How to Upregulate Dopamine Over the Long-Term

 

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upregulation

For this post, I want to discuss an idea that is rather nuanced and complex: how to chronically upregulate dopamine (DA) levels.

You can find hundreds of articles on “how to boost dopamine”, but this is only half the story. In reality, it’s not as simple as merely boosting a neurotransmitter and expecting a positive result.

In order to explain this distinction, I will need to provide a brief overview of some key brain mechanisms, namely homeostasis and synaptic transmission. If you want to skip ahead you can feel free to do so, but this information is worth knowing.

A Brief Lesson in Neurochemistry

Synaptic Transmission

 

 

The image above is a simplified illustration of synapse, which is connection between two nerve cells (neurons).

The brain contains about 100 billion neurons, and neurons are connected to one another in a complex web of synapses. There are over 100 trillion synapses in the brain, and each one is used to send and receive chemical signals from neurons.

Neurotransmitters are created and stored in pre-synaptic neurons as seen at the top of the illustration. Once released, they are absorbed by the post-synaptic neurons as seen at the bottom.

Both pre-synaptic and post-synaptic neurons contain receptors that regulate how much a neurotransmitter is released and how much it is absorbed. When DA is flooded into a synapse, it will “vacuum up” any excessive DA back up into pre-synaptic receptors.

Drugs like cocaine work preventing this “vacuuming” effect (typically by blocking the action of a transporter called DAT). This process is commonly referred to as reuptake inhibition. Antidepressants like Zoloft and Prozac share this mechanism, but act as serotonin reuptake inhibitors instead.

 

Homeostasis

homeostasis

The brain is constantly trying to maintain homeostasis: a stable, steady state of equilibrium. If you abuse a drug like cocaine, your brain will be constantly flooded with unnaturally high amounts of DA. Your brain will recognize this, and will respond by downregulating the amount of post-synaptic receptors, decreasing your sensitivity to DA.

In reality, these neurological processes are much more complex than this, but this will give you a general idea of how homeostasis works. Many people who are familiar with these basic concepts will understand the limitations of trying to raise DA levels.

These feedback mechanisms partially explain why drugs like cocaine are so addictive. Once the effects of the drug wear off, repeated doses will be required to maintain high levels of DA. Over time, baseline DA levels will decrease due to this downregulating effect.

These self-correcting steady-state mechanisms of the brain are not limited to drugs of abuse; the brain is constantly making adjustments to maintain a consistent state, from even the most trivial of activities.

 

Methods of Upregulation

Fortunately, there do appear some effective ways of increasing average DA levels over the long-term. This list will include both supplements and physical tasks; I will attempt to explain the mechanisms behind each in relationship to this goal.

 

Uridine

Uridine is a naturally-occuring nutrient and nootropic that is critical for brain function. It is ubiqitous in nature as it used to form RNA in the brain and is produced in the bodies of all living creatures.

Uridine works by repairing dopaminergic neurons and preventing overstimulation in the striatum.1https://www.ncbi.nlm.nih.gov/pubmed/83720962https://www.sciencedirect.com/science/article/pii/009130579500169W3https://www.ncbi.nlm.nih.gov/m/pubmed/2050447118https://www.ncbi.nlm.nih.gov/pubmed/2906500

By preventing overstimulation of striatal DA receptors, uridine may help promote more stable and consistent levels of circulating DA in the brain.

Accordingly, uridine has been shown to enhance DA release through potassium channels. In rats, striatal DA levels were measured after 6 weeks of supplementation. DA release was shown to be significantly higher in treated rats; the treatment group had basal DA levels of 341+/-21%, while the control group had basal DA levels of 283+/-9%.4https://www.ncbi.nlm.nih.gov/pubmed/16055952 This measurement was seen after both 1 and 6 weeks of supplementation.

Taken together, it would appear that uridine may upregulate DA by both preventing excessive DA levels and by repairing/restoring neuronal DA functionality.

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CDP-Choline

CDP-Choline, also called citicoline, is a naturally-occuring compound and nootropic that is typically supplemented to improve cognitive performance.

In one study, CDP-choline was provided to aged rats over the course of seven months. After seven months, levels of striatal DA were measured. In the one treated group, a dose of 100mg/kg was used, and an 11% increase of DA receptor densities was found. In the another treatment group, a dose of 500mg/kg was used, and this time a 18% increase was found.5www.ncbi.nlm.nih.gov/pmc/articles/PMC1908237/

Interestingly, a third group received no citicoline at all, and they showed a 28% decrease in receptor density. This is because DA receptor densities decrease with age, at a rate of about 3% per decade.6https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1991.tb12471.x

The exact mechanism by which cdp-choline upregulates DA is unclear. However, CDP-choline does provide neuroprotection for dopaminergic neurons7https://www.tandfonline.com/doi/abs/10.1080/10623320600934341, and this protection play a key role.

It should be noted that the differences between the treatment groups and the nontreatment group was quite significant. Additionally, given that rat lifespans are quite short, 7 months is quite a long time, which suggests these changes may be permanent.

Buy CDP-Choline at Pure Nootropics

 
 

Forskolin

Forskolin is an herbal extract that is touted for many alleged health benefits. It has many interesting properties that warrant further research, but one of the lesser-known properties of the plant is its effect on DA receptors.

Forskolin has been noted to upregulate DA receptor densities quite significantly. In the first study I will be referencing, supplementation was shown to modify two unique DA receptors: D2L, and D2S.

  • D2L: a “long form” post-synatic receptor,  which allows DA to get absorbed and utilized
  • D2S: a “short form” pre-synaptic receptor, which regulates DA synthesis, storage, and release

In regards to receptor densities, forskolin increased D2L receptor densities by 43%, and increased of D2S receptor densities by 107.5%.9http://www.ncbi.nlm.nih.gov/pubmed/9353595

In short, what this study suggests is that the brain:

  1. Becomes sensitized to DA by increasing its availability to be absorbed
  2. Becomes more effective at regulating DA release, which may maintain stable DA levels over the long-term.

In the next study, rats were directly injected with forskolin into their cerebrospinal fluid for 5 days. Afterwards, it showed the same results as the previous study; increases in both the post and pre synaptic densities. Interestingly, D1 receptor densities were decreased.9http://www.ncbi.nlm.nih.gov/pubmed/9353595

In this third study relating to forskolin supplementation, similar results were found. In rats, D2L receptor densities were increased by 43-96%, which indicated DA supersensitivity.13https://www.sciencedirect.com/science/article/pii/0922410694900817

The results of this are a bit more ambiguous, especially in regards to the ratio of receptor changes. However, as the 3rd study indicated, it would appear that forskolin does in fact lead to DA sensitization in the brain through modulatory effects on DA receptor densities.

Buy Forskolin at iHerb

 
 

Inositol

Inositol, also referred to as Vitamin B8, is a molecule that is structurally similar to glucose. It is critical for cellular signalling in the brain and facilitates communication between neurons.

Inositol is considered a pseudovitamin, as inositol is metaboized in the kidneys from glucose. However, it may be a key nutrient in regulating mental health, and deficiencies have even been implicated in schizophrenia.14https://www.ncbi.nlm.nih.gov/pubmed/1352895

There is some emerging evidence that suggests inositol may be able to elevate DA levels over a long period. One notable study was conducted recently to determine the effects of inositol on mental health by analyzing its effects on various neurotransmitters.

In this study, guinea pigs were given oral inositol (1.2 g/kg) for 12 weeks (about 15-20g a day for humans). The result were promising: chronic inositol induced a significant increase in striatal D2 receptor density.8https://www.ncbi.nlm.nih.gov/pubmed/11267629 There was no data on whether this effect is maintained after treatment nor the degree to which the densities were changed depending on dosages used.

Inositol is known to be a key signalling agent for neurotransmission, which may be enhanced by regular supplementation. As such, upregulation may occur in part due to the increased cellular communication.

Buy Inositol at iHerb

 
 

Exercise

Lately, the mental health benefits of exercise are gaining a lot of traction. There is now an increasingly large amount of evidence that exercise can increases DA receptor availability in the striatum.11https://www.ncbi.nlm.nih.gov/pubmed/26503310

In one study, exercise was shown to reduce the neurological damage that occurs from methamphetamine abuse. Adult men and women with methamphetamine dependence were given supervised exercise therapy while recovering. After exercising for three days a week for 8 weeks, the treatment group showed a significant increase in striatal D2/D3 function.11https://www.ncbi.nlm.nih.gov/pubmed/26503310

One rat study showed similar results. Rats were subjected to eight weeks of a food-reinforced running-wheel exercise. Levels of DA were noted to be upregulated after the eight week period, although a compensatory downregulation of the receptor densities was also noted.12https://www.mdpi.com/2076-3425/3/1/39/htm

The upregulatory effects of exercise on DA levels does not not appear come from modulating receptors. Rather, it was found that DA binding affinity was increased.12https://www.mdpi.com/2076-3425/3/1/39/htm

Additionally, this study suggested that exercise training upregulated DA by increasing levels of serum calcium. This is because the enzyme responsible for DA synthesis (tyrosine hydroxylase) is partially mediated by calcium influx in the brain.

It’s unclear which form of exercise is most effective. A mix of weight training, HIIT, and cardio is generally a safe bet.

 
 

Sunshine Exposure

Here’s another behavioral change you can implement to increase DA sensitivity. In this study, the goal was to identify the correlation between sunshine exposure and DA levels. This was accomplished by comparing 68 volunteers who had either high levels of sunlight exposure or low levels sunlight exposure.

The study found that striatal D2/D3 receptor availability was significantly greater in the group with high exposure than the low exposure group. This was even after controlling for age, sex, and smoking status.20https://www.ncbi.nlm.nih.gov/pubmed/20875835 Furthermore, this does not appear to be related at all to Vitamin D levels. This means that sunlight is not only essential for synthesizing vitamin D in the body, but also for dopaminergic regulation.

 
 

Meditation

While scientific evidence on meditation is still in its infancy, there is emerging evidence of many incredible benefits to brain health and function. There are two studies which show that meditation modestly increase DA levels, although effect did not appear permanent unless it was practiced regularly.15https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044190/16https://www.ncbi.nlm.nih.gov/pubmed/11958969/

One very interesting study measured spontaneous eyeblink rates, which is strongly correlated with striatal DA activity. Here, the authors stated that meditation has been shown to affect cognitive functions such as mind wandering, cognitive flexibility, and attention. These cognitive functions, in turn, were shown to be correlated with eyeblink rates as well.

The goal of this study was to determine the effects of long-term meditation on eyeblink activity; the results of which can be used to infer the effects on striatal DA levels.

Both long-term meditators and new meditators were examined over 8 weeks of a mindfulness-based stress reduction course. The long-term meditators were found to have blinked less often and had a different pattern from the the new meditators.17https://www.ncbi.nlm.nih.gov/pubmed/26871460

The study concluded that “long term meditation practice induces stable changes in baseline striatal DA functioning.”17https://www.ncbi.nlm.nih.gov/pubmed/26871460

The authors mentioned that individual differences in DA function may have acted as a self-selection factor in meditation practice. In other words, people with specific DA levels are more likely to practice meditation. While this is a possibility, I find it very unlikely that this accounts for every individual case. More studies are urgently needed.

 
 

References

  1. https://www.ncbi.nlm.nih.gov/pubmed/8372096
  2. https://www.sciencedirect.com/science/article/pii/009130579500169W
  3. https://www.ncbi.nlm.nih.gov/m/pubmed/20504471
  4. https://www.ncbi.nlm.nih.gov/pubmed/16055952
  5. www.ncbi.nlm.nih.gov/pmc/articles/PMC1908237/
  6. https://bpspubs.onlinelibrary.wiley.com/doi/pdf/10.1111/j.1476-5381.1991.tb12471.x
  7. https://www.tandfonline.com/doi/abs/10.1080/10623320600934341
  8. https://www.ncbi.nlm.nih.gov/pubmed/11267629
  9. http://www.ncbi.nlm.nih.gov/pubmed/9353595
  10. https://www.ncbi.nlm.nih.gov/pubmed/9376541
  11. https://www.ncbi.nlm.nih.gov/pubmed/26503310
  12. https://www.mdpi.com/2076-3425/3/1/39/htm
  13. https://www.sciencedirect.com/science/article/pii/0922410694900817
  14. https://www.ncbi.nlm.nih.gov/pubmed/1352895
  15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3044190/
  16. https://www.ncbi.nlm.nih.gov/pubmed/11958969/
  17. https://www.ncbi.nlm.nih.gov/pubmed/26871460
  18. https://www.ncbi.nlm.nih.gov/pubmed/2906500
  19. https://www.ncbi.nlm.nih.gov/pubmed/11981225
  20. https://www.ncbi.nlm.nih.gov/pubmed/20875835

14 thoughts on “How to Upregulate Dopamine Over the Long-Term”

  1. The meditation, excersise and b8 didnt give any actual data for the increase which leads me to believe receptor density increase by these methods are negligible. The herb was shockingly good I take daily doses of tianeptine sulphate and CDP form of choline,will probably add in forskolin and uridine but these have made a big difference in motivation energy mood and focus so I can vouch for a few of these.

     
  2. Hello,

    thank you for the informative and well-researched article.

    Would you advise using all these strategies together (obviously uridine and choline; yes)?

    These strictly have to do with the upregulation. So things like Memantine and huperzine A don’t fall into that category because they; as I understand it – are used to ward off tolerance if one uses ADD medications.

    How about Bromantane and Pregonole?

    Do upregulation and tolerance avoidance go hand in hand? Or do you have to choose between one or the other?

    Can you just throw everything in there or is that a BIG NO NO!!:)

    Kind regards,
    Patrick

     
    1. Hi Patrick

      I would suggest staying away from memantine period, it’s a very complex drug and it’s really not worth taking just to reduce tolerances to other substances. Bromantane is interesting, it’s unclear whether its a safe and reliable way of upregulating dopamine but I may do some more research and see if it belongs on this page. The other two you mentioned don’t really fit in here, overall tolerance and upregulation are two totally seperate processes.

      But in short, yes in theory you could start taking all the compounds in this post. The only problem is that it will be harder to figure out the optimal doses for everything if you’re taking it all at once. The biggest risk you have might come from excessive uridine or cdp choline, which can cause flat moods as they both raise acetylcholine quite a lot as well.

      Thanks,

      Jacob

       
  3. You say long term but there haven’t really been any long term studies on humans with these compounds right? I’m curious what makes you think that for example the inositol induced increase in dopamine receptor density will stay after you stop taking inositol. Or do you have to keep taking it?

     
    1. My theory, and perhaps I should have explained this better, is that these changes last indefinitely as long as you keep taking the supplement(s). I do think in some sense that you can consider these effects permanent even if it requires continued supplemention. In the case of most if not all of these supplements, the upregulation that occurs seems to “stick” so long as you keep taking them ie your new baseline DA levels will stay higher than your previous baseline levels. That said I do think some of the supplements may induce lasting changing even upon cessation, uridine for instance actually repairs dopaminergic neurons and that in and of itself is a long-lasting effect.

       
  4. Dear Jacob,

    Would it make sense to put together a preformulated stack based on your suggestions, minus ‘tia’ that is? And what would it look like assuming it is safe and without adverse effects? Let’s say a dopaminergic maintenance stack if one was on prescribed, ADHD meds at therapeutic doses. For this, thas or the other reason my medication stops working once in a while almost overnight. I always panic as I’m a professional writer and can’t get a decent amount of work done without my meds. And I’m not talking about 8 hours of cranking out storylines. I’m much calmer now then I used to be, I accept it and try to tell myself, maybe in a couple of hours. Otherwise, the worry spirals out of control, turns into anxiety. I eat (and cook) healthy, sleep enough, take long walks every day (not running, but not walking either:). But on some level, it would help to know I’m attending to my dopaminergic hygiene.

    I already take a stack with Alcar, NALT, and P.S. three times a day. More or less based on a colleague of yours. And some amino acids as well. Or is the whole idea os synergy between several of the substances you described rubbish? It’s just scary when that happens. Any advice would be much appreciated.

    Regards,
    Patrik

     
    1. Hi Patrick,

      I would think taking all of these supplements at once is fine and I doubt it would increase the risk of side effects. With tianeptine gone now, you’re basically left with uridine/cdp choline, inositol, and forskolin. Of those, the only one with notable side effects is forskolin, so I might suggest being more cautious with that. The issue with taking numerous supplements all at once is that it’s hard to fine-tune them to figure out the optimal dosage for you, plus it can be hard to pinpoint which substance is working for you and which isn’t. I would start with uridine and/or cdp-choline to see how you react to them. After that I would incorporate inositol and eventually forskolin. I should note I have not actually tried forskolin myself, but I will be sometime soon. I’m still trying to adjust to the 20g a day of inositol which does have some annoying GI discomfort.

       
  5. So what’s the best strategy? If you can’t do everything at once?
    Pick one? Skip Inositol because you need to take so much?

    or a combo or trio?

     
    1. I would strongly suggest starting with uridine and/or cdp choline at smaller doses and work your way from there. You could add in inositol to that pretty soon but I would suggest working your way up to the full 18-20g daily dose as that can cause a bit of GI discomfort.

       
  6. Hi all, several years ago I collected a lot of research and notes about neurotransmitters and it’s modulators. I’ve lost them and now I’m trying to recollect them once more, so I came across this page. I would like to give some food for thought: uridine and citicoline are probably redundant, because supplementation of one increase the other; the oral dosage for citicoline for a person of 75kg would be of about 1000mg, but as I know, sublingual administration increase bioavailability by a factor of 4-5, so the sublingual dosage shoud be 200-250mg to achieve 11% increase in D2 receptors (I don’t think that it is worth trying to achieve the 18% increase, because to less than double the dosage you have to increase dosage by a factor of five); even if percentage of receptors increase with inositol is not reported, I don’t think is negligible, because at high dosage it has the same efficacy of SSRIs for OCD and there are studies that reports a noticeable increase in SSRIs for OCD; about forskoline I don’t have a reference on dosage, but it worried me more than others supplements due to the risk of developing mania (inositol don’t increase responsiveness to amphetamine like substance, while forskoline does).

    And last, I would cite the use of ultra low dose antipsychotic.

     
  7. Hi Jacob,

    First off thank you for this wonderful article.

    Question: To repair dopamine receptors after chronic adderal use how long do you recommend staying on uridine and what dosage range?

     
    1. Hi Sam,

      I would start on the low end, perhaps 100mg per day, and slowly work up 50mg a time and see how you feel. There is no universally accepted dosing regiment for uridine, it varies with the individual.

       

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