Oxytocin

Oxytocin is vastly overlooked as a balancing agent for an addict’s brain. It is the Yin to dopamine’s survival Yang. Dopamine may lead the charge and actions to find a mate, but there is no propagation of the species without oxytocin. It controls arousal in both males and females. So much so that it is prescribed to both for sexual dysfunction. There are no natural erections or orgasms without it. In addition, it is necessary for labor, breastfeeding and postnatal bonding. Oxytocin regulates social interaction and makes it rewarding. For addicts, oxytocin is a game changer. Amazingly, it can reset tolerances to drugs of abuse. Why is this important? To reset a tolerance, incredible things must happen.The epigenetic over and under expression of enzymatic neuromodulators must be reset along with changes in neuroplasticity toward homeostasis. First and foremost, oxytocin intranasal supplementation forces dopamine expression at the D2 receptor back toward normal expression levels. Remember from earlier, D2R expression is what is lacking on the brain scans we looked at. I have only found two substances that can safely achieve this with long lasting effects after cessation of application. The most unique and crucial element of oxytocin is that supplementation allows it to upregulate itself long term.

This is pivotal and what has been missed! Long term upregulation of oxytocin ensures proper D2R expression. What were our main objectives on this quest? Homeostasis of glutamate and dopamine were the aim. Proper D2R expression modulates D1 excitability and the ensuing norepinephrine imbalance. Dopamine is the direct precursor for norepinephrine. Too much excitatory dopamine leads to a norepinephrine storm that can cause anxiety and its following negative protein clusters, along with inflammation. As a bonus, oxytocin supplementation has been scientifically proven to curtail overeating and food cravings. Let’s look at some research so the citation police don’t get in a lather. Oh but first, and here is where having an ex addict on board is helpful. There is so much debate over how and if oxytocin is absorbed nasally. It has been debated on paper for years. Well, I made mine and used it at the max clinical trial dose. Definitive onset came within the first hour and lasted for about 18 hours. It was one of those situations where I was happy to have an illustrious drug use past. The common man may have panicked. I started at 300 IU and I do not recommend it. Most studies centered around 24 IU.

24IU twice a day will give the D2R benefits we are looking for with a side of clear mellow and good sex, if you are into that sort of thing. Stay clear of this if you are pregnant, breastfeeding, or have the possibility of becoming pregnant. Supplementation would be detrimental to that developing universal cosmonaut.

Research:

Within the reward circuits of the brain, dopamine and glutamate are primarily tasked with processing reward salience and motivation. Excitatory transmission by either between the prefrontal cortex (PFC) and reward centric areas like the ventral tegmental area, nucleus accumbens, amygdala and hippocampus can drive addictive behavior. Oxytocin receptors are coupled with dopamine and glutamate receptors along these paths and have influence on the intensity of their signaling. Oxytocin administration can quell the strength of phasic dopamine and glutamate blasts typically seen in drug seeking behavior. Phasic swells occur from anticipation and capture of rewards from drugs of abuse, food, porn, gambling, etc. Oxytocin filters these blasts while still allowing stable tonic levels.

“OXT counteracts the effects of rewarding substances, as seen by its ability to reduce drug-induced behaviors, drug-seeking behaviors, and cravings for addictive substances. OXT attenuates behaviors induced by cocaine, such as locomotor hyperactivity, repetitive behaviors (e.g., sniffing), and behavioral sensitization to cocaine in rodents. OXT (0.1, 0.3, 1, 3 mg/kg; i.p.) also dose-dependently reduced lever presses for cocaine in male rats in a self-administration paradigm. Reinstatement behavior, similar to drug relapse, is influenced by OXT administration as well. The administration of OXT into the NAc decreased the cued reinstatement of cocaine self-administration.Similar effects of OXT are found for other drugs of abuse. Methamphetamine seeking, as measured by active lever presses, was decreased dose-dependently by systemic OXT treatment. Peripheral (0.6 mg), intracerebroventricular (0.1, 0.5, and 2.5 μg), and NAc core and subthalamic nucleus (0.6 mg) injections of OXT all reduced the acquisition of methamphetamine-conditioned place preference (CPP). Additionally, OXT attenuated both drug-primed reinstatement and the cue-induced reinstatement of methamphetamine. When directly injected into the NAc core, OXT (1.5 and 4.5 pmol) dose-dependently reduced meth-primed reinstatement. Regarding opioids, both peripheral and central treatments of OXT have successfully attenuated opioid tolerance in rodents, specifically to analgesic morphine and heroin. In heroin-tolerant rats, a single dose of OXT (0.05, 0.5, and 5 µg; s.c.) was all that was required to reduce heroin self-administration and block the expression of heroin tolerance. However, this effect was not found in heroin-naive rats]. The acute intracerebroventricular administration of OXT (1 µg/5 µL) reduced alcohol self-administration and prevented the ethanol-induced release of DA in the NAc in rats both chronically exposed and naive to ethanol .Looking at the effects of OXT on behaviors induced by natural rewards, peripheral (up to 6 mg/kg; i.p.) and intracerebroventricular (1–10 µg) OXT administration dose-dependently reduces food intake in food deprived rats. Another study by Mullis and colleagues (2013) found that OXT directly injected into the VTA decreased the consumption of a sucrose solution. They also discovered that OXTR antagonists inhibited this effect and returned sucrose intake to normal levels, establishing that OXT attenuates sucrose intake via OXTRs in the VTA. Additionally, the systemic administration of OXT was found to attenuate the expression, but not the acquisition, of sucrose CPP]. These findings, which demonstrate that OXT can decrease the seeking and intake of natural rewards, suggest that the neuropeptide could be used to reduce the overconsumption of food and sugar caused by maladaptive processes in reward processing. Thus, OXT may have a role in combating diseases associated with the overconsumption of food and sugar, such as diabetes and cardiovascular disease.Several clinical trials have been initiated to test whether OXT curbs drug-seeking in humans. Pedersen and colleagues (2013) had alcohol-dependent subjects undergo alcohol detoxification with the treatment of lorazepam, as needed, and were to either receive intranasal OXT (24 IU; twice daily for three days) or a placebo. The subjects who received OXT demonstrated fewer withdrawal symptoms and used less lorazepam than the control group. Another clinical trial found that a single intranasal OXT administration (40 IU) reduced drug cravings, stress, and anxiety in cannabis-dependent individuals. Clearly, OXT has a profound effect on addictive behaviors and is a promising candidate to be a therapeutic for addiction. However, the mechanisms by which OXT reduces drug-induced behaviors are not well-established. This review aims to examine how OXT impacts maladaptive changes in the reward circuit, specifically focusing on its interactions with Glu and glutamatergic pathways to attenuated reward-seeking behaviors.” (1)

I am focusing on glutamate as it does not get enough credit for maintaining addiction. Sure dopamine is the initiating neurotransmitter, but it takes a backseat to glutamate once addiction is already established. Inflammatory responses to excitotoxic dopamine levels recruit heightened glutamatergic responses between the PFC and the reward centers of the brain. It is glutamate hyper firing along these paths that constantly remind you that relapse would be a great idea. Here is where your ancestral DNA gets hijacked into chasing substances that are perceived as highly rewarding based off of the original phasic dopamine rushes. We are ill prepared genomically to handle what our technology has created.

I will give glutamate a voice to put into perspective the importance of correcting it. Glutamate is the driving force behind classic zingers like “ just do enough to feel normal”, “let’s just taper off with what we have left”, Oh My God!, Jenny knows where to score some”, “You deserve this”,

“The bar on 15th is a stellar place to get relief”. It reminds you of the people and places associated with maintaining addiction and fires incessant cues that something is not right and needs immediate attention. I digress, back to oxytocin.

Here is the crux of how oxytocin modulates dopamine and glutamate.

“It is possible that OXT’s impact on addictive behaviors occurs due to interference with the DA and Glu interactions that occur in the reward circuit during the addiction cycle. This is supported by the fact that OXTRs are on both dopaminergic and glutamatergic neurons in the VTA [29,134]. At specific glutamatergic inputs to VTA dopamine neurons, OXT acts as a filter by selectively inhibiting excitatory synaptic transmission to the VTA through OXTRs alongside endocannabinoid signaling [9]. OXT has a greater gating effect on Glu neurons that fire only occasionally compared to those that fire repeatedly. These mechanisms lead to a decrease in Glu release in VTA DA neurons in the presence of OXT [9]. Glu-mediated DA release is also relevant to processes such as tonic-phasic DA activity; OXT suppression of Glu would allow for less modulation of tonic and phasic firing of DA neurons, which is a key component of reward processing. Similarly, glutamatergic synaptic transmission in the NAc was dampened in the presence of OXT through a presynaptic mechanism involving serotonergic inputs [9]. This modulatory interaction of OXT on Glu transmission in the VTA allows for regulation of both Glu and DA levels through their interactions [135].”(1)

Additionally, glutamate and its relationship with astrocytes is truly closer to the core of dysfunction, but that duo is covered in my astrocytes and inflammation chapters.

Let’s take a deeper dive into what makes oxytocin such a fucking unicorn. I mentioned earlier that exogenous oxytocin upregulates endogenous oxytocin long term. Considering that all of the “this is what an addict’s brain looks like” pet scans showing decreased striatal dopamine D2 receptor expression densities and the fact that oxytocin can modulate D2R expression back towards a normal level, just wow. It really doesn’t get any easier to do something very difficult.

Yet, practitioners, either uneducated or unwilling, choose to spray Lexapro, or the like, all over every addict they encounter. Interestingly, intranasal oxytocin applied in adolescence prevents alcohol abuse into adulthood and breastfed babies tend to have lower rates of addiction in general. I will say that when I attend cellular medicine or peptide training and conferences, most doctors simply are unaware of addiction related research. The primary focus tends to lean towards cellular senescence and longevity these days. Just a reminder to advocate for yourself and to not assume that the desire or knowledge is out there to help addicts.

Secondly, oxytocin can reset tolerances to drugs and foods of abuse. Sounds simple, but there is no tolerance off button to hit. Instead, aberrant pathways created during addiction must be reversed. It gets to our next point of inflammation and the undoing of epigenetic gene promoter suppression.

Next unicorn trait is the anti-inflammatory properties it possesses, especially in astrocytes. Inflammation in astrocytes is a free pass for glutamate to get crazy.

Lastly, oxytocin is a time machine that can let the brain travel back and amend trauma. It acts as a neural pathway editor by decreasing excitatory transmission along old memory trails. Many addicts suffer from trauma, anxiety and regret related to the past; oxytocin can paint a gentler picture. Along with N-acetyl cysteine, it works absolute miracles in my suicidal clients and fairly quickly. I bring this up beacause the genesis of suicidal ideations and relapse urges spawn from similar dysfunctions in glutamate transport. You cannot have repetitive harmful thoughts without mishandled glutamatergic firing from the pre-frontal cortex. I would go on to mention how it curbs overeating but that is related to the previous points.

If everything were a 1:1 transfer from research we would all just take oxytocin and be healed. The reality, however, is that this is one brick in the fortress we are building, a strong one at that. Used in conjunction with the synergists ahead, it is a formidable addiction foe.

Quick tip: The probiotic L. Reutieri is a safe and natural way to boost endogenous oxytocin.

My favorite oxytocin research and articles that are cited above:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957657/

Oxy and glutamate

Good reward cycle summary for Glu and DA ✅

https://elifesciences.org/articles/33892#:~:text=But%20exactly%20how%20oxytocin%20affects%20the%20activity%20of,another%20group%20of%20reward%20signals%2C%20known%20as%20endocannabinoids.

Exactly how it modulates dopamine!!

https://www.jneurosci.org/content/34/44/14503

Restores Glt-1

https://www.sciencedirect.com/science/article/abs/pii/S0166432821004782

Regulates dopamine and glutamate

https://www.sciencedirect.com/science/article/pii/S0896627317305019