
Prenatal THC exposure yields hyperdopaminergic phenotype rescued by pregnenolone - bookofjoe
https://www.nature.com/articles/s41593-019-0512-2
======
spraak
My wife spent months in the hospital due to Hyperemesis Gravidarum (a disorder
during pregnancy that causes continual vomiting and nausea. My wife vomited up
to 40 times a day, eventually vomiting blood and breaking vessels in her eyes.
She survived on a banana bag and lost 20% of her pre-pregnancy body weight.
She said HG feels like being on an unending roller coaster while you're hung
over and have the worst flu of your life). We lost the first baby. The second
pregnancy was only survivable due to cannabis. It was risk we knew but 7 years
later our child shows no signs of developmental disorders. I know, N=1, but
still worth sharing.

~~~
silencio
fellow HG sufferer (survivor?) here. i was on multiple medications since week
5 trying to prevent hospitalization, and still on zofran six months in.
careful use of medications can be literally lifesaving.

but... i would say due to easier access and state/local legalization, the
perceived use of cannabis has skyrocketed in all my pregnancy groups. much
much more than 3 years ago with my last pregnancy, i imagine worlds different
from 7 years. most pregnant people seem to be using it casually, even more so
than alcohol or tobacco. i do have to wonder what we’ll see from this trend,
and i’m generally glad for any research to define safer amounts of
consumption.

~~~
spraak
Yes when my wife was pregnant it was not common at all to use it during
pregnancy, and was barely even medically legal outside of pregnancy. She
became allergic to Zofran, Diclegis (?) didn't work, and neither did any of
the other commonly used HG medicines.

------
notafraudster
I'm not a neuroscientist, I'm not a smoker, and I'm not a woman. The headline
result seems like it could be plausible. However...

My first instinct reading the abstract is that the conclusion which finds an
effect on male rats and not female rats is an unjustified subgroup analysis
and likely a spurious result.

Given the sexiness of the topic (people think weed is harmless, but what if
it's not), publication filters for stat. sig results, low a priori power, no
adjustment for multiple comparisons, no pre-registration, and this bizarre
subgroup contingent result... should we expect this to replicate?

Is there a strong theoretical basis for expecting the subgroup heterogeneity?

~~~
Obi_Juan_Kenobi
You think that sexual dimorphism doesn't apply to .. brain development?
Frankly, it's absurd to claim that's an inappropriate subgroup. There are
certainly valid criticisms to this particular paper, but this sort of analysis
is standard and eminently justified for mammalian development work.

I'm also not sure what 'low a priori power' means. Statistical power is well
defined and depends only on the sampling involved. You don't need to make any
assumptions about it, Bayesian or otherwise.

As for the statistics, if anything the low p-values they get are even more
impressive given the modest power of these analyses. The effect size must be
enormous. Granted the gross PPI response didn't give a dazzling p-value, the
followup is quite convincing, showing obvious quantitative changes by a number
of metrics, particularly the NAcS Dopamine time-response.

I'm curious where you think a multiple-comparison adjustment needs to be be
made. The authors are quite focused on a narrow analysis of the systems
implicated in observational PCE studies.

Where I agree is that I would like the authors to have discussed the sexual
dimorphism to some degree. It would be handy to know if there is any pre-
existing literature that suggests that PCE affects males more than females;
all that I could find was one that found effects in females, not males.
Someone in the field likely has some reasonable ideas about what might be
going on. However, I'd hesitate to say the issue is avoided; Nature has strict
length requirements and such a discussion would necessarily be somewhat
meandering.

~~~
notafraudster
I think there are probably three things I want to follow up on:

1\. I do not believe sexual dimorphism is necessarily irrelevant here. I do
believe that any subgroup analysis is a researcher degree of freedom and an
avenue for p-hacking or fishing. Ideally subgroups would be well specified in
advance: particularly the expectation of an effect in male rats and a null in
female rats. Given that this did not happen, I would expect in-text
justification for the subgroup analysis. I assume there are many brain
development processes which are sexually dimorphic, and many which are not. To
trust the study I need to know that this is one such case without reference to
the study's results. Your end-of-post comment suggests that dimorphism is
valid to explore, but the dimorphism should favour effects in the opposite
direction, which causes me to further doubt this study's results (in this
statement only I am introducing a Bayesian notion of belief)

2\. By "low a priori power" I mean that the number of units they chose would
typically not be well-powered for modest effects in the subgroup. I am not
talking about anything Bayesian. If I knew nothing about this subject, but
picked a modest effect size on the quantity of interest and did a power
analysis, I would find the study is well under 80% powered to detect the
effect. That the effect was detected in the actual study should not lead us to
say "wow, if it was underpowered but still detected, the effect must be huge",
it should lead us to say "wow, this effect is very sensitive to any kind of
confounding". This raises additional study integrity concerns and
replicability concerns.

3\. There are different points of view about multiple comparison adjustment.
In the absence of pre-registration, I am inclined to believe that even closely
related hypotheses that are all well justified theoretically should be
adjusted for multiple comparisons. The authors report some null results and
some significant results, and we are made to infer the null results are true
nulls and the significant results are truly significant. The error rate for
that joint set of inferences is much higher than the nominal error rate.

To reiterate, my concerns here are exacerbated by the fact that this is a
topic likely to get public traction, and which speaks directly to political
agendas on both sides of the marijuana policy aisle.

I have limited interest in following up on the neuroscience/biology stuff,
since that is not my field. I want to speak only to responsible scientific
practice. If neuroscience routinely publishes these kinds low-power multiple-
comparison subgroup-analyses, I suspect there will be a replicability crisis
in the near future.

------
bitwize
> The increased legal availability of cannabis has led to a common
> misconception that it is a safe natural remedy for, among others, pregnancy-
> related ailments such as morning sickness.

Cannabis has been widely recognized among stoners as a natural miracle cure
for everything from hangovers to stage IV cancer, and because it is produced
by "nature" it is thought to be superior to "chemicals" found in ordinary
pharmaceuticals.

If anything, legalizing cannabis will increase the visibility of studies like
this and give us a clearer picture of its benefits and drawbacks.

~~~
colechristensen
Cannabis attenuates inflammation and inflammation is an underlying or
contributing cause to just about every disease so the stoners are right, in a
way.

[https://www.health.harvard.edu/newsletter_article/Inflammati...](https://www.health.harvard.edu/newsletter_article/Inflammation_A_unifying_theory_of_disease)

~~~
lukeschlather
Inflammation is part of the immune response. It's not a cause, it's a symptom.
And much like other symptoms like vomiting or fever, the symptom is actually
an effective way for the body to fix root causes.

Being in a perpetual state of fever, vomit, or inflammation is clearly an
unhealthy state, but that doesn't mean suppressing these symptoms is useful.

~~~
Obi_Juan_Kenobi
Dysregulation of the inflammatory system is, to a growing extent, being
considered as a cause of disease _per se_. So it's somewhat more complicated
than that; it's plausible that the broad anti-inflammatory effects of cannabis
could treat a variety of common diseases.

------
wil421
How much THC did they give the rats compared to human quantities? I read an
article about monkey brains showing some type of symptom when they looked at
white matter under a microscope. Turns out the poor monkeys were given the
equivalent of an adult smoking a pound a day.

~~~
notafraudster
2mg/kg subcutaneous. I don't know the conversion between subcutaneous and
other forms of ingestion, but this would be equivalent of ~150mg of THC for an
adult male. I also don't the THC content of weed, but it doesn't sound like an
unfathomably high dose. I think the other design concerns are more likely to
be the culprit here than external validity worries about dose.

~~~
jjjensen90
Normal weed "flower" is 10-30% THC. So 1 gram of weed is 100-300ish mg of THC.
A single prerolled joint is usually 1 gram of flower. So this dose is around 1
joint.

Edit: importantly this info is for smoked flower, edibles and concentrates are
a little different because of how they are absorbed.

~~~
loeg
Smoking an entire 1g preroll by yourself is a _huge_ dose for a human who
doesn't have a high tolerance.

~~~
filoleg
I mean, it would depend on the THC concentration, right? A 1g pre-roll with
30% THC would be 3 times as potent as the one with 10%, so I can totally see
someone with rather low tolerance smoking a full 10-12% joint by themselves
and feeling just fine.

------
sneilan1
What does this mean in plain terms?

~~~
colechristensen
You usually shouldn't draw such conclusions from single studies. This was a
rat model studying a specific gene and a drug therapy for it, it might be one
datum among many if you were surveying the literature to try to draw
conclusions about plain terms conclusions to extract.

A quote from the abstract "Emerging clinical evidence, however, indicates that
prenatal cannabis exposure (PCE) predisposes offspring to various
neuropsychiatric disorders linked to aberrant dopaminergic function." is about
the best you can do. There is growing clinical evidence that cannabis exposure
during gestation leads to problems with dopamine.

~~~
apacheCamel
So, correct me if I am wrong, but to summarize: Smoking marijuana while
pregnant is bad for the baby?

~~~
arpa
Possibly. There is growing body of evidence it might be.

~~~
bendbro
Please confirm: can I counteract the effects of marijuana on the developing
fetus with Cocaine? My drug friends tell me they act like opposites in the
body. Thanks

------
alexandercrohde
I hope "Don't smoke when pregnant" goes without saying. The mother's blood IS
the baby's blood during pregnancy, anything the mother takes the baby gets.
That's why 90% of medications are unsafe to take when pregnant.

I would hope this would be common knowledge.

~~~
loeg
> The mother's blood IS the baby's blood during pregnancy, anything the mother
> takes the baby gets.

This is not really true[0]:

> In the villi, these vessels eventually branch to form an extensive arterio-
> capillary-venous system, bringing the fetal blood extremely close to the
> maternal blood; but no intermingling of fetal and maternal blood occurs
> ("placental barrier").

There is some pass-through effect, but it is not 100%, and varies depending on
the particular chemical.

[0]:
[https://en.wikipedia.org/wiki/Placenta#Fetoplacental_circula...](https://en.wikipedia.org/wiki/Placenta#Fetoplacental_circulation)

------
ropiwqefjnpoa
Not the full article but a longer summary of it:
[https://medicalxpress.com/news/2019-10-thc-rat-pregnancy-
res...](https://medicalxpress.com/news/2019-10-thc-rat-pregnancy-result-
brain.html)

------
SolaceQuantum
Only in male mice, according to the abstract. The arbitraryness of it makes me
suspicious.

~~~
ultraism
I might be misunderstanding you or the abstract but I think the effect occurs
in only in male rats. It isn't that they only tested male rats.

~~~
SolaceQuantum
Yes, the effect only occurs in male rats. It's extremely specific which is why
I'm suspicious.

------
jMyles
> Here, we show that male, but not female, offspring of
> Δ9-tetrahydrocannabinol (THC)-exposed dams, a rat PCE model, exhibit
> extensive molecular and synaptic changes in dopaminergic neurons of the
> ventral tegmental area, including altered excitatory-to-inhibitory balance
> and switched polarity of long-term synaptic plasticity.

Very possible that this effect will not be observed in humans. Certainly not a
good reason to cease cannabis use if it's part of your pregnancy or birth
plan, coordinated with experienced prenatal and neonatal professionals.

The opening of the abstract costs this study substantial credibility in my
opinion:

> The increased legal availability of cannabis has led to a common
> misconception that it is a safe natural remedy for, among others, pregnancy-
> related ailments such as morning sickness.

There is no source provided for the claim that increased legal availability
has led to a change in perception, but the use of this phrase to open the
abstract betrays an unambiguous agenda.

I'll wait until more human longitudinal studies (the current corpus of which
includes many which appear favorable to cannabis as part of a prenatal
regimen) before changing my mind.

