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RESEARCH BREAKTHROUGH: CANNABIS & AUTISM


RESEARCH BREAKTHROUGH: CANNABIS & AUTISM

An interview with Bonni Goldstein, MD
An interview with Bonni Goldstein, MD
Byline:
Project CBD
By Project CBD on January 25, 2022



TRANSCRIPT: RESEARCH BREAKTHROUGH - CANNABIS & AUTISM


AN INTERVIEW WITH BONNI GOLDSTEIN, MD

(This transcript has been slightly edited for clarity.)

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.

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.

Pharmacometabolomics is a way to look at how your body is responding to a
particular intervention, to a treatment.

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.



Related story
Autism and Endocannabinoid Dysfunction

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.

We were able to show that with cannabis treatment their biomarkers corrected
toward the neurotypical physiologic range.

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.



Related story
Autism, Rare Cannabinoids & the Endocannabinoid System

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’ve never been afraid to use THC in my patients. Children do not have fully
developed cannabinoid receptors, so they may be less sensitive to the effects of
THC.

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.

Revision date: 
Jan 25, 2022

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autism.” Published in Nature, the study found that just under a third of
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improvements while using CBD-rich oil derived from cannabis (30% CBD, 1-2% THC).
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Tags: 
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