A Deep Dive Into Oxytocin for Mental Health, Addiction, and the Endocannabinoid Connection

Oxytocin and mental health

 

In our research, we've come across curious studies on oxytocin.


We're moving way past the original maternal-infant bonding and nursing aspect of it.


New research is pointing to links for anxiety, depression, autism, addiction, and more!


After our deep dive on CBD and mental health, this is furtive territory to look at especially since there's a connection there with oxytocin.


That being said, oxytocin deserves a full review on its own merit.


After all, it appears to be a key player in all things social.

  • Trust
  • Empathy
  • Loyalty
  • Fidelity
  • Risk-averse or risk-taking behavior
  • Fear, suspicion….even lying?

The love of the family, team, and even country springs from oxytocin in ever-increasing rings of "us".

 

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We'll touch on that briefly but we really want to focus on mental health and addiction (two sides of the same coin).


Here are the topics we'll get into:

  • What is oxytocin and what roles does it play in the brain
  • Oxytocin is a neurotransmitter
  • Oxytocin and depression
  • Oxytocin and anxiety
  • Oxytocin and autism
  • Endocannabinoids and oxytocin
  • Oxytocin and addiction
  • How to support oxytocin

Let's get started. 

What is oxytocin and what roles does it play in the brain

This is an important piece from which the rest flows.


Oxytocin is a ring of amino acids with a little surprise on the back end.


An amide.  Similar to anandamide, palmitoylethanolamide, and other endocannabinoids.


We'll get into that later but back to oxytocin.


In general, oxytocin acts as a promoter of social interaction and bonding.


Since human behavior is so complex, this shows itself in many different ways.


A slew of studies have teased out some of the following:

  • Oxytocin increases empathy but not altruism
  • Oxytocin increases lying if it helps the group
  • Oxytocin increases fidelity with married men but single men
  • Oxytocin increases trust 
  • Oxytocin promotes engaging in social interaction (risk-taking)
  • Oxytocin is totally baked into sexual arousal, orgasm, and romantic bonding
  • Oxytocin promotes calm and fights anxiety

https://en.wikipedia.org/wiki/Oxytocin


Those are just a few examples of how it shapes our social world.


In general, it pushes humans to be social.


There are gender differences as estrogen promotes oxytocin while testosterone suppresses it.


Did we just explain the differences between the genders?


Maybe.  Partially.


There's also the curious connection of when estrogen drops out (during the cycle and at perimenopause) for anxiety (see CBD and perimenopause anxiety).


The origin of oxytocin's journey beyond labor and nursing turns to the vols.


These animals are known to mate and form lifelong, monogamous bonds.


Researchers found that:

  • if oxytocin was blocked, they would mate but not form bonds
  • If they were injected with oxytocin but prevented from mating, they still formed bonds

There's a great walkthrough here:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3183515/


On our way to mental health and addiction, let's look more closely at oxytocin and the brain.

Oxytocin is a neurotransmitter

Oxytocin is a hormone but it also operates as a neurotransmitter.


In order to affect aspects of social interaction, it must interact with serotonin, dopamine, and more.


Serotonin manages all human behavior so let's start there (see CBD and serotonin).


When scientists serotonin to look at what areas of the brain showed increased oxytocin, one area really stood out.


The amygdala!


Importantly, the amygdala appears central in the regulation of 5-HT by OXT: 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4060712/


5HT is short for serotonin.


This makes perfect sense if you check out our CBD and the mechanisms of anxiety.


Our fear and emotional processing center is the amygdala.


Oxytocin has been known to create calm and trust which speaks to this effect.


Simply put:

OXT administration is known to inhibit amygdala activity and results in a decrease of anxiety, whereas high amygdala activity and 5-HT dysregulation have been associated with increased anxiety. 

Serotonin is key to the repair process of the brain called neurogenesis (see CBD and brain repair) which is writ large across all mental health in today's research.


Let's turn our attention to dopamine.


Dopamine is critical to focusing our mind's eye...our attention to something of importance.


This is great for motivation but also the root of addiction (focus is on the drug of choice).


Oxytocin appears to shift the focus of our minds to social cues.


Several groups of researchers have posited that oxytocin’s ability to influence behavioral responses to social stimuli is at least partially mediated by its capacity to increase the salience of social cues 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877159/


Salience is a fancy word for what's important or noteworthy among all the cues we get.


We'll see how this comes into play directly with addiction where dopamine and the reward circuit has been hijacked towards a given drug.


Learn more about it at CBD and dopamine.


Finally, GABA...our brain's "brake" pedal.


What's behind the feeling of "calm" described with oxytocin?


A big part of that is GABA as we know from how benzos work (See CBD versus benzos or CBD and GABA).


It's a pathway shared by alcohol:

Oxytocin stimulates release of the neurotransmitter GABA, which tends to reduce neural activity. Alcohol binds to GABA receptors and ramps up GABA activity. Oxytocin and alcohol therefore both have the general effect of tamping down brain activity—perhaps explaining why they both lower inhibitions.

https://www.scientificamerican.com/article/there-is-a-fine-line-between-love-and-drunk/


No wonder falling in love feels so good!


This is all well and good but how do we use this information?


Let's turn to very common mental health issues as examples.

Oxytocin and depression

We've covered the mechanics of depression in-depth at our CBD and depression review.


A quick synopsis:

  • Inflammation, immune response, and other assaults damage or reduce parts of the brain
  • Repair mechanisms are unable to keep up
  • Serotonin and BDNF play key roles in the repair process

That's very quick...lots of research and detail at that review.


Where does oxytocin figure in?


Mother nature tends to reuse existing pathways for dual purposes.


We see this all the time in the research.


Oxytocin has a starring role during delivery in that it directly drives contraction of the uterus.


Needless to say, this is an extremely stressful event!


As a result, oxytocin has a side gig of reducing inflammation, pain, and even stress hormones!


First, the inflammation piece.


One example is how maternal separation can cause depressive-like symptoms and inflammation in the brain (stress and anxiety driving the last piece).  


Look at oxytocin's effect there:

treating stressed animals with OT (intracerebroventricular, i.c.v. injection) attenuated the MS-induced depressive-like behaviors through improving mitochondrial function and decreasing the hippocampal expression of immune-inflammatory genes.

https://pubmed.ncbi.nlm.nih.gov/28259722/


Dual-purpose.  Make it easier to be away from a newborn.  Oxytocin.


Another study looked at oxytocin's effect when bacteria proteins were introduced:

Using the BV-2 microglial cell line and primary microglia, we found that OT pre-treatment significantly inhibited LPS-induced microglial activation and reduced subsequent release of pro-inflammatory factors.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4831099/


Let's translate because this is very important.


Microglia are the general's of our brain's immune system.  When hyperactivated, they can cause a great deal of damage and are tied to every mental health issue we can find.


This is the new direction of research on the "inflamed brain".


Oxytocin calmed this response in the brain!


Then there's the repair side...serotonin and BDNF (our brain's fertilizer).


Remember that stress (either acute or chronic) is the enemy of the brain when unchecked.


A study looked at oxytocin's effect on the repair process to stress:

In the stress+oxytocin groups, thigmotaxis time (indicating anxiety) decreased, but VEGF and BDNF levels increased.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4294596/


Check out CBD and brain repair or CBD and BDNF to really understand why this is the most important piece of mental health research these days.


It's how SSRI's, the leading class of antidepressants, actually work until they stop due to tolerance (see How SSRIs really work).


Speaking of stress…

Oxytocin buffers cortisol responses to stress in individuals with impaired emotion regulation abilities

https://www.sciencedirect.com/science/article/abs/pii/S0306453010003148


Cortisol is our primary stress response hormone.  


The curious piece is how oxytocin really helped those individuals who lacked control over the emotional response to stress.


It almost points to oxytocin as the missing puzzle piece to these people.


Here's the key piece:

Oxytocin can inhibit the stress-induced activity of the HPA axis to promote the return of cortisol levels to normal levels after stress is experienced 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442937/


The HPA axis is the entire complex of the stress response and if left unchecked, damage occurs in the brain.


The net effect of this damage can be depression.


Let's jump into then...what does research show for depression and oxytocin?


First, the association is showing up everywhere.


It does appear that high-stress situations is where oxytocin showed the most effect.


For example, looking at new mothers experiencing depression:

among women who reported high levels of psychosocial stress, higher levels of plasma OT were associated with fewer depressive symptoms and more sensitive maternal behavior.  T

https://d1wqtxts1xzle7.cloudfront.net/40277519/Psychosocial_Stress_Moderates_the_Relati20151122-26100-wmyava.pdf


Other studies are looking at the balance between oxytocin and vasopressin:

Specifically, OXT exerts anxiolytic and antidepressive effects, whereas AVP predominantly increases anxiety and depression-related behaviors. W

http://fisio2.icb.usp.br:4882/wp-content/uploads/2016/08/Oxytocin-and-vasopressin.pdf


What about levels of oxytocin in people with anxiety and depression?


Results showed a significant negative correlation between oxytocin and the scored symptoms depression (r ¼ 0.58, p ¼ 0.003) and anxiety (r ¼ 0.61, p ¼ 0.005)

https://orbi.uliege.be/bitstream/2268/154551/1/PlasmaOT.pdf


What about the gene for oxytocin?


Many studies have revealed that the oxytocin receptor gene (OXTR) is associated with emotional salience and depression among females.


Emotional salience means "what's important" emotionally.


We look forward to further studies but the impact on neurogenesis and stress response is promising.


Let's turn to anxiety.

Oxytocin and anxiety

We walk through the basics of anxiety in our CBD and mechanisms of anxiety but some quick takeways.


In general, anxiety is thought of as a mismatch between our emotional part of the brain (amygdala) and our rational constraint on that area, the prefrontal cortex.


Many things can contribute to this:

  • Poor stress response
  • Endocannabinoid deficiency (see more here)
  • Inflammation
  • Hyperactive immune response
  • Gut microbiome imbalance
  • Hormone deficiency (especially progesterone and estrogen)

The primary lever that pharma has targeted is GABA, our brain's brake pedal but there are nasty consequences to benzo use (see CBD versus benzos or CBD and GABA).


There's interesting research on oxytocin and this brain connection.


Oxytocin reduced right-sided amygdala responses to all three face categories even when the emotional content of the presented face was not evaluated explicitly.

https://www.psychologie.uni-freiburg.de/abteilungen/psychobio/team/publikationen/2007Domes2007_oxytocin_fmri_BIOL_PSYCHIATRY.pdf


Essentially, oxytocin calmed the alert system to emotional (translated scary) faces.


What's the net result to calming this hyperactivation of the amygdala?

 

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Decreased EEG power in the amygdala, as caused by oxytocin, may be related to both reduced anxiety and increased social behaviors.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4518468/


What about social anxiety which seems so pertinent to what we're discussing?


Oxytocin reduces increased activation of the ACC and MPC in individuals with social anxiety disorder in response to sad faces.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573563/


The ACC and MPC act like mediators between our primitive brain area (amydala - fear and anxiety) and the newer part (prefrontal cortex) which makes us human.


Essentially, oxytocin slows down the constant fear signals to our processing brain.


Think negative thoughts, ruminations, even OCD.


Check out CBD and negative thoughts, CBD and social anxiety, or CBD and OCD for more research.


Key to all anxiety and especially social anxiety is how we see ourselves.  Hyperawareness of ourselves may be the defining aspect of much of what we consider anxiety.


This is where oxytocin may be promising:

The anxiolytic effects of oxytocin are supported by research demonstrating diminished negative self-judgment during a social task and decreased anxiety in response to social rejection

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573563/


Check out CBD and public speaking to learn more about this "self-statement" effect.


Look at the effects of differences in our oxytocin gene:

In past studies, the G allele was found to be connected with prosocial traits like empathy, trust, and optimism; whereas the A allele was associated with sensitivity to stress, less optimism, less social skills, and lower self-esteem.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5573563/


  • G means more oxytocin function
  • A means less oxytocin function

We look forward to further studies and you can learn more at CBD and phobias.


Let's turn to more fascinating research on oxytocin.

Oxytocin and autism

We did a huge review of CBD and the pathways of autism.


Along with oxidative stress, gut imbalance, inflammation, there's is a known effect on social function.


Let's start with the animal studies.


Our results showed that oxytocin improved the behaviors of autistic mice, with less anxiety, depression and repetitive behavior, and ameliorated social interaction. 

https://www.sciencedirect.com/science/article/abs/pii/S0753332218330993


And the underlying attributes?:

Further study showed that the elevated oxidative stress and inflammation in autistic mice were alleviated after treatment of oxytocin.


Newer research is now pointing to oxytocin as a key player in this pathway:

The results suggest that children with autistic disorder show alterations in the endocrine OT system. Deficits in OT peptide processing in children with autism may be important in the development of this syndrome.

https://d1wqtxts1xzle7.cloudfront.net/50879116/green_2001_biological-psychiatry.pdf


Which makes the study out of Standford so interesting:

The brain hormone may help treat social impairments in children with autism whose baseline oxytocin levels are low before treatment, according to new Stanford findings.

https://med.stanford.edu/news/all-news/2017/07/oxytocin-improves-social-abilities-in-some-kids-with-autism.html


Since baseline oxytocin is lower in children with autism, this appears to be relevant.


One note...this was for the social interaction aspect only...not repetitive motions or anxiety.


Check out CBD and autism anxiety for more info.  As for repetitive thoughts/motions, look at CBD and GABA, the brain's brake pedal.


Another study (double-blind, placebo) found an array of benefits with long term use and follow up:

Among the secondary outcome measures, treatment-specific improvements were identified in the Repetitive Behavior Scale and State Adult Attachment Measure, indicating reductions in self-reported repetitive behaviors (p = .04) and reduced feelings of avoidance toward others (p = .03) in the oxytocin group compared to the placebo group, up to 1 month and even 1 year post-treatment. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964112/


Along with improved vigor and mood states.


Another study focused on autism with intellectual disabilities:

We observed significantly more events regarded as reciprocal social interaction in the OT group compared with the placebo group.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473850/


We look forward to more studies and you can learn all about the pathways of autism here.


In fact, the endocannabinoid system interaction with oxytocin is coming front and center:

They further suggest that oxytocin-driven anandamide signaling may be defective in autism spectrum disorders and that correcting such deficits might offer a strategy to treat these conditions.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4653148/


We'll go there next.


We picked just three mental health issues to look at.  Let's now turn to a curious connection with the endocannabinoid system.

Endocannabinoids and oxytocin

We need to introduce a new player….anandamide.


Anandamide, named after the Hindu goddess of bliss, is one of two primary endocannabinoids in our brain and body.


We covered it in detail at our review on endocannabinoid deficiency and how to boost endocannabinoids.


A great deal of CBD's impact occurs by supporting anandamide.


What's the relationship between oxytocin and anandamide:

A small number of neurons in the brain make oxytocin and use it as a neurotransmitter. When the scientists stimulated those neurons, they saw an increase in anandamide creation in the nucleus accumbens.

https://news.uci.edu/2015/10/26/love-hormone-helps-produce-bliss-molecules-to-boost-pleasure-of-social-interactions/


Essentially, the brain uses anandamide (bliss) to lock in the positives of socialization (oxytocin).


When they blocked anandamide,  the social promoting effects of oxytocin went away!


They go on to discuss out to support oxytocin by blocking the breakdown of anandamide, so-called FAAH inhibitors.


That's exactly what lead us to write our Endocannabinoid deficiency review (which is massive, even by our standards).


When you see how much is affected by this pathway, you start to wonder if it's the root of many modern ailments (autoimmune, pain, mental health, etc).


Just check out CBD and schizophrenia or the woman who can't feel pain or anxiety as powerful examples.


Let's take a detour to addiction.

Oxytocin and addiction

Here's where the research really gets interesting.


First, the oxytocin system develops over a period of time, and shocks to the system can affect its final state.


This could be stress, infection, social isolation, etc.


One fascinating example:

Only the combination of being exposed to prenatal stress and being raised by a prenatally-stressed rat dam resulted in adult male offspring with a decreased number of OXT-positive magnocellular neuron

https://www.sciencedirect.com/science/article/pii/S0091305713002219


Stress is the enemy because remember that oxytocin is part of our stress response system.


Exposure to drugs prenatally also directly affected the architecture of this system.


From there, we have a range of effects from oxytocin supplementation on addiction.


Let's look at the following:


Oxytocin and alcohol


We'll jump right into it:

The experiments demonstrated that when oxytocin is administered systemically, intranasally or into the brain, it blocks excess drinking that develops in alcohol-dependent rats, but not in normal, nondependent rats.

https://www.scripps.edu/news-and-events/press-room/2019/20190416-roberto-alcohol.html


It did this via effects on GABA.


The more intriguing piece is whether an oxytocin deficiency partly drives alcohol addiction.


It's fascinating that supporting oxytocin levels would reduce the need to drink and withdrawal symptoms unless it was an underlying issue.


Check out CBD and alcohol addiction to really look at the research.


Next up.

Oxytocin and opioid addiction

A double-blind, placebo study just looked at oxytocin for opiate addiction.


The results:

Acute OT administration reduced craving and withdrawal scores but did not change anxiety significantly.

https://www.karger.com/Article/Fulltext/496194


Interestingly, CBD had powerful effects as well including the anxiety piece.  See CBD and opioid addiction and withdrawals.


Oxytocin's primary effect was in addressing the changes to our stress response system (HPA) that occurs with addiction.


What about stimulants?

Oxytocin and cocaine addiction

Starting with the animal studies:

Recent cocaine self-administration studies from our laboratory have shown that systemic oxytocin decreased active lever presses, cocaine intake, and conditioned cue-induced cocaine seeking following extinction in both males (Zhou et al., 2015) and females 

https://academic.oup.com/ijnp/article/20/10/844/3979852


These are the studies where rats can self-administer cocaine as much as they want and eventually do so over water, food, and mating.


By administering oxytocin, the rats stop craving cocaine as much.


Another study looked at methadone users:

Two weeks of oxytocin (but not placebo) significantly reduced cocaine craving at day 15 compared to baseline 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5424696/


Here's an interesting effect:

Oxytocin led to a significant switch from implicit self-association with drugs to implicitly associating drugs with others (mean change±SD: 0.25±0.35, p=0.037) and a trend-level reduction in self-reported cocaine use over time


Think about this in the context of what oxytocin does in the brain.


There's a known effect of addiction in modifying oxytocin's function in the brain.


We know that oxytocin drives focus to our "in-group".  Perhaps addictive drugs are able to marbelize their use into our core identity.


The above statement is fascinating in resetting this "drugs are not US" worldview.


Check out CBD and cocaine addiction for more research on the driver of cocaine addiction.


Next up (what originally caught our attention)...

Oxytocin and cannabis addiction 

We covered quite a bit of our CBD and cannabis addiction.


We also looked at whether people addicted to THC were trying to calm glutamate or deal with endocannabinoid deficiency.


THC, after all, mimics anandamide in the brain (albeit with nasty side baggage).


First, the withdrawals:

Oxytocin reduced both MCQ total score and DHEA levels from before to after the TSST. It also decreased anxiety, but not subjective stress ratings.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3729589/


MCQ is a test of marijuana craving test.


DHEA is a hormone tied with the stress response.


Then the effects of oxytocin on treatment for cannabis addiction:

Participants receiving oxytocin showed reductions in amount of cannabis used daily and number of sessions per day. Participants receiving placebo did not evidence significant reductions.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5361569/


As we discussed in our CBD and cannabis addiction review, the issue with THC is that the brain will start to push back against its effects over time.


If THC mimics anandamide and give oxytocin it's punch, look what happens with excessive THC:

Chronic exposure to THC downregulates oxytocin and oxytocin-associated neurophysin in specific brain areas

https://www.researchgate.net/publication/200112613_


Goodness...reduction in the "love" drug over time.  This has always been the issue with THC (See CBD versus THC).


Tolerance.  


Let's look at ways to support oxytocin without causing this rebound effect.


Speaking of support…

How to support oxytocin

The list of things that can release or boost oxytocin is intriguing:

  • Sex
  • Cuddling
  • Falling in love
  • Singing
  • Dancing
  • Yoga
  • Massage
  • Warm temperatures
  • Exercise
  • Meditation
  • Petting animals (for us and them)
  • Nursing
  • Hugs

Are you seeing a pattern?  It's all touchy, feel-good stuff.


Then there are needed mediators:

  • Magnesium
  • Vitamin D
  • Melatonin
  • Estrogen

Then you have detractors such as BPA used in canned lining:

Our results demonstrate prenatal exposure to BPA can eliminate sex differences in OTR expression in three hypothalamic regions, and that male OTR expression may be more susceptible.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750986/


What was scary is that studies on exposure actually reduced oxytocin levels for 4 generations in animal studies.


Add this to the list of hormone-disrupting chemicals (sunscreens, cosmetics, food additives, etc).


Of course, there is intranasal oxytocin which can be purchased now from compounding pharmacies.


Our first batch to test is coming in tomorrow.  We'll report on our experience!

 

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Always work with a doctor or naturopath with any supplement!

The information provided here is not intended to treat an illness or substitute for professional medical advice, diagnosis, or treatment from a qualified healthcare provider.





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