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Project CBD: I’m Martin Lee with Project CBD, and today we’ll be speaking with Dr. Bonni Goldstein. Dr. Goldstein is a pediatrician and a pioneering cannabis clinician. She’s the director of Canna-Centers, a California-based physician network that focuses on cannabis therapeutics. And Dr. Goldstein is also the author of the highly recommended book Cannabis is Medicine. Welcome Dr. Goldstein.

Transcript

(This transcript has been slightly edited for clarity.)

Dr. Goldstein: Good morning, Martin. Thanks for having me.

Project CBD: My pleasure. I wanted to talk to you today about an article you co-authored which was recently published in the journal Cannabis and Cannabinoid Research. Let me start by reading the title of the paper: “Cannabis Responsive Biomarkers: A Pharmacometabolomics-Based Application to Evaluate the Impact of Medical Cannabis Treatment on Children with Autism Spectrum Disorder.” That’s an intimidating title, I think, for someone who is not a doctor or a scientist. So maybe you can explain in a broad sense what the findings are and what is “metabolomics”? What does that mean, and how is it related to cannabis?

Dr. Goldstein: Sure. Just the same way that we can draw bloodwork to measure white blood cell count or how much sodium you have in your bloodstream, we can measure different types of chemicals in the body. And these chemicals reflect the pathways and the changing chemical nature of kind of how cells are working.

So, a couple of words that need to be defined: Biomarkers. What we’re using is something called cannabis responsive biomarkers – these are just chemicals in our body that are part of chemical pathways that help our cells functions. For instance, one of the biomarkers that we measured is what’s called “spermine” – funny name, but it’s called spermine –  and it has been associated with inflammation and pain. It’s a chemical that can be picked up in saliva, in blood, and it can be measured. By establishing – just the same way when you measure white blood cell count in somebody, any time you get infection or you get a doctor check-up – every year they check what’s called your CBC, your complete blood count. Doctors look at your white blood cell count to make sure your immune system is functioning. It’s a reflection of what’s going on in your body.

If you were to have a bad bacterial infection, your white blood count would be elevated, that’s a tip-off to a doctor, okay, we have to start looking for some serious bacterial infection. If your blood count is low, it may reflect some other pathologic illness. And of course, we have what’s called the physiologic range. So, your white blood cell count will vary, and normally it’s between for most people 4,000 and 12,000 cells. When we measure it, we can see if you are within normal limits. The idea is that you have all kinds of chemicals in cells in your body that can be measured.

Classically biomarkers are used to look at someone’s response to chemotherapy or to cancer treatment, or even to reflect the presence of cancer. So, in men, a very common test is the PSA (the prostate specific antigen) and you just do a blood test and you can see if that’s elevated – that’s a tip-off, maybe there’s something going on with prostate cancer. And then, let’s say someone has an elevated PSA, they get diagnosed with prostate cancer and they go through treatment. What do doctors follow to see if their patients are doing well? They follow that PSA. And of course, you want your number to be a certain number. You want it to be within that what we call often “within normal limits” or what is really determined to be the normal physiologic range.

What we did in this study was we took children who were what we call neurotypical or typically developing, and we collected saliva looking for various and specific biomarkers. And we measured hundreds of biomarkers and kind of got it down to about 65 total biomarkers that we could really look at. And then we found about 31 biomarkers in our group of patients and we measured their biomarkers for autism that actually showed some relevance to the autism and to the cannabis treatment. And we were able to establish this physiologic range for the children who are neurotypical or typically developing. And then we compared the biomarkers in the children with autism with that physiologic range. Meaning, do their biomarkers fall within this? If they fall outside of it, does cannabis treatment correct it back into the physiologic range?

Ultimately what we found was that all of the children – it was a very small group, and that’s of course one of the limitations, we only had 15 children with autism participate – but we were able to show that with cannabis treatment their biomarkers corrected toward, trended toward shifting to that physiologic range, which was really fascinating.

Project CBD: I think this kind of data that you compiled from the study sort of buttresses what would otherwise be thought of as anecdotal or subjective accounts of improvement, which are considered generally of lesser value than other types of evidence. But here you have actual data showing no, it’s not just the person saying how they feel – there’s some movement in the cells, as you say. So, what would be some of the cannabis biomarkers specifically? You mentioned spermine. Were there others that were particularly relevant?

Dr. Goldstein: In the paper, we have 20-30 biomarkers that were significantly shifted. But, in the paper we were limited word-wise, so we talked about three particular biomarkers. One is called N-Acetylaspartic acid (NAA). And if you look at the scientific literature there’s evidence that NAA is – well we know that it’s a very prominent neurochemical, it’s an amino acid, and it is relevant for multiple reasons in that there’s evidence that, in fact, there’s a disease where if you don’t have it you basically don’t do well, it is terminal. You don’t have good brain function. You have some dysfunction within the brain. It’s involved in neuroinflammation, in laying down myelin, which is the coating on the neurons that’s very important for neuronal function.

And so, what we found with NAA was that – and what’s interesting by the way before I get into the findings, is that from my research on NAA, they talk about it’s not good to have too little and it’s not good to have too much. You want to have it balanced. You don’t want a deficiency and you don’t want an over. So, what’s interesting is that in the children that had their NAA measured that was out of whack, whether it was under or over, taking their medical cannabis treatment, an hour and a half later when we collected the saliva and re-measured, it shifted more to the physiologic range. If it was under it came up and if it was high, it came down. Which is so interesting because that’s what we talk about with cannabis, is helping to balance and create homeostasis – that kind of shift – not under, not over but everything leaning toward the middle. That was kind of interesting.

There are studies that show that people with a diagnosis of Asperger’s – there’s one study that shows that people with Asperger’s may have higher levels of NAA, and that other people with autism may have lower [levels]. And the only way, by the way, to measure it previously – remember it’s a neurochemical – was they were using functional MRI scans and so on, very high technology. This is from spitting into a tube, which is relatively easy to collect for most patients. It’s interesting because that particular neurochemical, again, has been shown to be an abnormality in this specific group, in people suffering with autism spectrum disorder.

And I mentioned spermine was one of the other ones that we talked about and that has to do with inflammation and pain. And I’ll share with you that I have a lot of families that have non-verbal children with autism, who have difficulty communicating. And many of the parents will say their child – they must have pain somewhere, the child seems uncomfortable, the child is crying or shouting or having a lot of difficulty. And this is very interesting to me that the spermine was high in many of these patients or very low, and then again shifted toward the physiologic range.

Then we looked at another one that we documented, what’s called DHEAS, dehydroepiandrosterone, which is a hormone, like a precursor that leads to male and female hormones. And this has been associated with, especially in males with aggression. And we found this was a cannabis responsive biomarker as well in our patients.

Project CBD: You say the dozen neuro-atypical patients that were part of this study, once they are administered the cannabis-based medicine, whether it was too high or too low in terms of what the biomarker shows, they’re coming toward normal, in either direction. Was it always the same remedy? People talk about CBD of course, that’s been a hot thing now because it’s not intoxicating.

Dr. Goldstein: That’s a great question, Martin. What we did in this study – and the reason I was involved was because I take care of a lot of children with epilepsy, autism, and so on – and when Cannformatics, which does the technology, approached me, they were looking for children to participate in this study who were already on a regimen of cannabis that seemed to be helping with either the child or the parents saying, as you mentioned earlier, anecdotally “my child is better, my child is doing well.” And as we all know the scientific community doesn’t accept this as evidence – someone saying they feel better is not evidence to the scientific community. We want to see numbers, scans, something that shows better or improvement. And that it not only that it’s there, but that it’s statistically significant. And what we mean in the scientific community when we say “statistical significance” is that it’s not some other factor or just random or by chance that we found these results.

So, what we did in the group is we recruited ages 6-12 with autism who were on a cannabis regimen where they were showing improvement, and at least it had been stable for over a year. Now, we may have made some changes during that year, but the patient was showing ongoing continued benefits from cannabis medicine based on not only parental reports but reports from therapists and teachers. And the reason we recruited these patients was because, as you know, it’s not one size fits all (I steal that from you!), cannabis medicine is very personalized and customized. And when you very first start out on cannabis, what I call the cannabis journey, it can take months sometimes to figure out what works best for any particular individual.

What we didn’t want was in our population of patients, we did not want to have patients who were switching things up and who were having bad days, and here we are coming and trying to measure something, but they’re not showing a response. We wanted to document in these patients that were showing benefits, that it correlated physiologically – that there was a correlation between the chemical underpinnings and what the parents were telling us. And it’s very important to point that out.

It can take time. Some of these patients have been on my treatment for longer than one year – three years, five years – before we really found a nice place. And then you have to remember too, autism is a spectrum disorder. So, there is no one size fits all, because patients have different symptoms. Some children are very aggressive and some are never aggressive. Some patients are fully verbal and some are completely non-verbal. So that’s why it’s a very heterogenous population to study, and it can be difficult to draw conclusions.

I just want to point out that we collected saliva in the morning before they got their morning dose of medical cannabis. And then we collected the saliva again at around 90 minutes, and that correlates to when the parents said we saw a child responding to the medicine. And by the way, in the paper Table 1, which you’ll find on page 3, it lists the children by age and how many doses a day they were taking, and what the cannabinoid makeup was. So CBD, THC, CBG, CBN, THCA, and CBDA. And when you look at that chart, they’re all over the place, because again it’s personalized to them.

Project CBD: There was just a study I think that came out of Israel focusing on autism and I think the conclusion or the upshot was THC works better than CBD. Are we looking for the best cannabinoid here? Or, as you say, it’s really a combination that’s going to work best and the combination may shift from person to person?

Dr. Goldstein: Right. It depends on who you recruit into your study. If you recruit only children who are highly aggressive, I would agree that THC plays a very large role. But if you recruit into your population of patients in your study that half are aggressive and half are not, you’re going to find something that may not run through all the patients. I mean there is some correlation that I use clinically. Somebody comes in and says my child’s tearing up the house and beating us up, and is highly self-injurious, I lean more toward initiating THC earlier unless the parents have some other information or a preference not to use THC. But that would have me lean toward using more THC than not. Or at least as part of the mix.

I’ve never been afraid to use THC in my patients. And you have to remember too that there are now a number of studies that document that children with autism have low levels of anandamide, which is a natural endocannabinoid that we make, which I love that you call your inner cannabis compound. When you have low levels, a deficiency, you have to remember that for anandamide CBD is not a direct replacement for anandamide. It can help make the body’s own anandamide work better, but for some patients they need THC because as we know from Dr. Mechoulam and others, THC seems to be the direct replacement for anandamide.

I want to make it clear to anybody listening, my patients are not walking around stoned and incoherent and impaired. Some patients, the parents will call me, oh we upped the dose and his eyes are a little red and he seems a little silly right now. We make very tiny changes and we try to avoid any kind of making the child uncomfortable or impaired. But I will tell you that many of these patients because they are deficient in anandamide, they can handle a lot higher doses of THC than most adults. And we also know from a study that it looks like children do not have fully developed cannabinoid receptors, so they may be less sensitive to the effects of THC. And remember, what we’re trying to do is kind of feed the brain just that little bit of trigger at that receptor to help send that message of homeostasis.

Project CBD: You indicated when we talked earlier that you accumulated a lot of data as part of this study, much of which didn’t make it into the paper. Can you give us a hint of what’s in store, of what’s next? Will there be other research papers published based on this work that you’re doing?

Dr. Goldstein: So, we are planning to publish a second paper based on the same group of patients because we measured so many biomarkers and there were so many interesting and significant results that we couldn’t pack it into one paper. The next paper being published is looking specifically at what we call the lipids, the lipid biomarkers, those that fall into the fatty acid category. What’s so fascinating about that, and what’s fascinating about the result is you have to remember that our endocannabinoid system is mostly made up of compounds that are fatty acids, anandamide and so on. And remember the compounds from the cannabis plant, the phytocannabinoids that we’re using to help feed this system are also lipophilic fatty acids. We want to be able to – we’re going to publish that data to kind of show that these compounds that are changing in response to the cannabis treatment, not only does it affect other areas of the brain but also within that endocannabinoid system.

Project CBD: My last question Dr. Goldstein is, what implications does this type of research focusing on metabolomics have for cannabis therapeutics in general. As far as I know, I don’t think there’s been a study done like this. How applicable would this be for other conditions, not just autism?

Dr. Goldstein: We’re hoping to do a study looking at the pharmacometabolomics for those who are using cannabis to treat neuropathy, which is nerve-based pain. Hopefully that is another study that we’re doing down the line. But the way to kind of look at  pharmacometabolomics, is it’s a way to look at how your body is responding to a particular intervention, to a treatment. It’s interesting because this technology has been used before, like for instance, it was used to look at one particular cholesterol lowering drug, and how –  and it’s pretty technical, so I’m just going to kind of glaze over it – how people with certain gut issues, how they metabolize their cholesterol lowering drug, and why they may not fit with that drug.

So, pharmacometabolomics can look at, not only drugs but also just your own baseline chemistry and your response to drugs. Cannabis here is the drug we’re looking at, right. But really what we’re looking at is the underlying chemical response. I foresee this technology potentially to help with optimizing treatment and measuring response. So, if I have a patient who is brand new to cannabis and has not been using it, I can get a baseline profile of their biomarkers from saliva. And then three months into treatment I can then collect saliva again and look and see what seems to be beneficial, what’s improved. Are there biomarkers that are still off the charts that we should be addressing with certain cannabinoids? Like if we haven’t tried CBDA, am I noticing a trend in patients that CBDA helps to balance a particular biomarker that reflects, let’s say inflammation.

What we’re hoping is to expand this technology, and basically it’s just another way to measure. Am I seeing improvement? Not everybody gets better with cannabis. And one of the things I would love to see is: What are we missing in these patients? Why isn’t their body responding? What is happening? Why do only some people respond? I think this is just a tool. Rather than me sitting here trying to think of why the patient isn’t responding, I can have some objective data that I can look at and say, ‘Oh this is interesting, all the children with this biomarker that’s off the charts are not responding.’ Well, that’s interesting. What does this biomarker reflect in their chemical pathway? What if they’re missing an enzyme? What if they are low on a particular mineral in their body and we can correct that? I mean the whole goal of this is to try to achieve more knowledge to be able to help these patients get a response from cannabis, but also other medicines, as well.

Project CBD: It’s really fascinating. And very encouraging. We look forward to hearing more about what you’re coming up with, and good luck with all of this. Thank you Dr. Bonni Goldstein.

Dr. Goldstein: Thank you, Martin.

Copyright, Project CBD. May not be reprinted without permission.



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