again, to highlight the endocannabinoids may be playing roles in other systems that we don’t even know.

Sean Quigley: Yes, really, it’s highly complex, and hopefully, as time moves forward, and medical marijuana, you know, the legislation is opening up, so hopefully, there will be more information available for everybody. A of studies have found changes with cannabis, changes with LH, FSH testosterone, mostly a decrease in these hormone levels, sometimes they are fighting not a change, rarely an increase, but even an increase is maybe not optimal for reproductive health.

Spence Pentland: In balancing, yeah.

Sean Quigley: Yes, just balance, exactly. The other thing that I found, and who knows where this is coming from, but some research is finding a decrease in the size and weight of the testes, changes in the physiology of the seminiferous tubules, which is where sperm is developed, the prostate changes, seminal vesicles can be affected, even coming down to libido and just sort of sexual function, so kind of this whole world connected with the reproductive help, has been shown to be affected, as much as I hate to say it.

Spence Pentland: The studies you talked about, I found that some of those two, they’re mostly dogs, and rat, and rodents, and also with the decrease in size of sexual organs, which was shocking, but also in decrease in LH receptors on these organisms.

Sean Quigley: LH receptors are affected, suddenly the Leydig cells aren’t working properly, and testosterone can’t get developed, and then there’s just a cascade.

Spence Pentland: Right. And we’ll see too later with the smoke aspect and estrogenic effects, how that can be hit from different sides. But anyway yes, sorry I interrupted you there.

Sean Quigley: No, it’s all good. Go ahead. I think we are going to dive into now a little bit more details, in terms of what some of these studies are showing in terms of direct effects on reproductive health.

Spence Pentland: Where did you want to go from here, Sean? Did you want to hit concentration, or did you have more to talk about erectile function? I saw you had a couple of notes there.

Sean Quigley: Well, what I have just mentioned, this whole notion of a libido and erectile dysfunction is a factor in infertility and reproductive health, especially chronic use. That’s also up for debate, how do we define chronic use. All of these studies have different parameters, and I assume that a lot of these studies are defining chronic use as probably something very little, something that maybe just everyday person wouldn’t necessarily define as chronic. Maybe you’re smoking once or twice a week, or a little bit at night to help you sleep, that could be considered a lot in a therapeutic model,

Spence Pentland: And as we see, it could be affecting a lot. We’ll get to some of that. Some of these studies are older, especially when they talk about smoking and human populations, partly like we said because of the legalities, and now that it’s opening up, that will change. The legislation people won’t go to jail for reporting these things, but we’ll move on to this study here.  It’s a quite well-powered study from 2015; it was published in Denmark, talking about reduced sperm concentration. There was over 1,200 men in it, they were between the ages of 18 and 28, which I don’t think I’ve ever had a patient that young, but maybe that’s just my practice. It should be noted that it was about smoking marijuana. There’s so many new forms now that we don’t know as much about, but you know they were smoking it more than once, if they were smoking it more than once per week, it was associated with a 28% lower sperm concentration. And combining weed with other recreational drugs, reduce sperm concentration by 52%.

Now, the other recreational drugs weren’t all divulged in the paper, but some issues that you noted with this, Sean. It’s to be of note that they had smoked marijuana in the last three months, these same people were also reported to have a higher alcohol and caffeine intake. They’re also more often cigarette smokers, and had – I don’t know how that’s quite the report – had been exposed to mother’s tobacco in utero, and had higher stress and sleep scores, and were less often born with their cryptorchidism – I’m not sure with that. But they had a higher prevalence also of STDs and use of other recreational drugs. So, this may not be quite the same in our typical older male factor infertility patient population, but it shows a possible trend with cannabis users, not to pigeonhole.

Sean Quigley: I think looking at that younger population is important because, like you mentioned, most men with fertility or subfertility issues do tend to be a little bit older, so this is a better sample, just to see maybe what’s going. Because, these guys weren’t coming out of a fertility clinic, or they hadn’t already been diagnosed with fertility issues.

Spence Pentland: But bottom line, our older population as well might be more affected by exposures, you know, 35, 40-year-ol. Anyway, just to be a little bit more technical with this study here, there main age was about 19, and 8% of them, it said had been responsible for a pregnancy in their life already. So, some of them were trying to conceive clearly, and among them, like 45% of them had smoked marijuana in the last three months, and 61% had smoked less than once a week, so that’s pretty low, and a total of, what did you say, 11% had used recreational drugs other than marijuana, 94% of them less than once per week, so that wasn’t a huge factor, but maybe it is as well.

Sean Quigley: Let’s just talk about recreational drugs for one sec. If marijuana, if cannabis is taken out of that, because we’re adding in a new parameter here, so, is alcohol there, are we talking about MDMA, cocaine? I guess, heroin is recreational, it’s kind of getting more serious, or whatever. I mean, my point is, these things too are going to be affecting your sleep, possibly your diet, stress levels, so all kinds of other physiological changes are getting affected.

Spence Pentland: I want to touch on that later, I know there’s a good segue that we’ll jump into, but just the slip piece and marijuana, because it is a common slippery slope with its “medical” use, but there’s a ton of research now. You had a couple other studies you wanted to chat about sperm concentration?

Sean Quigley:  This connected well getting into DNA changes in genetic, like the actual genetics of the sperm getting modified but, one study out of the US, in 2018, just last year found that the difference of 10% between users and non-users in DNA methylation, which is that process of altering the gene expression, and then possibly changing the function, depending, of course, which genes are getting altered, getting more complicated. I mean, how do we test for that except for – anyway, it’s challenging.

Spence Pentland: Clinical observation maybe for now, and a deep genetic study.

Sean Quigley: Yeah, but these same studies also did find the connection with lower sperm concentration. So, now we’re getting concentration and just genetic fragmentation happening. I mean, this is significant, because the genetics of the sperm, this is the crux really, because this is what we’re talking about in terms of recurrent miscarriage success rates for IVF. And then possibly, this whole notion of unexplained infertility, like, these are kind of parameters that unless they’re dug out really deeply, and a lot of fertility clinics, endocrinologists, and urologists, it just doesn’t happen that much what people are finding out about the genetics.

Spence Pentland: Or the DNA meditation, or these other things that we’re going to talk about, like fertilization capacity and stuff.

Sean Quigley: Exactly. And then just to support that, previously in Italy, a lot of these studies too, they’ve come out of Europe, just because of the categorization of cannabis in the States especially, but that’s changing.  2010 in Italy, again, the THC, so this would be more smoked, but again, finding DNA remodeling and damage in the genetics and also morphology. So, now, we’re seeing changes in the shape of the sperm as well. Again, all these studies, the last thing they’ll say is, given the effects, given the deleterious effects of cannabis, we recommend people taking a closer look at this, more studies need to be done.

Spence Pentland: Exactly. Again, we’re going to probably touch on that a million times because of the regulation. Let’s jump quickly into the fertilization capacity because it seems to be primarily that cannabinoids are affecting the concentration which we just talked about, but the fertilization capacity and the motility of the sperm, so just those are takeaways. I’m going to try and chew through a paper or a study that came out 2012 in Europe again (Lewis et al.) I think it was published in an online peer-reviewed journal, and to compare the differences between fertile and infertile men in the endocannabinoid system. So, a pretty deep dive here, which is great. But for 180 fertile and infertile men, they tried to determine the differences in their endocannabinoid systems, and it showed differences, again jumping back to gene expression, in the endocannabinoid system, and differences in the presence of cannabinoids in the seminal plasma. So, in my opinion, this may be a more accurate indicator of fertility than a traditional semen analysis. And I know we were talking about this before we pressed the record button, but which traditional semen analysis, most fertility specialists that I know don’t really regard it as an accurate measure of male factor infertility. It’s more a direction for treatment, you know, but the gene expression side may be getting more to the root of the issue. So, if gene expression is different in the endocannabinoid system and infertile men, versus fertile men regardless of cannabis use, then introducing cannabis pushes their systems too far obviously, or definitely theoretically could. And, again, it’s showing how important the ECS is to our understanding of reproduction and sperm function health.

The conventional semen analysis can’t really discriminate between sperm fertile and infertile men because men with poor semen analysis often father children.

Sean Quigley: And the date supports that, the data from that study as well. They did look at typical sperm parameters and the differences between fertile/infertile. This is significant. I think it involves a massive shift in how, guys like us, who do work with men and fertility, and getting other people’s wrapping their head around this kind of old notion. Okay, we got to start really looking at this differently.

Spence Pentland: Experts that I know we trust look at this test as, it’s not really useful diagnostically or prognostically – I mean, it’s reaching semen analysis again, they just direct treatment often. There is very little that western medical reproductive field model as to treatment with, even if there is these biomarkers that show possibly less fertility. We talked about it as well that during DNA fragmentation rates, the acrosome reaction and the endocannabinoid system gene expression – these are all things that are never really tested for.

Sean Quigley: No, very rarely. In fact, I know you’re based in Vancouver now, but I don’t believe any of the fertility clinics there do DNA fragmentation or even recommend it. You have to send it to the States to do it. I’ve been working with a patient here, who is working out of Toronto, and they have been doing DNA fragmentation testing at a fertility clinic, which is great because it just gives people a little bit of a deeper look and helps them. You know, the important part is just helping you figure out, okay, what changes do I need to make.  Or, like you said, how do we direct treatment. Is IVF or ICSI a better option, or do we make lifestyle changes for six months and see what happens.

Spence Pentland: Yeah. And DNA fragmentation, we know that the index can be quite high, the issue with the sperm even when a normal semen analysis is produced. In recurrent loss, some of these conditions that might be contributing, repeated IVF failures. The men already have such a little focus on them that, “I’m getting my wife pregnant, she’s miscarrying, the focus is on her.” All the testing, bottom line, might shed some light, and also, what I find mostly clinically is that something that men are quite good at, not necessarily getting into the clinic, but if a test shows something is off, often they will be motivated to make some changes, so it can be beneficial in that respect to do more extensive testing.

Sean Quigley: Yeah, suddenly everybody starts talking about antioxidants, and exercise, and testosterone, and yeah, people get into the details of it more for sure.

Spence Pentland: This also touched on the acrosome reaction that we are talking about.

Sean Quigley: Yeah, in the infertile sperm, and this is looking at infertility aside from cannabis use. Infertile sperm, there is a compromised capacity for the acrosome reaction, so this reaction as the sperm gets closer to the egg, that acrosome, that sort of shell around the head of the sperm has to go through a biochemical process so that it can finish its journey, so to speak.

Spence Pentland: And penetrate.

Sean Quigley: And penetrate. This is the key, without fertilization nothing matters.

Spence Pentland: True. I mean, if sperm can swim and get there, and there’s lots of them, and that’s where they fail – it doesn’t matter.

Sean Quigley: Maybe you want to touch on this study out of Buffalo that looked a bit deeper into this chromosome reaction.

Spence Pentland: Yeah. Let’s see, 2003, University of Buffalo. Sperm that was exposed to higher levels of THC show changes in the sperm enzyme cap called the acrosome, which we were just chatting about. So, exogenous THC reduced fertilization capacity of the sperm through inhibition of this acrosomal reaction. As it approaches the egg, it’s this biochemical reaction that Sean was talking about, just doesn’t seem to happen the same way, or happen completely, or I don’t think that’s exactly understood, but this study also linked it to a reduction in the normal vigorous swimming patterns that the sperm need to sprint, get to the egg. It was interesting because it reported that the sperm were like sprinting too early and burning out before they got there.

Sean Quigley: They were stoned.

Spence Pentland: They were stoned, they were overexcited. It was like they could see a 7/11 far down the road, start running, but they ran out of juice quick. The results also showed the both volume and seminal fluid and the total number of sperm from marijuana smokers were significantly less than the fertile control men.

Sean Quigley: Significantly, like again, this is from 2003, they’re talking about smoking the flower, THC levels as opposed to – I mean, this is a lot of the stuff we don’t know yet, like, all of these new ways of ingesting cannabis, and then also the percentages, things are getting more detailed in terms of what’s available to the public. And then, also medically, obviously, doctors can prescribe things in a very specific way.

Spence Pentland: I like what you said here too. That should be noted because so far we’re not shedding very positive light on cannabis use here for reproduction system.

Sean Quigley: Well, we’ll be doing a flip later.  

Spence Pentland: Yes, stay tuned for some interesting different perspectives. I like what you said about, it’s men who are most likely affected, likely have borderline fertility potential when they’re coming in to this. And marijuana or the cannabis use pushes them over the edge into infertility.

Sean Quigley: That study previously from the EU of 2012, just looking at the difference in the cannabinoid system and gene expression with fertile and infertile men, again regardless of cannabis intake, they’re already seeing a compromised acrosome reaction, like that’s an important point. And so that that cannabis use – something happens and things go downhill.

Spence Pentland: There was a couple other notes that you wanted to touch on – did you already speak to the acrosome reaction, just a couple other studies that you had dug up?

Sean Quigley: Yes. This whole notion of motility, so another study out of Italy in 2005, this is significant. Italy, again, does have a similar cannabis uses to Canada and the U.S., like one of the highest per capita uses in Europe. I’m guessing maybe that’s one reason why some of these studies are coming out of there, just as a society they were interested. Again, another one in 2008, out of Italy.

Spence Pentland: Down here with the mitochondria?

Sean Quigley: Yeah, that’s when it starts to get into….

Spence Pentland: How the motility is affected. It’s a bit of a deeper dive into its mechanism, and how the motility is affected maybe primarily through it, interfering with the sperm mitochondria. And that 2008 Italian study, there are a few Italian studies, but I’m guessing this was a deeper dive because they found that it affected motility in 2005. In 2008, they published something, they reported the capability of the endocannabinoids to negatively impact the mitochondria of many different cell types, not just sperm. They were focusing down on the mitochondria a little bit more. And the next year in 2009, in study and fertility and sterility, even a little bit deeper. How the mitochondria is being affected in it, and its mitochondrial respiration was being negatively impacted. So, when Delta8, Delta 9 THC was added to sperm samples. It showed immediately decreased cellular respiration or mitochondrial respiration when it was added to wash sperm.

But interestingly, when I read deeper into this study, the same effect couldn’t be repeated when it was added to unwashed sperm, so just a pure sperm sample. Maybe their hypothesis is that the seminal plasma could have some sort of protective effects, and that would implicate assisted reproductive technologies, and cannabis use may be more impactful in that arena. And that’s just my theory, I don’t know, because all the sperm that’s used in those procedures are washed.

Sean Quigley: Yes, absolutely. That makes a lot of sense to me. It’s fluid, it’s a system, there’s a whole bunch of different things in there. I think that this part of the information is, it feels to me like it’s the key. Because looking at differences between fertile men, infertile men, and how these traditional sperm parameters are not a reliable way. So, how do we dig a bit deeper, and maybe they found it. And maybe it’s this whole endocannabinoid system.

Spence Pentland: You just have to pull that one study there that checked all the different gene methylation, or DNA methylation, and gene expression, which was so clear between fertile and infertile.

Sean Quigley: Now, we’re going to move a little bit into how do people ingest. So, smoking versus, I mean, obviously now, there’s different ways, you can take oils, you can eat it, you can vape it, you can remove all of the organic material – it doesn’t need to be a burned experience, or smoked experience for anybody anymore. Study out of Korea in 2006 did find estrogenic effects, especially or particularly around marijuana smoke and cannabinoids. Their results suggest that marijuana is considered an endocrine disrupting factor, specifically this smoke and estrogen. Smoking may be the culprit, or at least a strong co-conspirator in terms of how is this affecting fertility in general.

Spence Pentland: Because of the estrogenic component, even outside of the endocannabinoid system.

Sean Quigley: Again, another hormone disrupting factor. Another one, this is an older one from 1983, again this one was interesting because they looked at cannabis extract versus smoking, and significantly they found that the extract did not have an estrogenic effect. Especially in terms of if people do need to use it medically, and if they are having fertility issues, it’s like, okay, at least, at the very minimum, you need to stop smoking.

Spence Pentland: Yes, as a first step. I don’t know about you, but I’ve seen a couple of maybe more stubborn males in my life, or I’ve actually never seen them, to be more accurate, I just hear about them through their wives. “Will he take a multivitamin?” “I’m not sure if he’ll do that or not.”

Sean Quigley: Or he doesn’t want to do that hippie stuff. So, maybe vaping over smoking, it might be a good first baby step or something. I wanted to touch on that hormonal dysregulation piece is separate from the endocannabinoid system. That estrogenic component, it is significant in my opinion. We’ve got a minimized bottom line, and this is another topic that we’ll go through environmental exposures, but we’ve got to reduce our environmental estrogenic exposures. Bottom line, and that can start with smoking less marijuana combustible. Bottom line, these estrogenics are also making people obese. They’re a contributor to that. Obesity lowers testosterone levels, or chicken-and-egg here. And anyway, particularly in Canada and the US, our regulations aren’t near as stringent on so many of these other estrogenic environmentalist estrogenic. So, where we can minimize them, we need to.

We all know I think in the field that men sperm counts since World War II, I think is the frame of reference most people use, has dropped significantly, but what maybe isn’t as well understood is that men’s testosterone levels did the same thing. Interestingly though, Sean,  male testosterone levels over history have been on a slow decline so maybe we’re becoming less Neanderthal, like more civilized as men over time, but it made a really drastic drop, and that could contribute to obviously spermatogenesis that’s not as optimal as it would have been at one time. And again these increased estrogen levels can be both lowering sperm and testosterone levels.

And testicles are particularly rich in estrogen receptors, so it’s essential that we at least have this message, and this is one of our conclusions – don’t smoke pot if you’re trying to have a baby. I should reference it here, but there was this estrogenic exposure enough of it. A study done out in Japan on Medaka fish – I asked a colleague of both of ours, a good friend that’s from Japan, she knows them well. A lot of research has done there on them.

Sean Quigley: Why do they choose that type of fish?

Spence Pentland: I don’t know, maybe there’s a lot of them. I’d have to get back to you on that. Since Theo Colborn talked about our stolen future, how toxins are affecting our fertility, etc, and he talked about these estrogenic exposures, causing a worsening of – full change in some sexual organs of fish. But here’s the clincher: it’s also worsening in three successional, or transgenerational, or three levels of generations into the future – the effects of the toxins worsening as time goes on. It’s crazy. Anyway, I mean, minimizing estrogenic exposure. That’s that takeaway, long-winded.

Sean Quigley:  Well, it’s how do you do it, it’s a challenge.

Spence Pentland: Stopping smoking, as far as what we’re concerned with here now.

Sean Quigley: Next, I think we’re just going to touch on a study that looked at IVF outcomes and cannabis use. That’s really significant, I think, this was out of the US in 2006, not only are we looking at fertility issues, but this one found men and women with any kind of history of cannabis use, resulting in lower birth weight up to 16% lower birth weight.

Spence Pentland: Wow. That’s just like smoking then?

Sean Quigley: A lot is going on there, like that previous study out of Denmark that looked at those young men that smoked, they also were more prone to maybe drink a little bit more alcohol, maybe smoke cigarettes, these other things. That’s kind of risk-taking that comes along with it.

Spence Pentland: And something else too, Sean, because the industry is so – this kind of just popped into my mind – because the industry is so new, and regulations are so absent most likely. When people are smoking and ingesting these days, they are buying it from legitimate shops, they have no idea what pesticides and chemicals and fertilizers have been used on the pot as well that could have endocrine disrupted.

Sean Quigley: Yeah, there’s no way to know. Hopefully, that gets better, and we presume that the government has regulations, and things are getting organized properly.

Spence Pentland: It’s bottom line here, we should touch on this as well. A slippery slope is corporate entities entering this multibillion-dollar green-tech industry, and all the decisions made aren’t going to be in our best interest, that’s for sure.

Sean Quigley: No, that’s for damn sure. None of them, it’s all about the bottom line.

Spence Pentland:  And this is big money, the next big gold rush, the Green Rush.

Sean Quigley: It is a balance too. As a last point about that IVF study too, another important thing they found was, women who had smoked in the year previous to IVF had 25% less eggs retrieved.

Spence Pentland: If we’re already looking at it in advanced maternal age and diminished ovarian reserve – that is just like an absolute negative.

Sean Quigley: It’s an absolute killer. They didn’t talk about mechanism of action, and they didn’t talk about what’s going on there, they were just looking at the relationship. So, who knows what’s going on there.

Spence Pentland: Sean, I want to jump down because we’re there, just because we’re touching on the female side there a little bit, through this study that was published in the National Academies Press out of Washington DC in 2017 on prenatal, perinatal, and neonatal exposures,  and what I got out of it, I know you and I kind of found some different information in it, that smoking pot obviously correlates with the lower birth rate which you were just talking about. But timing is important in there, there is no good timing obviously, but in the first trimester during organogenesis, toxic exposures can cause birth defects. And later on, it correlates more with goals restrictions.

The studies done on pregnancy obviously are small cohorts, small populations and mostly involves smoking. And those that did were usually confounded with other exposures, like alcohol and tobacco, which is terrible. But you found something in that study too about women and their cognitive function.  

Sean Quigley: I think it was also talking about the cognitive function of the baby, and this being affected too. I don’t know how they tested this, but they’re finding a negative effect essentially.

Spence Pentland: I think we go into some of the more mental health conditions here in a second, and just kind of some of the opinions on that, but let’s flip here, like we’ve been promising people, to the other perspectives and other positive effects that cannabis may be having on our reproductive well-being overall.

Sean Quigley: Yeah, more like outcomes, as opposed to biochemistry.

Spence Pentland:  To epidemiological research, or in this case, can I chat about this study that was done a long-term study that was taken from populations from 2004 to 2011 in the US. I guess, since medical marijuana legislation was invoked in many states that these people found, I think they are economics majors, or economists, I forget exactly. They found that since then, it led to increases in birth rate. Now, quote them, there’s this passage: “We first replicate the earlier literature by showing that marijuana use increases after the passage of medical marijuana laws. Our novel results reveal that birth rates increased after the passage of a law corresponding to increased frequency of sexual intercourse, decreased purchase of condoms and suggestive evidence on decreased condom use during sex. More sex and less contraceptive use may be attributed to behavioral responses such as increased attention to the immediate hedonic effects of sexual contact, delayed discounting and ignoring costs associated with risky sex. These findings are consistent with a large observational literature linking marijuana use with increased sexual activity and multiple partners.” So, my point here, it’s just interesting, these researchers, their economics process from Georgia State. We’ve got the note there. It’s possible that marijuana users are more likely risk takers, or/and that we can maybe find in genetics eventually, or marijuana increases risk taking, or people with higher levels of testosterone are possibly more likely to smoke pot and conduct risky behavior, so self-fulfilling prophecy anyway.

Marijuana also has some aphrodisiac qualities, with acute use. Many people anecdotally report that over the years, and I don’t know, this is fun, love this big picture view, because it took both of us, I think, when we found this out of our microscope, the impacts of cannabis because  so far we had nothing really good to say about cannabis in reproduction.

Sean Quigley: No, I mean, that’s amazing thing about it, it’s like you look at these biochemical details, and it all looks bad, but then, fertility outcomes and stuff don’t really tend to support that information. Marijuana’s used since like 1990, that’s from that Joe Rogan podcast. Since 1992, marijuana use has just steadily increased and spiked in the 2000s, and now it’s just kind of plateauing. So, if cannabis was having such an effect on fertility, we should be able to directly correlate that with such an increase in cannabis use. But we’re just not seeing that.

Spence Pentland: The takeaway there is that, yes, what we’ve been talking about so far, theoretically, and in many studies, and in particular smoking, it most certainly has the potential to affect the endocannabinoid system. And therefore, malefactor fertility, and estrogenic component, and endocrine disruption could also be impacting, but overall maybe people are having more sex if they smoke.

Sean Quigley: Maybe, well, there was another good study out of the US in 2018, this is the Journal of Obstetrics and Gynecology, but again, they found very little, or no association between female or male marijuana use and the ability to have babies. So, increased marijuana use is not leading to less babies.

Spence Pentland: Something that comes to mind there is that in the population of patients that we see, that fertility clinics see, that are struggling with fertility – that is, again, where I loved how you put it, the men that have maybe borderline fertility that are partaking in cannabis use could be being pushed over the edge in that, especially with advanced maternal age as well. And again, more studies with how it’s ingested, vapin, eating.

Sean Quigley: I think more studies and creating cohorts that are more age specific as well, that would be important to tease out some of these details, because these ones that showed an increase in birth rates, from 2004 to 2011 in the US, a new medical marijuana legislation has changed, so we know how old are these guys, right.

Spence Pentland: Exactly. One indicator right here is that there’s a good chance that they may or may not have been married for a long period of time, or have been trying to conceive for a long period of time, because it said something about frequent marijuana use, more than once a week, being correlated with men reporting intercourse more than four times a week. I’ll leave that to everybody’s own conclusion making.

Sean Quigley: It’s a good point. That’s the reality. I think a lot of people, when fertility starts to shift around the mid-30s, they’re traditionally, and maybe you’ve been in a longer-term relationship, you’re a bit older, your libido – everything’s just changing. You’re a more stable. Even once a week marijuana smokers are probably not having intercourse four times a week.

Spence Pentland: Unless they’re 19.1, whatever the mean age of that Danish study was. You listed a paper from 2019, pretty new in human reproduction here. Recent news, I think it was Harvard press.

Sean Quigley: So, that was the big one that popped up in everyone’s newsfeed at the beginning of this year. All of a sudden, it was on the news, and people were like, “Oh, let’s smoke pot because it makes me have more sperm.” They did find that this was at a Harvard, just published in January of 2019. Men who have smoked marijuana at some point in their life, which is so arbitrary, and what a broad parameter – I don’t even know what that means. At some point of their life, they had significantly higher concentrations of sperm when compared with men who had never smoked marijuana. So, what’s your takeaway from that?

Spence Pentland: I could go far off with theories on that. Bottom line, again, it’s positive effects findings that we had, and we also don’t want to scare people away from, like recreationally, like experimenting with their friends, or their wife occasionally, in some sort of maybe ceremonial respect or something. Marijuana, it’s not evil, it just should be used with ration, depending on your goals in life.

Sean Quigley: Yeah, he authors here try and get their heads around a little bit, but one of their interpretations was that men with higher testosterone levels, which, you having higher testosterone levels may lead to a better sperm concentration in general, but that also leads to higher risk-taking behavior. So, people just more engaged with risk takings of marijuana, they are super crazy dudes, but also at the same time, their bodies are just hardwired a bit better to make more sperm.

Spence Pentland: And maybe more resilient in some respect. What we’re hearing more and more, and understanding more and more, is how important testosterone levels are, and women know their hormone levels are paramount to their health. We’re finding the same with men, so if testosterone levels are higher, and haven’t been affected quite the same as that large drop since World War II, they just might be more resilient to fending off environmental exposures.

Sean Quigley: It could be. One of the issues with this study, and we’re talking about lower concentration or higher concentration in marijuana smokers, but this whole sample, 662 men out of this in this study, the entire sample of men were from a fertility center, they had already been treated or diagnosed with subfertility, like already having fertility issues. So, really, to get a true idea, you’d need more of a random sample.

Spence Pentland: Anyway, more research again. That’s our positive side. I wanted to jump back to where we had mentioned cannabis use in mental health. There’s a good paper written here, and I’d have to quickly click in because I forget the date and location, but I think it summarized things nicely, the European Archives of Psychiatry and Clinical Neuroscience. I think it was 2019, so this is really recent risk-benefit here for cannabis use. Important notes were, they talked about at-risk populations, and younger people could face more negative and cognitive psychological impacts for cannabis use, but certain populations may also find benefits in cannabis use for certain things. Again, more research is definitely needed, not enough evidence exists to know who should be picking what, and how much or for how long these things are the basics of most medicine, you know, dosage and administration, so again caution should be taken. We all know, if you’ve ever used THC, the active component, psychoactive component, you know there’s intoxication in that. Obviously, it could be correlated to psychosis, so there are correlations there. CBD, what people think was interesting to me here, and everyone thinks is so safe, but larger doses had dissociative effects. CBD, THC dosage, administration, how it’s being taken, ratios of the two – all these things are hopefully stuff that’ll be researched more now that there’s a deregulation.

But bottom line, in my opinion here, to the cannabis disturbs sleep, both REM and non-REM stages. And just going down a rabbit hole, I’ve been doing a lot of studying of Dr. Matthew Walker’s work, he’s a head of neuroscience and sleep research out of Berkeley California, and his bottom line is that any biological function is negatively affected by poor sleep. And I know a lot of people are using cannabis for sleep, but it’s pretty conclusive in the research now that it is actually disrupting sleep. It’s like very similar and has physiological effect like Ambien, or other sleep medications that get you to sleep. But really, your sleep stages are quite disrupted, and I just wanted to touch on a couple studies: the negative impacts of insomnia raise cortisol and inflammatory cytokine levels, it decreases testosterone levels, there is also a connection between sleep and decrease sperm parameters, and also the nitric-oxide pathway, which is responsible for blood flow to our penis and our erections, aka Viagra’s mechanism. It also gets worse with age – there’s just so much associated with sleep. Interestingly to the DNA fragmentation can have negative impacts with poor sleep, and something else that has motivated me, often people will crash so hard when they drink or when they smoke pot. And if they’re carrying a little extra weight, they’ll sleep on their back, and sleep apnea is so common. Just start asking your men.

So much so that we’ve put in our forms that if your partner has sleep apnea, and is disturbing your sleep, first thing you got to get them out of your room, so you can sleep. But B, you get that checked because sleep apnea in this one study that I’ve found here is directly associated with decreased sperm quality, not to mention the plethora of other things that poor sleep – Dr. Walker goes through that poor sleep can impact, from hormones to cognitive abilities performance, reproduction, emotions, your microbiome, you name it, any biological function is negatively impacted. So, marijuana is not good for sleep, you got to find other ways to get to sleep, and so that’s my take away with that.

Sean Quigley: You also get that what Dr.Walker talked about, that rebound insomnia effect. Your system starts to rely on it to get to sleep, and then when you try and pull back, and stop, suddenly, you get a little bit more agitated at night, and sleep gets more difficult. It’s a circular issue for sure.

Spence Pentland: I wanted to jump to this 2004 UK study that was kind of weird – cannabis and other lifestyle effects on sperm morphology.

Sean Quigley: 2014.

Spence Pentland: Yeah, sorry. It was a systematic review, and it ended up showing the most lifestyle habits have a little impact on sperm morphology, which is, if you know anything about sperm morphology and how difficult it is to understand itself and its actual impact on fertility, is another story as well. No one’s really quite sure, but what it did find is that samples given in June to August, and men, who used cannabis in the three months prior to their sample, were more likely to have morphology of less than 4% normal forms. And all the men that were there in that study had been trying to conceive for more than 12 months.

Sean Quigley: That is interesting. Do you think that’s connected with the summer months and the heat? Or, like, why that time of year?

Spence Pentland:  Yeah, that makes sense to you and I in Chinese medicine. The number one enemy for sperm is heat, cooking our balls is the number one enemy.

Sean Quigley: Especially in terms of what can we control as well. Or, at least to some extent.

Spence Pentland: Absolutely. Maybe it’s time for conclusions, because there’s so much more we could kind of dive into and discuss, but I think we’ve done a nice job of covering things, but to try and wrap things for people here. The bottom line for me is with legalization, particularly Canada and Uruguay very interestingly, for recreational use, and the United States more and more leaning toward that, and Europe, more people will be using cannabis.

In a harm reduction paper that was published this year as well and current drug research reviews by Mefferd et al in Palo Alto, I thought it was great, and some of the things they went through, I had some thoughts there too, and Sean, please chime in. There’s currently no accepted medical uses for treatment, resulting in dosage and proper research just not being done, due to it’s still not in the U.S. at least, being scheduled as drug, like you had mentioned before. And until this legalizations happen proper research on the use of cannabis for medical purposes, and its efficacy remain up-to-date largely anecdotal in small sample sizes, and largely smoking, which you and I talked about because vaping and ingesting is relatively new. These small sample sizes, any study that’s done with very small sample sizes is really susceptible to the researcher bias, what they kind of want to find out. And to date, like we said before to call for-profit entities, like haven’t really had an interest in swaying research, because why bother, but now that this green tech era, this next multi-billion dollar industry grows, we need to watch the money trails of the research that’s coming out in the years to come, and understand our sources. And that’s important with any research, just as a takeaway, to anyone listening, don’t just read a paper and take it as the gospel, or start putting headlines on the newspaper about it. Because without digging a little bit deeper and finding out the size of the research, and the money trail largely, and the sources, and the reputation of the other researchers.

The other thing that you wanted to touch on, the slippery slope to abuse that legalization has, like specially, in patients who will self-medicate their mental health conditions, Sean?

Sean Quigley: Well, hopefully now that it’s opening up, and you can talk to your doctor about it, that needs to be the way people want to approach, if you are self-medicating. “Ok, I’ve been using marijuana for anxiety, for sleep, for inflammation, any of these uses, it’s like, well, why don’t we change our model a little bit, and let’s talk to a doctor, someone who knows.” So, you can figure up the dosage, and you can figure out the ratios that are going to help your condition. I mean, recreational use is something else. I believe that any country that has legalized, including Amsterdam, which has been decriminalized for many years, and marijuana use hasn’t increased. And importantly, with sort of young adults and teenagers. I think it’s still up in the air, in terms of what’s going to happen with that. I mean, Canada and the U.S. already have significant – I think it’s 15-16% of that population will at least admit to smoking cannabis, but probably a lot of that’s underreported. So, who knows, it could be 20% or more.

Spence Pentland: And you touched on going to your doctor, and that’s great. I honestly know very few physicians that are digging deep, even our industry, and that’s why it’s important that people like you and myself, and our teams here that have done some pretty deeps. A lot of the female practitioners that work with, also we’re diving into the female side more too. The use of cannabis has remained in the realm of like shamanic healing. And healers would be more understanding of dosage, and the experiences, and the negative impacts, and the basic pharmacokinetics of cannabis. I think we’re in this gray area right now, where no one knows a lot, and we’ve got corporate interests moving in, and just bottom line, a lot of caution should be taken moving forward because of the possibilities, like we talked about, with reproductive disturbance, the sleep disturbance that we talked about, at-risk populations with adolescents, and the research showing decreased frontal lobe functional activities, and increased risk of psychosis among genetically susceptible populations. But also, it’s going to have some really great benefits I’m sure.

We already see some of the side effects of cancer and epilepsy, showing amazing promise, far outweighing the risk in those populations.

Sean Quigley: Yeah, absolutely, helping with nausea, helping to improve appetite, pain reduction, seizures.

Spence Pentland: We know in our field again here that THC crosses the placenta, so pregnant women, for that reason and others that we talked about, need to be very cautious. The elderly might be another high-risk population because the boomers are all maybe going to be jumping in full force and spending some of their retirement money on this new green rush, either investing in it or using it. A nice paper that I read on eight related issues by a cosegent et al that talked about, there’s a good likelihood that it could hasten age-related declines we just don’t know. Or interactive drugs, or increased cardiovascular disease risk.

Sean Quigley: Yeah, considering what you know, what you laid out for everyone at the beginning of our talk, just how important this and the cannabinoid system is, and how prevalent it is in so many of our tissues and functions in the body. It’s profound.

Spence Pentland: I mean, bottom line, just step back and say, “Wow, anything that can intoxicate like that has got some strength and power to it. And people with propensity to addiction, that’s going to be another area. I know you said Amsterdam use has an increase, but I wonder when things became legalized to start with if there was a sharp increase in use and then it plateaued. Budney et al showed a dependency similar to other drugs and alcohol. So, there’s for sure going to be people that are more likely to fall into addiction and having issues with ganja as well. Basic risks: don’t drive, caution with dose, CBD, THC, ratios, you know, education, education, education like research. Listen to a podcast like this, there’s lots out there, it’s a hot-button topic. Smoke versus other administration routes, if you do one experiment, maybe micro dosing with someone who has an understanding of the of cannabis, there needs to be labeling standardization, possible known drug interactions – these all have to come with more research. And hopefully, that’s going to be happening. As we can see, with all the info presented, regarding reproductive health and the potential impact, we should definitely proceed with caution, and encourage our patients and all people to be smart about this Green Rush. It’s a corporate push that might captivate us to some degree, but I think Sean and I would agree that if you’re having trouble conceiving and you are using cannabis, it’s time to stop.

Sean Quigley: You just need to accept that it could be a factor.

Spence Pentland: Take it up again later in life if you really need to. Your goal is a baby. You should put down whatever cannabis.

Sean Quigley: Especially, given that idea of that gene expression in infertile men is already kind of compromised, in terms of the endocannabinoid system. And then with the addition of cannabis, it’s just too much for the system to handle.

Spence Pentland: Yeah, reproduction, sleep, cognitive behavior, learning, performance, I mean the list goes on, likely any biological function that we have would be impacted to some degree by cannabis. So, if your goal is reproduction, and you’re having difficulty, it’s time to lay down the cannabis. Sean, until our next section, thanks for the deep dive.

Sean Quigley: Amazing, thanks so much for inviting me.

 

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