Post Menopause Libido-3/17/24

Non-Estrogen Drugs and Procedures For Post-Menopausal Sexual Health

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 ***DISCLAIMER. I have no medical, psychological, or scientific training of any kind.  This is simply a comprehensive list of publicly available information. It is a work in progress.  Please send me any corrections or additions. 

Speak to your doctor before trying anything***

This is an overview of non-estrogen drugs, procedures, and supplements that may improve sexual health in post-menopausal women. It is organized into an introduction and seven sections:

Introduction, Summary, Quick Recommendations

• Why such a list is necessary.  If these options are credible, why are they not more widely used? 

• Underlying theory and summary of the rest of the document in quick recommendations

• 1) Main Options, ranked from lowest impact to highest impact

• 2) Other Procedures, including various wands and O-shot

• 3) Supplements and Vitamins.  Some of these I think have pretty high evidence, others less so

• 4) Drugs in Earlier Stages of Development or Off-Off-Label.  Organized as Systemic Libido, Comfort/Pain, Topical Arousal.  Among these are drugs that are available now for other purposes (and thus clearly safe).  This section also includes drugs that clearly work but that do not have much active research into them

• 5) Ruled Out or Not Considered.  Includes mostly estrogen related substances, but also substances that are inferior versions of items in (1) 

• 6) Note on drug mechanisms.  Brief, laypersons overview of how relevant mood drugs work on libido

• 7) Random notes.  Assorted products, notes, etc.  I also have a separate list of secondary psychotropic drugs or really random finds, but this list is long enough as a first cut of easily obtainable, safe, and effective drugs. 

Introduction

• The purpose of this review is to provide a menu of sexual health options for post-menopausal women who want to avoid estrogen related substances, because of a history of breast cancer or for any other reason. The idea is to try to create an end run around estrogen (and possibly testosterone) and eliminate the need for it (for libido purposes).

• While the list is tailored for postmenopausal women, it will have useful ideas for pre-menopausal women, men, trans people, or people with post SSRI sexual dysfunction (PSSD).

• Can we find answers where most doctors cannot?  It is not that dramatic. There are studies that suggest these substances work and there are even more studies that show they are safe.  This is not ivermectin and there is no conspiracy.  Many doctors know about all this and have created similar lists. I link to some of them below.  Doctors prescribe these drugs off-label all the time.  You just don’t know about it because there is no money in marketing generic drugs.

• Can the answers to such a basic question hide in plain sight?  I give you the case of GLP-1 agonist drugs for weight loss (Ozempic etc).  In 2023 these drugs burst onto the scene and are now revolutionizing healthcare in the developed world. But the truth is that they have been around since 2005 and approved for weight loss since 2014.  You just didn’t know about them until now due a complicated set of regulatory, social and market factors.  Similar factors hold back solutions for sexual health in post-menopausal women.

• If you have training that I do not, you will find mistakes in my comments below.  But you should highlight them to me or you should WRITE YOUR OWN REVIEW instead of telling women “just take estrogen, oh you can’t? Too bad” and giving the topic no further thought.

• Low libido is only a problem if you think it is. There is no “correct” level of libido.  There is a large contingent of people who believe you should not try to “fix” your libido in any other way than improving your relationship, if even that.  This group says that “Low libido is not a problem to be solved”.  Decide whether you are in that group and if you are, stop reading.  If you don’t want sex and don’t want to want sex, there is nothing wrong with you.

• If you do view low libido as a problem, that does not mean is a chemical or physical problem.  It is often driven, in whole or in part, by relationship or personal issues.

• But there are many people who have a first or a second order desire to have higher libido, who are distressed about it, and who do not believe that most or any of their libido decline is relationship-related.  This list is for them.

• Some libido issues are chemical or physical and are unwanted, and the medical community does not give enough attention to these for women. Because pharmaceutical solutions are not as easy as they are for men, or are heavily reliant on problematic estrogen, there is an excessive focus on the idea that something must be wrong in some part of a woman’s life or relationship.  It must be in her head in an emotional sense.  Maybe, but maybe not.  Download the main books by Emily Nagoski and Esther Perel, two influential authors on sex and relationships, or the recent one by Fogel and Vencill, and do a word count for “menopause”. It is shocking how little it even comes up.  Nobody ever says to a 55 year old man that an erection problem, or even a libido problem, is in his head or in his relationship.  But for women that is our default response.

• It is not wrong to use substances for this purpose, provided the questions above have been thoroughly examined and safety questions are addressed first. We use substances and procedures for just about every other physical and mental health condition, including aging and other “natural” changes like hair loss.  Hair loss is not a “problem to be solved” either, and yet many people (men and women) want the hair they had ten years ago.  Aging and physical decline is a reality in all our lives. That does not mean we have to like it.

• Yes, obviously not all desire is spontaneous.  Much of it, especially for women, is responsive.  Nothing here precludes the idea of responsive desire being the dominant model. These ideas would just create more “response” in the responsive desire.

• I do not want to oversell any of this.  This list is a mix of high quality studies that find modest effects, lower quality studies that do not replicate, and substances that are barely studied at all but have some small evidence behind them.  It seems easy to create a study that finds a positive effect for a supplement, for example.  I suspect this is the result of publication bias.   That’s why the first question to ask is always the side effect profile.

• This is a great paper that criticizes the study designs of other papers and prompts some humility (from me, anyway):

  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691110/

• Note that drugs are different for everyone. There are many people who believe some of the substances here (Wellbutrin, Buspar, Vyleesi) have caused sexual dysfunction.  I do not think this a likely outcome for most people, but I would encourage you to read the PSSD (Post-SSRI Sexual Dysfunction) community on Reddit.

• Last, people get hung up on specific definitions of HSDD, FSIAD, FSAD, FSD, FOD, arousal, libido, sex drive, and other terms. These are important distinctions, but the categories are all connected.  The conditions feed into each other and what works for one condition might work for another.  Indeed, the interconnectedness of various terms is why some of these categories have been merged in the latest DSM manual.

Memo: Blood Test and Cancer

• The main sex hormones are obviously a separate issue and they are what bring us to the topic of libido in the first place.  But it is worth a blood test to check on a few other items that can hold back libido and could signal other health issues, especially thyroid and prolactin levels.  Thyroid issues are unlikely unless one has other symptoms, but elevated prolactin can be the result of a (benign) tumor that is often unnoticed.  Elevated prolactin can also be caused by Buspar.  https://www.sdsm.info/female-diagnostic-tests/blood-tests

• If you are pursuing non-estrogen options, it is presumably because cancer is a particular concern.  The only substance on this list that I have extensively reviewed for breast cancer risk is testosterone. But note that many of the substances here have some sort of link to cancer, mostly anti-cancer but some pro-cancer.  For any substance you choose to take, you should research the cancer benefit/risk in detail and discuss it with your doctor. 

Summary

Theory:

The theory behind these recommendations is that sex drive* is a multi-directional relationship between the different parts of brain and the body. All the pieces work synergistically such that the whole is more than the sum of the parts.  Two individual treatments might not have much effect by themselves, but then the same two treatments might work well together or with a third.  Increasing the volume on one instrument does not make a symphony.  Depending on how you count, there are 8-10 separate biochemical “instruments” to create libido. 

Another way of looking at this, the “dual control model” systematized by Bancroft and Janssen, is that the brain has various libido accelerators and brakes, grouped into the Sexual Excitation System and the Sexual Inhibition System. The SES facilitates the response to environmental stimuli and triggers arousal at sexual cues. The SIS provides all the reasons not to engage in sexual activity: social or moral constraints, fear, distraction, performance anxiety, etc. Bancroft and Janssen argue that the two systems work more or less independently of each other and that it is the balance between them that determines the outcome. They do not detail the neurotransmitters involved, but it seems that serotonin acts as a brake, while dopamine and norepinephrine act as accelerators.  Some of the links in Addyi section and the oxytocin section do a good job illustrating the interconnected nature (especially the patent application). You basically want to increase dopamine and norepinephrine while decreasing serotonin. Prolactin has a clear “brake” role. Acetylcholine and histidine are other neurotransmitters that either take everything where it needs to go or are directly involved in arousal and attention. Oxytocin, melanocortin, alpha-1, 2 adrenergic antagonists, and sex hormones either to tie it all together or stimulate the correct mix of other neurotransmitters.  This is a good overview: https://www.psychiatrist.com/jcp/targeting-circuits-sexual-desire-treatment-strategy/

See section at the end that discusses the various dopamine and serotonin receptors.  

Other supplements and PDE5 drugs then work on the physical side, mostly via circulation, or adjust the neurotransmitters above.  So if you combine testosterone (if appropriate), Buspar, Wellbutrin/apomorphine, oxytocin, PDE5 drugs, and supplements, it should provide a little bit of all the ingredients.  Melanocortin agonists (Vyleesi) and alpha-1, 2 antagonists (phentolamine, yohimbine/Rauwolscine) are optional adds ons if necessary. 

This is not a matter of just doubling up on more and more substances. The approach outlined here is not analogous to taking Advil, Aleve, and Celebrex all at the same time. Those drugs are all in the same class, NSAIDs, and you would risk overdose. The categories of substances I list in this review work on different parts of the system, adding up to a coherent whole. A closer analogy would be taking nausea and pain meds post surgery to target different recovery problems.  

I would not get too caught up in exactly what sequence of what hormones drive which neurotransmitters and which physical and psychological effects.  They all work together. 

In my view, this is why many drugs fail in trials. They are too focused on one part, when what you need is a combination. It may not be necessary to use all of these ideas at once, but experimenting with different mixes is a good idea (with doctor supervision). It is better to take small doses of many substances (ticking each category box) than a large dose of one substance.  Most of these drugs and supplements play well together, and I have indicated where they might not, but you should ask your doctor

*Sex drive is not a “drive” in the sense of being a biological imperative.  This is a popular point to make, but making it does not accomplish much, outside of intra-psychology debates. As the word “drive” is normally used, it is indeed a drive, much as we have a “drive” for many non-biological needs, like connection or career success.  Insisting that sex drive is not a “drive”, and reclassifying it as an “incentive motivation system” is just a word game.  The urge toward sex is an incentive that is strongly or not strongly held, and it is spontaneous or it is responsive, and we can have it as either a first or a second order desire (wanting something versus wanting to want something.) 

These are lists (some by doctors) that are quite comprehensive:

• https://poynorhealthnewyork.com/sex-low-libido

• https://poynorhealthnewyork.com/sex-after-breast-cancer/09h8cr5ji1udayxthc39lw6vj66ykq

• https://poynorhealthnewyork.com/sex-and-vaginal-health-after-menopause-those-who-desire-or-cannot-use-estrogen/

• https://www.vulvodynia.com/assets/files/Drugs_in_early_clinical_development_for_the_treatment_of_female_sexual_dysfunction.pdf

• https://neupsykey.com/sex-and-pharmacological-sexual-enhancement/#CR63

• https://coda.io/d/Treatment-options-for-sexual-dysfunctions-and-PSSD_dBTFx_oXX31/Best-treatments-for-sexual-function-and-PSSD_suOnz#_luB50

Quick Recommendations for Non-Estrogen Libido:

Comfort / Sensitivity / Vaginal Atrophy:  

• Use Co2LitftV and one or more wand options / O-Shot

• Look into topical Tamoxifen gel for atrophy

• Use Oxytocin gel for both atrophy and libido 

Supplements and vitamins

Take key supplements and vitamins every day, or at least in the days leading up to sex, though see more detailed discussion and warnings in my vitamin section later in the document.  These substances include: 

• Blood flow and circulation: Gingko (every day), arginine, citrulline, Pycnogenol, beet root, ginger (important), pomegranate

• Dopamine: Mucuna Pruiens (not every day, just in days before and 90 mins before), Phenylalanine (as DLPA), Tyrosine

Neurotransmitters: 

• For Acetylcholine: Choline (not with Inositol), acetylcarnitine, B5 (pantothenic acid), Phosphatidylserine, Huperzine A, Alpha-GPC, Lecithin, CBD, Black Pepper, kaempferol.

• For histidine, take histidine (just day of and day before)

• For prolactin, take vitamin B6.  See prolactin discussion below.  This one is potentially important

-General: Zinc, magnesium, C with rose hips, D, Omega 3.

(Note that I am excluding ginseng and several others that can have pro-estrogen effects, see below.  Some of these are likely effective, so if you are not worried about estrogen you can use these.)

I would probably not take all of these at once because among other things it would just be too many pills. Just cycle different things in and out and see what works. To reduce number of pills you can also find some supplements that combine multiple ingredients if you hunt around on Amazon.  

Balancing of Dopamine, Norepinephrine, Serotonin: 

• 1-6 hours before sex, take Buspar (90 minutes before) and Wellbutrin (immediate release 90 minutes before, XR 3 hours before, SR 6 hours before).   I think there is great value in combining these two drugs, as Buspar adjusts serotonin at a particular receptor site and Wellbutrin increases dopamine.  Basically, Buspar reduces inhibition while Wellbutrin enhances pleasure. 

• An alternative to Wellbutrin would be apomorphine, ideally by nasal spray or sublingual troche 20-30 minutes before.  There is an argument that apomorphine is better than Wellbutrin since apomorphine would just be as needed.  Another alternative would be the set of dopamine specific supplements.  But you need something to tick that dopamine box. 

Alpha-1, 2 adrenergic antagonists

• If needed, add a small dose of phentolamine (alpha-1 and 2) or alpha-yohimbine (alpha-2), adrenergic antagonists (another pathway) that have some evidence. Alpha-Yohimbine/Rauwolscine is much better tolerated than regular Yohimbine.  Take 60 minutes before sex. 

Blood flow and circulation: 

• 70-120 minutes before sex take Cialis (120 mins) or Viagra (70 mins) as well as another ginger.  Oral Cialis/Viagra can be swapped out for their topical versions, or added. 

Oxytocin: 

• Then 20-30 mins before sex take oxytocin nasal spray and vaginal gel.  Sublingual will work but you have to keep it in your mouth for awhile. 

If that doesn’t work, switch one of the Buspar/Wellbutrin to be every day (sustained release for Wellbutrin). If that doesn’t work, switch both to every day.  If that doesn’t work, add Trazodone to the mix, very low dose.  Note that using Trazodone in either combination would require more care and medical advice than Buspar or Wellbutrin or Buspar+Wellbutrin (which is fine).  Speak to your doctor. 

If you are not taking Wellbutrin or apomorphine, the dopamine supplements are useful. If you are, don’t double up by taking them, or maybe take less. 

This list covers just about every non-estrogen part of sex drive. The one exception is melanocortin, in particular the MC4R receptor, which is implicated in sex drive.  The only real way to target that pathway is with Vyleesi.  This drug is highly effective but the side effects can be unpleasant. However, not everyone has the side effects, so it is worth trying if you find something extra is needed.  Nasal spray might be a good option here and might have fewer side effects.  And if you are doing everything else listed here, the needed Vyleesi dose would be very small, since we are just trying to tick that last box of MC4R. Note that Wellbutrin might also target melanocortin, see section below.  

Evaluate testosterone as appropriate, while considering other health issues first.  

Boxes to tick represented by the above list:

• Comfort and physical: flexibility

• Comfort and physical: circulation and sensitivity

• Dopamine and norepinephrine (increasing/agonizing)

• Serotonin (mainly agonizing 5-HT1A and antagonizing 5-HT2A)

• Oxytocin (increasing)

• Acetylcholine (increasing)

• Histadine (increasing) 

• Alpha-1, 2 (antagonizing, optional choice A) 

• Prolactin (reducing) 

• Melanocortin MC4R (agonizing, optional choice B)

• Testosterone (supplementing, if appropriate)

1)  Main Options

Low impact

Oral PDE5 Inhibitors/ED Drugs (Viagra, Cialis, Levitra, Stendra)

Erectile dysfunction drugs work by increasing blood flow to erectile tissue.  Erectile tissue is obviously in the penis but it is also in the nostrils and the vulva, especially the clitoris.  These drugs have no mental or hormonal connection. If they were to work on women, the theory would be that increased blood flow leads to more sensitivity and better lubrication, and that this sensitivity creates a positive mental feedback loop.  

Most studies do not show much benefit for women, certainly not in spontaneous desire. They do sometimes show a benefit with responsive arousal and with reaching orgasm.  Many women anecdotally feel it is more helpful than the studies suggest, and note that the positive physical effects seem to create positive mental effects.  Also, as I detail below, a Dutch company called Freya Pharma is researching formulas that include as-needed Buspar, Testosterone, and Viagra. So they at least think that if you combine a little bit of mental and a little bit of physical, you get positive feedback loops. 

Topical Viagra (see below) operates by the same principle and is intended for and widely used by women (still off label).   

Viagra is the oldest drug in this class and has the most side effects.  Cialis would be better to use, at least orally, and can be taken every day if necessary. Stendra is the newest and best but is also very expensive.  These drugs are low risk and if you start with small doses, you get a sense for side effects, if any. 

• https://hellocake.com/products/libido-lift-rx-hello-cake-intake/

• https://www.vice.com/en/article/dy3wwk/why-women-are-experimenting-with-viagra-now

• https://www.nature.com/articles/nrurol.2009.25

• https://www.goodrx.com/health-topic/womens-health/can-women-use-viagra

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1480594/

• https://www.verywellhealth.com/can-women-take-viagra-sildenafil-7547644

• https://pubmed.ncbi.nlm.nih.gov/12969584/

• https://www.vogue.com/article/womens-pleasure-menopause-viagra

It might be the case that PDE5 inhibitors require the presence of estrogen or testosterone to work properly.

https://www.sdsm.info/female-treatments/pde5-inhibitors

Topical PDE5/ED Drugs-Scream Cream (or OMG! cream)

This is topical Viagra (sildenafil) along with some other vasodilators and (usually) arginine.  Its main use is to increase orgasm frequency and ease, along with sensitivity and lubrication.  Sildenafil and related drugs are very safe for men and for women.   Despite being the same mechanism of action as oral ED drugs, topical has received more positive studies for women.  Various companies are seeking FDA approval for this, but in the meantime it has been available for many years and can be easily acquired online with a teledoc prescription. 

Notably, the main company seeking approval, Daré Bioscience, claims that their phase 2 data demonstrates improvement across multiple dimensions, including desire, orgasm, and arousal.  

• https://darebioscience.com/pipeline/sildenafil-cream/

• https://ir.darebioscience.com/news-releases/news-release-details/dare-bioscience-present-international-society-study-womens

• https://pubmed.ncbi.nlm.nih.gov/29176500/

• https://hellowisp.com/products/omg-cream

• https://www.thehcginstitute.com/scream-cream

• https://nationalpharmacyrx.com/womens-health/sildenafil-cream-for-women/

Wisp OMG cream is a 1% Sildenafil concentration. BayView Pharmacy and HCG have various formulations of both Sildenafil and Tadalafil at higher than 1%.  HCG seems highest at 4%. Mobile Healthcare Shop has several such creams. It also has Oxytocin gel (see section below).  A few of these formulations have Nitroglycerin, which has been shown to help (see last section). 

https://mobilecarehealth.shop/product/womens-sexual-health/

A similar approach would be topical Alprostadil, which is a vasodilator that works differently and is approved for men in Europe and Canada. See last section. 

CO2LiftV

CO2LiftV delivers carbon dioxide topically to improve blood flow, improving vaginal sensation, lubrication, and wall thickness. The approach here is an age old theory about carbon dioxide and is very sound.

CO2Lift and CO2Lift V are often offered by dermatologists, see below for example.  Their webpage also talks about aging and about pairing it with their Viveve laser. It is also generally the case, throughout this topic, that the same treatments are often indicated for both tightness and looseness, since the objective is flexibility.  

• https://weloveskin.com/dermatology-blog/why-were-obsessed-with-this-new-v-product

• https://weloveskin.com/procedures/sexual-health 

• https://www.lovelyskin.com/c/co2lift?search_origin=AutoComplete&term=co2&sp=constructorio

• https://co2lift.com/products/co2liftv-the-at-home-carboxy-vaginal-treatment-kit-3-count

• https://artisanofskin.com/products/co2-liftpro-3-count?variant=47732705296667#

• https://pubmed.ncbi.nlm.nih.gov/33878192/

Here is a similar study that looks at application to the face:  https://cdn.shopify.com/s/files/1/2382/3079/files/Study-On-CO2Lift-Carboxy-Gel.pdf?v=1640725407

And a more general study https://www.mdpi.com/1422-0067/24/6/5181

CO2LiftV seems speculative but low risk. But it does have at least one study backing it up (albeit with a small sample size).   

CO2Lift has a normal version and a “pro version” that is less available but 30% better. See one of the links above. 

See last section for Carboxytherapy, which is a similar idea but with a more invasive delivery.  

Moderate Impact (could be high, hard to say) 

Oxytocin

Oxytocin seems promising for both libido and physical and mental health.   Despite its name, it is not an opiate and has nothing to do with OxyContin.  It is available as a nasal spray, a sublingual pill, or a vaginal gel/cream, all via online pharmacies.  Oxytocin has a major role in creating bonds between people during sex, emotional connections outside of sex, and it acts as a barrier to sexual interest in others. It seems like there is a lot of evidence for Oxytocin, but I don’t want to give the impression that it has gold standard research attached to it.  The Vox article below contains a good overview of some of the research limitations. Oxytocin is widely viewed as overhyped, but it is still intriguing. 

Several hours before administering Oxytocin it may be useful to take Vitamin C, Zinc, and Magnesium. This apparently helps it work properly.  It seems quite possible that nasal spray would help with desire and orgasm and that gel would help with discomfort and possibly with orgasm.  Note that its mechanism of action might be enhanced by the presence of estrogen, though that isn’t clear because the gel/cream mostly seems to be for postmenopausal women, and Oxytocin also works well for men.  

Below is a patent application made by a highly credentialed Boston psychiatrist.  She does a very good job outlining my basic theory of how all these substances work synergistically. 

• https://hellocake.com/products/libido-lift-rx-hello-cake-intake/

• https://patents.justia.com/patent/20220080024

• https://www.renewyouth.com/hormone/oxytocin-in-women/

• https://www.harborcompounding.com/oxytocin-intranasal-spray

• https://www.transformyou.com/about-oxytocin

• https://pubmed.ncbi.nlm.nih.gov/32169019/

• https://www.nbcnews.com/health/health-news/oxytocin-keeps-attached-men-away-hot-women-flna1c7048131

• https://www.universityofcalifornia.edu/news/oxytocin-helps-old-muscle-work-new

• https://www.vox.com/science-and-health/2019/2/13/18221876/oxytocin-morality-valentines

There are several studies using Oxytocin vaginal gel instead of estrogen for atrophy in cases where estrogen is to be avoided.  Most have found success. 

• https://bmcwomenshealth.biomedcentral.com/articles/10.1186/s12905-020-00935-5

• https://www.tandfonline.com/doi/abs/10.1080/0092623X.2020.1738606#:~:text=The%20results%20of%20this%20study,in%20hormone%20therapy%20is%20recommended.

• https://www.issm.info/publications/research-summaries/the-effect-of-oxytocin-gel-on-vaginal-atrophy-in-postmenopausal-women

• https://www.harborcompounding.com/oxytocin-vaginal-gel

• https://www.bayviewrx.com/formulas/Oxytocin-120-U-Gm-Vaginal-Gel-Postpartum-Hemorrhage-Uterine-Atony-Retained-Placenta-Incomplete-Abortion-Subinvolution

Though to be clear, what seems to me the highest quality study did not find an effect:

https://bmcwomenshealth.biomedcentral.com/articles/10.1186/s12905-023-02645-0

Note that the above study mentions Oxytocin as having some anti-cancer properties, and the first below study talks specially about anti-breast cancer specifically.  I have a much longer write up on Oxytocin and breast cancer. 

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6153127/#:~:text=Using%20cell%20viability%2C%20invasion%2C%20and,as%20a%20measure%5B69%5D.

• https://www.nature.com/articles/s41388-020-01415-8.pdf?pdf=button%20sticky

• https://papers.ssrn.com/sol3/papers.cfm?abstract_id=4081669

• https://mobilecarehealth.shop/product/womens-sexual-health/

• Forms of Oxytocin:

• Nasal Spray: This is the most common form for non-medical use. It’s easy to administer, and absorption through the nasal mucosa is generally efficient. It’s often used for social bonding, stress reduction, and potentially libido enhancement.

• Sublingual Tablet: Placed under the tongue for quick absorption into the bloodstream, avoiding the digestive system for more efficient uptake. Used for similar purposes as the nasal spray.

• Vaginal Gel: More specialized and may be focused on sexual health or reproductive issues. Less common for general use compared to the other forms.

Moderate to High Impact

Wellbutrin (Buproprion)

Wellbutrin is an NDRI (Norepinephrine Dopamine Reuptake Inhibitor).  It is an anti-depressant that is also used off-label for anxiety.  Many studies have found that it helps with sex drive, presumably by increasing dopamine and norepinephrine—activating the “Sexual Excitation System”, in Bancroft and Janssen’s terms. Notably, a decline in estrogen tends to decrease dopamine production cells, so supplementing dopamine makes some sense and represents a key part of our “end run” around estrogen. See Yale link below. 

Wellbutrin does not work for everyone but it definitely does work for some. There are studies that show this and there are countless anecdotes.  I think there are two approaches: 1) actually be on Wellbutrin; 2) take a dose of Wellbutrin immediate release several hours before sex.  There is evidence that it can work on an as needed basis, referenced by the Harper’s article below and by the research on Lorexys (below).  

I think Wellbutrin (especially combined with Buspar) is likely as or more effective than Vyleesi or Addyi, with a much better side effect profile. 

Interestingly, some research suggests that a lower dosage of Wellbutrin is more effective than a higher dose, though little has been written on this and I find it hard to believe (it is referenced in the nih.gov meta analysis below).   

Wellbutrin also appears to target the melanocortin receptors. But for such an old and well-studied drug, I can find very little research on Wellbutrin and melanocortin.  “To our knowledge, bupropion does not activate MC4R directly however there is evidence supporting an indirect activation of MC4R via modulation of POMC and/or α-MSH expression”

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7023989/

• https://www.frontiersin.org/journals/psychiatry/articles/10.3389/fpsyt.2021.764720/full

Wellbutrin is one of the most well-studied and longest, most widely used anti-depressant / anxiety / mood pills (since 1986.) It has a good safety and side effect profile.   It is the 18th most commonly prescribed drug in the US.  Too high a dose of Wellbutrin can cause seizures at 3x the rate of other mood drugs, so that dose level is worth being aware of. 

Note that some people find the positive effect from Wellbutrin to be almost immediate and for others it can take two months or so.  Others notice nothing at one dose and then the entire effect with a slightly different dose. For some it lasts as long as they take the drug, for others it goes away or decreases after a few months.  And for many it does not have much effect at all. It can even have a negative effect. 

• https://www.harpersbazaar.com/beauty/health/a1631/the-happy-sexy-skinny-pill/

• https://www.psychologytoday.com/us/blog/all-about-sex/201211/the-antidepressant-drug-best-sex

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9886814/

• https://nextlevelprimarycare.com/2021/07/taking-sex-for-a-drive/

To be clear, not every study reports positive results. But enough of them do. Here is a recent study that did not find an effect:  

https://pubmed.ncbi.nlm.nih.gov/34882500/

And this discusses the above study and criticizes the context of it:

https://ascopubs.org/doi/10.1200/JCO.21.02654?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub%20%200pubmed

Good general article, recent:  

https://karger.com/pha/article-pdf/doi/10.1159/000535587/4149013/000535587.pdf

Related:

https://medicine.yale.edu/news/yale-medicine-magazine/article/estrogen-deprivation-associated-with-loss-of-dopamine-cells/

Buspar (Buspirone) 

Buspar is an anxiety drug that has been found to enhance libido in some studies, though it comes up less frequently than Wellbutrin and it is usually for people who are taking an SSRI that is suppressing sexual interest.  Buspar works differently than Wellbutrin.  It is a partial serotonin 5-HT1A agonist, meaning that it selectively activates serotonin at that specific receptor site, which apparently leads to a serotonin reduction in the correct part of the brain and a small increase in dopamine.  That site has been identified as being involved in sexual response.  Addyi is a full agonist at that site.  I think the connection with anxiety is that 5-HT1A is effectively part of the “Sexual Inhibition System”.

Buspar has contradictory effects on dopamine.  Agonizing 5-HT1A helps produce a dopamine response and indirectly increases dopamine.  But Buspar also antagonizes receptor D2 with low affinity, which by itself would be bad for libido. Gepirone (below) is almost certainly better on this front. 

Buspar also metabolizes into 1-(2-pyrimidinyl) piperazine (1-PP), which antagonizes the alpha-2 adrenergic receptor, which helps sex drive.  

Some research also suggests elevated prolactin can be caused by Buspirone, in some people at least.  By itself, this would have a dampening effect on libido. 

My general impression is that Buspar might be a better drug than Wellbutrin for these purposes, despite being much less studied.   Buspar has an active Reddit community that informs my view, so it is admittedly anecdotal. But, a Dutch company called Freya Pharma (see below in section 5) is currently in advanced trials for two female libido drugs:  1) Lybrido: testosterone plus Sildenafil (Viagra); 2) Lybridos: testosterone plus Buspar.  Testosterone is covered below as a separate topic, but this suggests to me that Buspar may have broader application than just for people on SSRIs.  These trials appear to be pretty far along in Europe (phase 3) and a little farther behind in the US (phase 2).  Lybrido and Lybridos are taken on an as-needed basis, which strengthens the idea that either Buspar or Wellbutrin could be taken as-needed.  These studies appear to have been very successful. 

Buspar is quite safe. It has been used since 1986 and is the 55th most prescribed drug in the US.  

The same (random) pattern for when Wellbutrin works applies to Buspar. 

• https://www.pharmaceutical-technology.com/news/female-sexual-interest-drug-reaches-tipping-point-with-phase-iii-plans/

• https://freyapharmasolutions.com/the-science-behind-lybrido/

• https://www.menopausalmedicine.com/blog/is-there-a-libido-pill-for-women

• https://nextlevelprimarycare.com/2021/07/taking-sex-for-a-drive/

https://www.ncbi.nlm.nih.gov/books/NBK531477/#:~:text=Buspirone%20is%20available%20in%205,desired%20clinical%20response%20is%20achieved.

This is a good article on both Wellbutrin and Buspar: https://www.forhers.com/blog/buspar-and-wellbutrin

Buspar and Wellbutrin should be combined.  Since they work differently, they should have a synergistic effect on libido, with Wellbutrin helping with dopamine and Buspar with serotonin receptor 5-HT1A.  One approach would probably be to be on Wellbutrin XL or SR and then to take Buspar only a day to a few hours before sex. But many people are on both drugs daily and I have personally tested this, with no side effects. But speak to your doctor about it. 

https://karger.com/pps/article-abstract/76/5/311/282319/The-Combination-of-Buspirone-and-Bupropion-in-the?redirectedFrom=fulltext

Exxua (Gepirone)

In September 2023 the FDA approved Exxua (Gepirone) a drug very similar to Buspirone and in the same class.  I am not really clear on the difference between them, but Exxua seems more focused on depression and Buspirone on Anxiety.  However, even that distinction seems to have been the result of the approval process.  I have seen reference to Exxua having fewer side effects, but I’m not sure whether this is accurate.  

Exxua’s manufacturers and some initial studies suggest this drug is effective for libido.  The link below discusses a current FDA process to test this.  Notably, compared to Buspirone, Gepirone has similar activity at 5-HT1A but much less affinity for D2 receptors. Like Buspirone, Gepirone metabolizes into 1-(2-pyrimidinyl)piperazine (1-PP), which antagonizes the alpha-2 adrenergic receptor, which helps sex drive.  

Gepirone is an old drug but it was only recently approved. When it becomes more widely available, I think it is likely better than Buspar for libido purposes. 

• https://fabrekramer.com/exxua-for-hypoactive-sexual-desire-disorder/

• https://www.reddit.com/r/BusparOnline/comments/111eobz/anyone_else_paying_to_the_development_of_gepirone/

• https://www.sciencedirect.com/science/article/abs/pii/S1743609515335037?via%3Dihub

• https://www.sciencedirect.com/science/article/abs/pii/S1743609515336559

• https://www.scopus.com/record/display.uri?eid=2-s2.0-84863394383&origin=inward&txGid=f6749f45a49676a98235e254a2bf0f44

• https://pink.citeline.com/-/media/pmbi-old-site/supporting-documents/the-pink-sheet-daily/2015/november/gepirone_ac_fk_briefing.pdf

High Impact

Vyleesi (Bremalanotide / PT-141)

Vyleesi is one of two drugs that are FDA approved specifically for HSDD. It works on libido, but not via estrogen or testosterone.  Vyleesi is an agonist of the MC4R receptor site, which is implicated in appetite, libido, and melanin.  

Some people say that Melanotan II, which is used for tanning, has fewer side effects than Vyleesi, but I have not researched this. Melanotan II is a non selective agonist of melanocortin receptors, whereas Vyleesi targets just MCR4, which is the one most clearly implicated in sex.

You take Vyleesi as needed via injection in the leg.  To be clear, Vyleesi (and Addyi, see below) are only about 25%-35% effective, just 5-10% better than the placebo, according to the studies that led to their approval. Anecdotally (as I can attest), user reviews seem much higher than this, but that’s what the data said. 

Side effects can include nausea. But the nausea seems to diminish after the first few tries, and people also pair it with Zofran.  Vyleesi’s half-life is three hours, but anecdotally the effects seem to last much longer than that. The studies, and thus the approvals, are all for premenopausal women, but as the article below notes, this is almost certainly a result of easing the FDA approval process. 

Vyleesi is also fine with alcohol, which Addyi (see below) is not. 

Vyleesi is low risk because it’s an as needed injection that wears off and it is not activating estrogen or testosterone in any way.  It does not work for everyone, but works very well for many.  It is worth reading a lot of reviews because it’s a disappointment for some and a lifesaver for others. 

Vyleesi works on men too, as it should, since it’s a general aphrodisiac.  Note that if men take Vyleesi they should be careful with taking too much or pairing with PDE5 drugs.  This is a great combo but it can lead to an overnight erection.  If you find that an erection won’t go away the first thing to do is to have a few more orgasms and the second is to take Sudafed (the real one, not the fake one).  Worst case scenario, set your alarm to go off every hour and lose your erection with cold water. Worst worst case scenario, go to the ER. 

If you try Vyleesi as either gender, it is important to experiment with the dosing.  Try to get right mix of intended effects and side effects. Vyleesi (as PT-141, available online) can also be taken via nasal spray. This is definitely less effective, but does it have less side effects?  In my personal experience, yes. It is also easier to titrate the dose to get the right level. 

I think if one were to use Vyleesi, it would make sense to use a very small dose, perhaps nasal spray, and to use it as part of a cocktail. This drug (and IMCIVREE or Melanotan II) are just about the only way to target melanocortin, which is an important part of libido. With a small dose, maybe you tick the melanocortin box without too many side effects. 

• https://www.aarp.org/health/drugs-supplements/info-2019/new-drug-women-sex-drive.html

• https://www.drugs.com/comments/bremelanotide/vyleesi.html

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9525110/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8788464/

• https://en.wikipedia.org/wiki/Melanocortin_4_receptor

• https://www.jci.org/articles/view/152341

Where to buy

• -Prescription.  But this makes it hard to regulate dosing since it is a pre-loaded syringe

• -Peptide Suppliers.  This is most cost effective. You mix it yourself.  It is actually perfectly reputable and some sort of regulatory loophole.  Try Peptide Sciences. Get bacteriostatic water and syringes from Amazon, use an online peptide calculator and do your math very carefully. Take notes. You could also mix it into a nasal spray yourself, but this will make dosing hard to figure out unless you know what you are doing

• -Nasal spray: Various online pharmacies

• https://usa.pharmagrade.store/product/pt-141-peptide-nasal-spray/?attribute_size=15ml

•  https://mobilecarehealth.shop/product/pt-141/  

• -Lozenges: mostly the same online pharmacies. This is not a great delivery method, as the stomach kills it. But some will be absorbed under the tongue. The best method would be to keep it in your mouth for 15 minutes while swishing around before swallowing, similar to oral ketamine

Testosterone

Testosterone would be the most dramatic substance to take. Because it is a hormone, anyone who has had or is at risk of breast cancer should approach this with caution. But there is a good argument that testosterone, used properly, reduces risk of breast cancer or breast cancer recurrence. 

“Data presented at the American Society of Clinical Oncology conference demonstrated the beneficial effects of T on the relief of severe hormone deficiency symptoms in breast cancer survivors (stage 0–4) …Survivors were treated with the combination of T with A combined in the pellet implant. …In addition, there was (and continues to be) a reduced incidence of breast cancer recurrence in patients treated with subcutaneous T + A implants….

T+AI implants (anastrozole or letrozole) used to treat symptoms of hormone deficiency in breast cancer patients, have also significantly reduced tumor size, including complete clinical and complete radiological responses (Fig. 7). Multiple case reports on the in vivo tumor responses to T+AI therapy have been published demonstrating the unarguable direct beneficial effect of T on invasive breast cancers.”

There are various other health benefits from testosterone, including neuro-protective effects and likely increased bone density. But obviously there is only one risk factor increase / reduction that we care about, and it is the literature on that topic that makes me raise it.  And to be clear, I do not rely on anyone else’s idea of a “safe level” because we have seen how estrogen HRT gets presented for premenopausal women.  They think a 50 bps increase is “safe”; I do not.  So what caught my eye is not the magnitude of the testosterone and breast cancer recurrence claim, but the directionality of it. 

https://www.liebertpub.com/doi/10.1089/andro.2021.0003

There is something intuitive about this in that male hormones and female hormones sort of fight each other. There is isolated data on related topics that suggests a protective effect. Ie, female to male trans people who take male hormones have lower incidence of breast cancer (presumably controlling for other changes in breasts, like, you know, removing them). 

“These findings build upon previous work showing androgen receptor activation suppresses tumor growth in estrogen receptor-positive breast cancer,” said Simon Knott, PhD (https://researchers.cedars-sinai.edu/Simon.Knott), assistant professor of Biomedical Sciences and Medicine at Cedars-Sinai, and senior author of the study. “Androgens seem to counteract the effects of estrogen and could potentially be used to prevent estrogen-driven breast cancers.”  

This study was just published in March 2023. 

• https://www.cedars-sinai.org/newsroom/study-reveals-new-understanding-of-how-androgen-therapy-affects-breast-tissue/

• https://pubmed.ncbi.nlm.nih.gov/31888528/

• https://performancemedicine.net/2022/11/01/testosterone-pellets-in-women-with-breast-cancer/

• https://drlindseyberkson.com/episode-121-testosterone-therapy-for-breast-cancer-survivors-the-science-and-mechanisms/

• https://drlindseyberkson.com/episode-119-can-cancer-survivors-take-hormones/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025725/

• https://pubmed.ncbi.nlm.nih.gov/26160683/

• https://ar.iiarjournals.org/content/38/12/6615.abstract

Most of this work comes from a handful of doctors.  But these are recent reports from different groups, some supportive, others more ambiguous. 

• https://www.avl.nl/en/news-items/2021/testosterone-may-suppress-breast-cancer-cells/

• https://www.nature.com/articles/s41591-020-01168-7

• https://www.adelaide.edu.au/newsroom/news/list/2024/02/12/strongest-contender-in-decades-in-fight-against-breast-cancer

To be clear, not everyone agrees, at least on their first pass.  The Susan Komen Center notes the common finding that breast cancer patients often have higher androgen levels.  But they don’t write much on it, and the others argue that this is an “association, not a cause”.  The study below seems to the source for that observation:

https://www.nature.com/articles/s41416-021-01392-z

But how does that fit with the trans research or the androgen vs estrogen antagonistic idea?  No clue. 

See Page 3, referencing the Nurses Health Study from 2001. This is the only explicitly negative study I can find. 

• https://www.jogc.com/article/S1701-2163(16)35385-3/pdf

• https://aacrjournals.org/cancerres/article/82/4_Supplement/P4-10-05/681078/Abstract-P4-10-05-Safety-and-efficacy-of-low-dose

Testosterone actually used to be used to treat breast cancer. 

https://ar.iiarjournals.org/content/34/3/1287

Finally, it should be noted that in 2004 the FDA denied the testosterone patch due to concerns about breast cancer.  But I think the issue was more theoretical, exacerbated by inadequate sample sizes.  https://www.nytimes.com/2004/12/02/business/fda-panel-says-sex-patch-needs-more-testing.html

As for whether testosterone actually works for womens’ libido, the studies are not as clear as you might think. But it is approved in Europe (though not marketed) and Australia for this purpose and there are various trials in the US. Most experts do seem to think it works. It definitely works for vaginal health. And testosterone is one where the popular consensus is overwhelmingly positive. I think if testosterone is combined with the items outlined above in recommendations, it works. 

• https://pubmed.ncbi.nlm.nih.gov/31353194/

• https://pubmed.ncbi.nlm.nih.gov/30521462/

• https://www.nature.com/articles/s41443-022-00613-0?utm_medium=affiliate&utm_source=commission_junction&utm_campaign=CONR_PF018_ECOM_GL_PHSS_ALWYS_DEEPLINK&utm_content=textlink&utm_term=PID100092383&CJEVENT=abaf7b97b0da11ee81319d0b0a1cb827

2. Other Procedures and Substances

Vaginal rejuvenation

Vaginal rejuvenation includes several distinct types of “wands” and various other types of procedures aimed at improving functional aspects of the vagina and vulva. This is a basic summary of rejuvenation based on pretty superficial googling.  Also this list does not include carbon dioxide application, which I covered in the section above in CO2LiftV.  

Here’s a list of the primary technologies and some specific product names:

• Low Level Light Therapy (LLLT) / Red Light Therapy (RLT)

  • Red light therapy (photobiomodulation) is a less expensive and lower power approach that is often for home use. There are various products available.  The evidence seems fairly good, and certainly low risk. See study linked in Harper’s article below. 

  • VScuplt

  • Joy Lux V Fit

  • https://www.harpersbazaar.com/beauty/skin-care/a60045046/led-light-therapy-for-vagina/

• Vibrational Therapy (Mechanical Stimulation)

  • Some vaginal wellness devices, including the Joylux VFit, also incorporate vibration therapy to stimulate muscle tone and improve blood flow. This is less well researched 

  • Perifit (biofeedback-based pelvic floor exerciser that uses vibration)

• Fractional CO2 Lasers:

• MonaLisa Touch: A CO2 laser system.

• FemTouch: A CO2 laser platform.

• Core Intima: A CO2 laser option.

• Radiofrequency (RF) Devices:

• ThermiVa: Uses RF energy for vaginal tightening and rejuvenation.

• Votiva: Uses RF and “gentle thermal tissue remodelling”. I think this is the same brand (maybe merged) as Forma V

• Viveve: Uses RF technology to treat vaginal laxity and urinary incontinence.  Viveve recently went bankrupt but was acquired by a company called InMode, a large aesthetics company

• Exilis Ultra Femme 360: Uses RF combined with ultrasound for vaginal rejuvenation.

• Extracorporeal Shockwave Therapy (ESWT):

• FemiWave and Alma Duo:  Uses ESWT for vaginal rejuvenation and to address various female sexual health concerns.

• Low intensity shockwave therapy (liSWT):  SoftWave (Urogold 100™) LiSWT device

• https://www1.statusplus.net/misc/posters/isswsh/annual2024/search/poster/98?redirect=pm

• https://www.isswshmeeting.org/2024/program. Across down to Poster Session 8 and click abstract

• High-intensity Focused Ultrasound (HIFU):

• Ultra Femme 360: Uses ultrasound technology for vaginal tightening.

• Cliovana. https://www.cliovana.com

• Platelet-Rich Plasma (PRP) or Polynucleotide Injections:  [see longer write-up below]

• O-Shot: Uses PRP injections in the vaginal area to enhance sexual function and alleviate some conditions.

• Polynucleotide (derived from salmon) has become popular recently.

• Topical Treatments:

• Platelet-Rich Plasma (PRP) Topical: Applied topically or injected to rejuvenate vaginal and vulvar areas

• Topical Carbon Dioxide, CO2Lift. Covered elsewhere.

• Hyaluronic Acid (HA) Injections

  • becoming increasingly popular in the field of vaginal rejuvenation. HA is widely known for its use in skin fillers, but in the vaginal area, it helps improve hydration and elasticity. It is sometimes combined with PRP or used on its own.

• Vaginal Inserts / Electromagnetic Energy

• Emsella: Uses electromagnetic energy to stimulate pelvic floor muscles for incontinence. While not exactly a rejuvenation device, it’s sometimes included in discussions about vaginal health technologies.

• Kegel8 Ultra (NMES technology for pelvic floor strengthening): uses electrical impulses to contract and strengthen pelvic floor muscles. It’s another method for improving vaginal tone and addressing urinary incontinence, especially in home-use devices.

https://weloveskin.com/dermatology-blog/what-are-the-benefits-of-viveve-for-female-sexual-health

Each of these technologies has some studies behind it, but none are FDA approved yet. It seems to me that the reason they are not approved is the large cost involved with the studies and the difficulty paying for it. According to the CEO of InMode (new owner of Viveve) these companies have spent upwards of $250 million collectively trying to get these approved so they can be covered by insurance, and many companies have gone bankrupt before the process is complete. 

The consensus seems to be that they work, though there are doubters.  If you Google “what type of vaginal rejuvenation technology is best” you will get the opinions of countless gynecologists.  This is a roundup of various formal studies:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5418869/

My instinct tells me that the radio frequency, shockwave, ultrasound or PRP procedures are the lower risk options.  Procedures based on laser or energy devices seem higher risk, though certainly not high risk. But I am not sure about this. 

O-Shot or Polynucleotide Injections

The O-Shot is a type of Platelet Rich Plasma (PRP) therapy. It concentrates your own blood and re-injects it back into you into the vaginal area with the intention of enhancing sexual function and alleviating certain conditions such as urinary incontinence or vaginal atrophy. The premise behind PRP treatments is that the growth factors released from the platelets can stimulate cell growth and healing in the treated area.  The O-Shot has just as much evidence as the other vaginal rejuvenation procedures.  And many reputable gynecologists and other doctors seem to think there is something to it. It is low risk. 

This is also available for men, known as the Priapus or P-Shot. It purports to improve erections and sensitivity.

Studies:

• https://journals.sagepub.com/doi/full/10.1177/15533506211014848

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7090261/

More recently, there has been some attention on polynucleotide injections, which is a similar idea but with the active ingredient derived from Salmon.

Studies and Articles:

• https://pubmed.ncbi.nlm.nih.gov/35389304/

• https://www.oatext.com/vulvar-rejuvenation-with-polynucleotides-hpt-and-benefits-on-postmenopausal-sexual-life-disruption.php

• https://www.researchgate.net/publication/337928829_Biorevitalization_of_postmenopausal_labia_majora_the_polynucleotidehyaluronic_acid_option

3. Supplements 

THC/CBD

There is a large contingent of women who swear by these substances. I am dubious, but apparently there is at least some research.  Most of this stuff is topical, though many use gummies etc. 

• https://vellabio.com/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9854104/

• https://www.nytimes.com/2022/04/01/well/live/marijuana-sex.html

I suspect most of the effect of THC and CBD is placebo, and I cannot find studies that seem designed to test for this.  On the other hand, anything that has either a relaxant or a stimulative effect could be effective for many conditions.  So in this case perhaps the “placebo” is kind of “real”.  

There is also evidence THC increases dopamine in the short term and potentially reduces it in the long-term. This could have a positive short term effect on libido and a negative long term effect with habitual use.  This is connected to the research that marijuana use can over time lead to general anhedonia. 

CBD, in turn, agonizes 5-HT1A, which you want.  So it is not crazy to think that CBD plus THC could have pro libido effects. But it seems like habitual use would be negative for libido.  There is also some research that finds that while a low dose of CBD agonizes 5-HT1A, a high dose acts as an “inverse agonist” (which I think you would not want).

THC and CBD have a few other interesting effects that could be pro-sexual. First, they are both inhibitors of the reuptake of anandamide, an endocannabinoid known as the “bliss molecule”. There is not much research into this but anandamide has some connection to the dopamine and oxytocin systems.

Second, both substances are also acetylcholinesterase inhibitors, so using them should increase acetylcholine.

Other Supplements

There is a long list of supplements that people use for libido, and mostly the same ones used are used for men and women.   They fall into a few categories: testosterone, estrogen, blood flow, dopamine, or a neurotransmitter.  Does any of it work?  Who knows. This is a basic summary of the mechanism of action and the evidence. I have noted an estrogen or testosterone connection where appropriate, but if you are avoiding estrogen or testosterone, do individual research on each of them.   

What you are targeting with supplements and vitamins should depend on what gaps you have left with medication. If you are taking Wellbutrin, for example, I would go light on dopamine enhancers.  If you are skipping Wellbutrin, go heavier on those. If you are taking either estrogen or testosterone, or avoiding them, don’t use those supplements. The general and blood flow ones should be good for everyone, same with neurotransmitters. 

As always with new substances, start one at a time before combining, and start with low doses before increasing.  Safety first. 

The list I would recommend is: 

• General:  Ginger (important), Zinc, Magnesium, D, E, C with Rose hips, omega 3

• Blood flow: Gingko, Arginine, Citrulline, Pycnogenol, Zinc, beet root, ginger, pomegranate 

• Dopamine: Mucuna Pruiens (only days before), Tyrosine, Phenylalanine, Phenylethylalamine PEA (only 15-30 minutes before, and see below on serotonin levels)

• Neurotransmitters:

• Acetylcholine: Choline, Carnitine, B5, Huperzine A, Alpha-GPC, Lecithin, and Phosphatidylserine.  

• Histidine: histidine (only days before)

Take them every day or at least days leading up to sex, but PEA only 15-30 mins before sex and Histidine only in days before.  I would probably not take all of these at once because among other things it would just be too many pills. Just cycle different things in and out and see what works. To reduce number of pills you can also find some supplements that combine multiple ingredients if you hunt around on Amazon.  

Summaries: 

Blood Flow

• Ginseng (Blood flow, Libido, Dopamine, but Potential Estrogen): Studies indicate potential benefits for both male and female sexual function.  Generally contraindicated for BCA. 

• Arginine, Citrulline, Pycnogenol.  Combined, these have some evidence for enhancing female sexual function.  Lady Prelox and Ristela are two popular brands with some studies behind them that have these three ingredients. Ristela has more.  Note that arginine has conflicting research regarding cancer, some pro and some anti.  

• Look for supplements that contain nitrosigine, a compound that increases the effectiveness of arginine.

• http://www.ladyprelox.com/

• https://www.mdpi.com/2226-4787/9/2/71#:~:text=The%20authors%20concluded%20that%20supplementation,%2C%20insufficient%20randomization%2C%20and%20blinding.

• https://pubmed.ncbi.nlm.nih.gov/24051943/

• https://hellobonafide.com/products/ristela

• https://hellobonafide.com/pages/ristela-information-for-healthcare-providers

• https://academic.oup.com/jsm/article-abstract/17/Supplement_3/S259/7012400?redirectedFrom=fulltext

• https://focus.psychiatryonline.org/doi/10.1176/appi.focus.20170049#:~:text=l%2Darginine,-l%2Darginine%20is&text=Improvements%20were%20observed%20in%20sexual,side%20effects%20reported%20(9).

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8103282/

• https://www.mskcc.org/cancer-care/integrative-medicine/herbs/arginmax#:~:text=ArginMax%20is%20a%20dietary%20supplement,%2Dcomplex%2C%20zinc%20and%20selenium.

• Ginkgo (Blood flow): Limited studies indicate it might help with sexual dysfunction caused by antidepressants and other studies suggest more general libido.  

• Pomegranate (blood flow):  antioxidant that increases blood flow and nitrous oxide.

• Beet Root (blood flow): somewhat anecdotal but has been used since ancient times. Thought to increase blood flow.

Dopamine

• Mucuna pruriens (kaunch beej) (dopamine):  This is about 20% L-Dopa, which is a precursor to Dopamine.  Take this one only in the days leading up to sex, and especially 90 minutes before sex

• Phenylalanine:  precursor to Dopamine. Take this as DL-Phenylalanine (DLPA), a form that combines different types.  Note that you cannot take this if you have phenylketonuria (PKU). You should know if you have this condition as you cannot drink Diet Coke

• Tyrosine: precursor to dopamine

• Phenylethylalamine (PEA):  This comes up in the context of relationships, notably by Helen Fisher. This is the substance in chocolate that people talk about. PEA is available at bulksupplements.com.   PEA influences the release of dopamine but it is very short-lived and rapidly broken down, so you take it 15-30 minutes before sex. 

• Note that PEA may also increase serotonin, which by itself would have a dampening effect on libido. So take the other supplements first and see what they do, then add PEA or maybe test PEA by itself (and by yourself). I have found that within 35 minutes of ingestion, PEA is actually an erection killer, perhaps because of serotonin.  I have not tested it outside of that window.

• https://nootropicsexpert.com/phenylethylamine/

Histidine

• Histidine might play a role in arousal and orgasm and can be directly supplemented. Take 30 minutes before sex. 

Acetylcholine

• Acetylcholine is an important neurotransmitter.  The best ways to increase it is with the following, all precursors to acetylcholine or inhibitors of its breakdown or reuptake:

• Choline (best form is probably CDP-Choline Citicoline.  Take alone, not with inositol, which can boost serotonin)

• Acetylcarnitine

• Vitamin B5 (aka pantothenic acid)

• Phosphatidylserine (also helps with dopamine)

• Sulbutiamine (derivative of B1/Thiamine, precursor to acetylcholine)

• Huperzine A (acetylcholinesterase inhibitor. Acetylcholinesterase breaks down acetylcholine, so inhibiting the enzyme increases acetylcholine)

• Alpha GPC

• Lecithin

• CBD and THC are acetylcholineesterase inhibitors, so they should increase acetylcholine. I would just take CBD unless you like THC.

General Libido or Unknown

• Black Pepper: Black pepper increases Anandamide and contains β-Caryophyllene, which agonizes a particular cannabinoid receptor, CB2. Some research seems to show this helps with libido

  • https://www.mdpi.com/1424-8247/13/10/309

  • https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.00567/full

  • https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471126/#:~:text=Exposure%2520to%2520β%252Dcaryophyllene%2520increased,increase%2520in%2520human%2520sexual%2520desire.

  • https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2018.00567/full

• Ginger: Recent study suggests Ginger helps with female libido. The design of the study seems odd and it’s only one study, so who knows. But Ginger is not harmful and probably has other health benefits.   https://pubmed.ncbi.nlm.nih.gov/36809190/#:~:text=The%20elevated%20disgust%20induced%20by,toward%20the%20subsequent%20erotic%20stimuli.

  • If ginger does work, I suspect it is because it agonizes 5-HT1A and reduces inhibition. This tracks well with the study above. https://pubmed.ncbi.nlm.nih.gov/20363635/

• Fenugreek (Libido, Testosterone): May help increase sexual arousal and desire in women https://pubmed.ncbi.nlm.nih.gov/25914334/

• Zinc (Testosterone): Essential for various physiological processes, including hormone regulation. It does increase testosterone but as a general mineral, I don’t think that’s dangerous

• Damiana (Turnera diffusa) (Libido, hormonal connection not likely but unclear): Mostly anecdotal or animal-based studies.

• Lecithin (Unknown): Very limited evidence, mostly speculative.

• Alpha-Lipoic Acid (Unknown): Not much evidence to support claims for improving libido.

• NAD+ and NMN are coenzymes that may have some connection to libido   https://renuebyscience.com/cart/

• Others:  Vitamin D, Vitamin E, Fish Oil, Omega 3

Prolactin

Higher prolactin is associated with a lower libido.  Vitamin B6, or its active form Pyridoxal 5’-phosphate (P5P), can lower prolactin levels and likely has other health benefits. Prolactin is also reduced by most drugs or supplements that increase dopamine. 

Vitamin B6 is in most multivitamins or B-Complex vitamins, but you have to take a relatively high dose of B6/P5P to lower prolactin levels, much higher than Centrum. But note that outside of specific medical intervention, the maximum dose you should take is 100mg of B6 per day.  Some commonly available B-Complex vitamins will give you MORE than this dose, so check the label. 

https://www.tga.gov.au/news/safety-alerts/health-supplements-containing-vitamin-b6-can-cause-peripheral-neuropathy

Certain conditions will increase the chance of a deficiency of this vitamin, making it more important to supplement. These include various autoimmune disorders and excessive alcohol intake. 

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426548/

• https://www.hsph.harvard.edu/nutritionsource/vitamin-b6/

• https://link.springer.com/article/10.1007/s40618-023-02101-8

Primarily Hormonal (and thus to be avoided for present purposes) 

• Ashwagandha (Libido, Testosterone): Preliminary studies suggest potential benefits for stress reduction and may indirectly affect libido.

• Tribulus (Libido, Testosterone): Some evidence suggests it might increase sexual desire in women.

• Maca (Libido, potential estrogen): Some studies suggest potential benefits in enhancing sexual function.

• Asparagus racemosus (shatavari) (Estrogen, Libido): Limited studies and mostly traditional use.

• Chlorophytum borivilianum (safed musli) (Libido, Testosterone): Very limited scientific evidence.

• Mondia Whitei (Mulondo) Root Powder (Libido, Testosterone): Limited research.

• Turkesterone (Testosterone): Limited scientific evidence, mostly related to muscle growth.

• D-Aspartic Acid (Testosterone): Limited research, mostly focused on men.

Anandamide

Anandamide is an endocannabinoid that has been identified as “the bliss molecule” and is involved in pain and pleasure. There is very little research into this for sex, but the fact that some people think THC / CBD helps is suggestive. A few ways to increase anandamide: THC, CBD, Black Pepper, kaempferol (which is also anti-cancer…it is a SERM that acts like estrogen in some places and blocks estrogen in others). All of those inhibit the breakdown or reuptake of anandamide. Maca apparently does too, but my sense is that maca has an estrogen connection.

Each of the substances I have listed above has boosters who believe it works, wherever in ranks on the evidence list.

See below estrogen comments on Ginseng:

• https://www.mskcc.org/cancer-care/integrative-medicine/herbs/arginmax#:~:text=ArginMax%20is%20a%20dietary%20supplement,%2Dcomplex%2C%20zinc%20and%20selenium.

• https://www.mskcc.org/cancer-care/integrative-medicine/herbs/ginseng-asian

• https://www.mskcc.org/cancer-care/integrative-medicine/herbs/ginseng-american

• https://www.komen.org/breast-cancer/survivorship/complementary-therapies/panax-ginseng/

This is a good list but hard to say what the evidence is for anything:

• https://www.medicinenet.com/what_supplements_are_good_for_female_libido/article.htm

A skeptical review of the evidence for many of these supplements:

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6519565/

Yohimbine/Alpha-Yohimbine/Rauwolscine-Alpha-2 adrenergic receptor antagonism

Yohimbine is a supplement but it deserves special mention.  

Yohimbine is bark extract from the Yohimbe tree, traditionally used for libido purposes. Rauwolscine (alpha-yohimbine) is a closely related compound.  They are both selective antagonists of the Alpha-2 adrenergic receptor, which aids in levels of norepinephrine.  They are among only a few easily available substances (along with Phentolamine) to antagonize this receptor, so it deserves special mention if you are trying to press every button. It also has some support as a standalone libido enhancer, but it is definitely better used in combination.  

My sense is that the effect of phentolamine is more purely physical due to vascular effects, while Yohimbine and its related compounds really is a bit of a libido enhancer.  But the effects can be complicated because Yohimbine can both increase dopamine and also act as an antagonist at D2 and D3, the net effect of which is unclear. 

However regular yohimbine can have unpleasant side effects, especially anxiety and increased blood pressure, which Rauwolscine/alpha-yohimbine seems to partly avoid. Phentolamine also avoids this by antagonizing alpha-1.  Either way, start with small doses. With any of these three, do your research, speak to your doctor, and even then start with small doses. 

One approach would be very a small alpha-yohimbine dose and very small phentolamine dose. 

Not every study finds an effect. 

• https://pubmed.ncbi.nlm.nih.gov/11289571/

• https://www.webmd.com/diet/supplement-guide-yohimbe

• https://pubmed.ncbi.nlm.nih.gov/9509380/

• https://pubmed.ncbi.nlm.nih.gov/12187545/

• https://pubmed.ncbi.nlm.nih.gov/11550783/

4. Drugs / Procedures in Earlier Stages or Off-Label

• Systemic Libido

• Comfort and Pain

• Topical Arousal

Libido Enhancers, in order

Substances covered in other sections: Buspar, Wellbutrin, Oxytocin, Vyleesi, Supplements (including THC, CBD, Alpha-Yohimbine).

Other substances:

Cabergoline (available with normal prescription) or other Dopamine agonists

Cabergoline agonizes the D2 receptor and reduces prolactin.  It is commonly used for both genders for various fertility issues. It has been found to increase libido in both genders. It does not seem like there is much research into it though. I have seen reference to it being effective on an as needed basis, not just ongoing. But I cannot find many studies.  

But this does seem worth trying if prolactin levels are even remotely elevated, so test for that. Note also that there is some emerging research for Cabergoline as a breast cancer preventive or treatment, via the prolactin channel. I think a low dose of cabergoline might be the easiest “base” change, to which you can then add other substances. It seems better tolerated than apomorphine and it may have some anti-cancer effect.

Other dopamine drugs like Piribedil might be more effective and better tolerated. Cabergoline seems to have some heart effects that are worth researching.

• https://pubmed.ncbi.nlm.nih.gov/29746287/

• https://go.drugbank.com/drugs/DB00248

• https://www.hims.com/blog/cabergoline

Apomorphine (easily available at online pharmacies) 

Apomorphine is a dopamine agonist so it is not surprising this works. It is derived from morphine but it is not an opiate. Its action is on dopamine receptors, not opiate receptors.  It is quite commonly used for libido purposes and is offered at multiple online pharmacies, linked below. 

Because apomorphine is taken as needed, it could rank higher on this list, above Wellbutrin. Early research was promising and then it seems to have been dropped.  Apomorphine seems to act mostly at D2, D3, D4. It also agonizes and antagonizes exactly the right serotonin and adrenergic receptors, though with varying strength and I have seen sources that disagree on these points. 

But this is the most credible pharmacological description I can find:

“the structural similarity to dopamine is conferred by the ortho-catechol group. Like many antipsychotic drugs, apomorphine also possesses a piperidine moiety. Apomorphine is often described as a dopamine agonist, but it has some differences from other oral dopamine agonists used in PD. Thanks to its catechol moiety, apomorphine acts as a potent dopamine receptor agonist with a broad spectrum on all D1- and D2-like receptors (D1, D2S, D2L, D3, D4, D5)….Apomorphine’s mode of action is therefore more like that of dopamine or its precursor levodopa. In addition, apomorphine has antagonist properties on serotonergic 5HT2A, 5HT2B and 5HT2C and adrenergic α2A, α2B and α2C receptors and agonist properties at serotonergic 5HT1A receptors. Unlike its mother compound, morphine, apomorphine has no affinity for opioid receptors.”

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6776563/

• https://www.sciencedirect.com/science/article/abs/pii/S1353802016304710

The sublingual medical dose of apomorphine is 10 mg up to 30 mg, per webmd.  The dose used in libido studies is either 2 or 3 mg.  The dose sold at online pharmacies is 2-6 mg.  Sublingual troches or pills would need to be kept in the mouth for awhile before swallowed.  Note that apomorphine causes nausea, but I do not think it can be paired with ondansetron because of low blood pressure concerns. So try another anti-nausea medication, but make sure it is not one that blocks dopamine. https://www.webmd.com/drugs/2/drug-179418/apomorphine-sublingual/details 

Apomorphine nasal spray seems ideal to me.  It has been researched for ED and for female libido but doesn’t seem to have gone anywhere.  Unclear why not, since it works. It is now mostly used for Parkinson’s. It is a common product but not easy to find without a real prescription.  

• https://www.invigoratemedspa.com/online-store/Apomorphine-2-Nasal-Spray-15mL-p712382199

• https://pubmed.ncbi.nlm.nih.gov/15134988/

• https://pubmed.ncbi.nlm.nih.gov/16429619/

• https://www.invigoratemedspa.com/online-store/Apomorphine-various-strengths-p263805975

• https://mobilecarehealth.shop/product/apomorphine/

• https://www.bayviewrx.com/formulas/Apomorphine-HCl-1-Nasal-Spray-Parkinson-s-Disease-Dyskinesia-Hypersexuality-Impulse-Control-Disorder-Tourette-Syndrome

• https://regen-doctors.myshopify.com/products/apomorphine-tadalafil-combination

• https://www.researchgate.net/publication/8552424_Intranasal_apomorphine_Nastech_Pharmaceutical

• https://mobilecarehealth.shop/product/apomorphine/

Lybrido / Lybridos (components are easily available at online pharmacies) 

A Dutch company called Freya Pharmaceutical is currently in advanced trials in Europe and preliminary trials in the US  for two libido drugs:  1) Lybrido: testosterone plus Sildenafil (viagra); 2) Lybridos: testosterone plus Buspar.   Testosterone is covered above.  But three facts are interesting: 1) the use of Viagra, 2) the use of Buspar for non SSRI patients; 3) the fact that it is taken as needed, not on an ongoing basis. This strengthens the idea that Buspar can be used on an as-needed basis.   Both Viagra and Buspar are easy to get and might be worth trying.   The Buspar doses used in this study were 5 and 10 mg. 

“Lybrido is designed to be taken only when desired – it is not necessary to take it daily.  Sexual motivation is increased between 3 to 6 hours after intake.”  “These 2 combination tablets are designed to be taken “on demand” (ie, only when desired, rather than continuous daily, like flibanserin).”

• https://freyapharmasolutions.com/

• https://www.sciencedirect.com/science/article/pii/S1743609517318519?via%3Dihub

• https://www.cambridge.org/core/journals/european-psychiatry/article/new-neurobiology-of-libido-a-complex-interplay-between-testosterone-5ht-and-5ht1a-receptor-functioning/C394DEEACF83A8B3285E3256FD4580A5

The last two paragraphs below are disturbing.  “More than one advisor to the industry told me that companies worried about the prospect that their study results would be too strong, that the FDA would reject an application out of concern that a chemical would lead to female excesses, crazed binges of infidelity, societal splintering.”

Nobody would ever say that about men.  It’s also a bizarre claim, since we do not yet have anything that reliably works, so it is weird to worry that something will work too well.  

• https://www.empr.com/home/news/too-much-libido-female-sex-pill-sparks-interest-concern/

This is a good article, from 2013. These drugs take forever to develop.  

• https://www.nytimes.com/2013/05/26/magazine/unexcited-there-may-be-a-pill-for-that.html?pagewanted=all

• https://www.sciencedirect.com/science/article/abs/pii/S0924933815300626#:~:text=Firstly%2C%20activation%20of%205HT1A%20receptors,a%20low%20dosage%20of%20testosterone.

Lorexys (components are easily available at online pharmacies) 

Lorexys is a drug in development that combines Wellbutrin with Trazodone.  Early studies showed increased effectiveness compared to Wellbutrin alone. I cannot find any updates past 2019.  This seems somewhere in Phase 2, at best, and it actually seems like it’s mothballed.  It is unclear to me whether this drug was meant to be used as needed or on an ongoing basis. I believe it is the latter. But it is interesting that this drug is a combination of two already approved drugs, so the components are easy to find and combine.   Note that using Trazodone in either combination would require more care and medical advice than Buspar or Wellbutrin or even Buspar+Wellbutrin (which is fine).  But some research suggests Trazodone can be effective for libido at a very low dose. 

• https://academic.oup.com/jsm/article-abstract/16/12/1885/6980721?redirectedFrom=PDF

• http://www.s1biopharma.com/pipeline/lorexys

• https://medicalresearch.com/author-interviews/ceo-discusses-lorexys-for-female-hypoactive-sexual-desire-disorder/

• https://www.thecut.com/2013/11/meet-the-men-behind-the-newest-female-viagra.html

This company has several drugs in the pipeline, both male and female. But it seems super half baked.   Their farthest along is Lorexys, but I cannot find recent updates. Seems like maybe the trials failed or money ran out.  

http://www.s1biopharma.com/pipeline

Using Wellbutrin + Trazodone would increase dopamine and norepinephrine and decrease serotonin at receptor 5-HT2A.  

Trazodone (easily available at online pharmacies)

Trazodone is an anti-depressant and anti-anxiety medication in a different drug class. It is also often used to help people sleep, apparently with less risk of addiction relative to other sleep medications.  Trazodone has been found to have some beneficial effect in sex drive, in scattered anecdotes but at least one study.  And it appears to be a known side effect. There is also one study that suggests it can be basically microdosed. 

The beneficial action of Trazodone seems to relate to its antagonism of serotonin receptor 5-HT2A, which reduces serotonin in certain parts of the brain and also agonist of 5-HT1A.  It’s action is very similar to Addyi.  

But there does not seem to be much active research on it, except as part of Lorexys (which itself does not seem very active). It also seems to sometimes have the opposite effect on sex drive. 

Trazodone is the 22nd most commonly prescribed drug in the United States.   It has been used since 1981.  

• https://www.sfsc.fr/publi/pub1202.htm

• https://academic.oup.com/smr/article-abstract/8/2/206/6880243?redirectedFrom=fulltext

• https://ajp.psychiatryonline.org/doi/abs/10.1176/ajp.143.6.781?journalCode=ajp

• https://www.medicalnewstoday.com/articles/drugs-trazodone-tablet#fa-qs

• https://addictionresource.com/drugs/trazodone/side-effects/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673442/#R68

Phentolamine

Phentolamine is one of two substances to antagonize the alpha-2 adrenergic receptor, the other being Yohimbine. Phentolamine appears to be better tolerated.  It is much less likely to cause anxiety than Yohimbine. Phentolamine was widely used for ED before Viagra came out, though Phase 2 tests were not successful. 

Phentolamine is also a vasodilator and causes a slight decrease in blood pressure. It is a non-selective alpha antagonist that blocks both alpha-1 and alpha-2.  Its blockade of alpha-1 reduces smooth muscle tone and its blockade of alpha-2 inhibits negative feedback on norepinephrine release. Both effects contribute to vasodilation. The effect is probably more local than central, in contrast to yohimbine. 

Some studies show that phentolamine requires the presence of estrogen to be effective for women.  I would not make too much of this as it is consistent with my general view that you need multiple agents. 

• https://www.empowerpharmacy.com/drugs/tadalafil-phentolamine-mesylate-capsules

• https://www.bayviewrx.com/formulas/Apomorphine-HCl-1-mg-Phentolamine-Mesylate-2-mg-Tadalafil-20-mg-Oral-Capsules-Erectile-Dysfunction-Parkinson-s-Disease-Hypertension-Raynaud-s-Disease-Pulmonary-Arterial-Hypertension

• https://pubmed.ncbi.nlm.nih.gov/10327383/

• https://pubmed.ncbi.nlm.nih.gov/9507837/

• https://www.nature.com/articles/3900885

• https://www.tandfonline.com/doi/abs/10.1080/00926230252851339

Kisspeptin (available at peptide suppliers)

Kisspeptin is a peptide that plays a role in regulating the reproductive system. Early research has suggested benefits for sexual desire.   Kisspeptin is easy to obtain from peptide suppliers, provided you are willing to reconstitute it yourself.  

Kisspeptin also has some anti-cancer role, apparently, unless it is triple negative. Though I think this is somewhat speculative and the second link below suggests it is very complicated and can be either pro-cancer or anti-cancer.  I think the basic summary is that in ER+ it potentially has a very helpful role. But if you have concern about breast cancer recurrence, this is not one to experiment with until researchers have more clarity.  

Also for men, long term administration can reduce testosterone, while short term administration increases it. I don’t think I would use this chronically.

• Cancer:

• https://www.sciencedirect.com/science/article/abs/pii/S1040842818302518?via%3Dihub

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3805993/

• https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2018.00437/full

• General:

• https://www.peptidesciences.com/kisspeptin-10

• https://www.imperial.ac.uk/news/242901/kisspeptin-hormone-injection-could-treat-drive/

• https://myhealth.ucsd.edu/Library/News/Headlines/6,1659364567

• https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2800937?utm_source=For_The_Media&utm_medium=referral&utm_campaign=ftm_links&utm_term=020323

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9606846/

• https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.928143/full

ARBs

Have not researched; may have benefit.

• https://pubmed.ncbi.nlm.nih.gov/14700518/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9162275/

• https://www.google.com/url?sa=t&rct=j&q=&esrc=s&source=web&cd=&ved=2ahUKEwianrq9jeWEAxXXOkQIHZVNBhMQFnoECAwQAw&url=https%3A%2F%2Fwww.ncbi.nlm.nih.gov%2Fpmc%2Farticles%2FPMC9143081%2F%23%3A~%3Atext%3DTaking%2520valsartan%2520for%252016%2520weeks%2Cof%252041%2525)%2520%255B29%255D.&usg=AOvVaw2nePhqLEY5AREczGDKetbj&opi=89978449

• https://pubmed.ncbi.nlm.nih.gov/14700518/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9162275/

Comfort / Pain, in order

Wands, O-Shot, Polynucleatide Injection, Co2LiftV

See above sections.

Dare-VVA1-Tamoxifen Suppository (gel/cream/pill available with normal prescription) 

Early studies by a company called Daré Bio Science show that a vaginal suppository with tamoxifen can work for vaginal atrophy in breast cancer patients where estrogen is contraindicated.  Tamoxifen is a Selective Estrogen Receptor Modulator, which means that it has different effects in different parts of the body. In breast tissue, it acts as an antagonist to estrogen by blocking receptor sites.  Daré‘s theory is that in vaginal tissue, tamoxifen can act like estrogen without the cancer risk side effects.  The institutions associated with these studies are quite reputable. 

Topical Tamoxifen is available as a gel/cream even prior to the suppositories being approved.  This is because it is being used by women to apply directly to the breasts as a breast cancer preventive measure and by men who are developing breasts. Tamoxifen is also available as regular pills.  

The question for an oncologist and gynecologist is whether one could use this cream prior to the Daré suppositories being made available.  

• https://darebioscience.com/pipeline/dare-vva1/

• https://www.linkedin.com/feed/update/urn:li:activity:7138550352173285376

• https://ir.darebioscience.com/news-releases/news-release-details/dare-bioscience-announces-fda-clearance-investigational-new-drug

• https://www.imrpress.com/journal/CEOG/46/2/10.12891/ceog4948.2019

• https://www.healio.com/news/womens-health-ob-gyn/20230624/vaginal-tamoxifen-capsule-safe-for-postmenopausal-vulvovaginal-atrophy

• https://www.tandfonline.com/doi/full/10.1080/13697137.2023.2211763

• https://www.tandfonline.com/doi/epdf/10.1080/13697137.2023.2211763?needAccess=true

• https://www.sciencedirect.com/science/article/abs/pii/S0378517319307367?via%3Dihub

• https://www.uhhospitals.org/for-clinicians/articles-and-news/articles/2021/01/investigating-a-solution-for-sexually-active-breast-cancer-survivors

• https://www.empowerpharmacy.com/drugs/tamoxifen-gel

Lasofoxifene (only available in some countries and then still need doctor) 

Lasofoxifene is a drug that was approved in 2009 in Europe for treatment of vaginal atrophy and osteoporosis. It was not approved in the US, and it seems to have not gained traction in Europe and the marketing license was pulled.  It is a SERM (Selective Estrogen Receptor Modulator) like Osphena.  But what’s interesting is that far from causing breast cancer, it is being investigated to treat and prevent it in high risk populations.  It was licensed to a US company called Sermonix to study for this purpose and it seems to be in advanced stages of development, I believe Phase III. Their tests seem promising for all three conditions: 1) breast cancer prevention/treatment; 2) osteoporosis; 3) atrophy. 

This one is not really an option to use now but it is worth staying on top of. If it gets approved, it could be valuable for cancer prevention. 

• https://en.wikipedia.org/wiki/Lasofoxifene

• https://go.drugbank.com/drugs/DB06202

• https://clinicaltrials.ucsf.edu/trial/NCT03781063

• https://finance.yahoo.com/news/sermonix-lasofoxifene-improves-vaginal-vulvar-140000771.html?guccounter=1&guce_referrer=aHR0cHM6Ly93d3cuZ29vZ2xlLmNvbS8&guce_referrer_sig=AQAAADNNc54b3yR6e-xAJxFcIGiJJMUIpF2-opPa_lTxZ1gSyXqeuIDrF417DBpfSv505r1xJrGIyhk0DGVTSBnmG9slwHymubBnMKsMI6fjGPwnbUngPxD5D9CarzMHcjGkzOttTlvAzJ5K9_eYpcFNvJO-Jdow6dcGYVl5YLEliFMQ

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2773750/#:~:text=In%20postmenopausal%20women%20with%20low%20bone%20mass%2C%20lasofoxifene%20improved%20the,resolve%20even%20with%20drug%20continuation.

• https://sermonixpharma.com/sermonixs-lasofoxifene-improves-vaginal-vulvar-symptoms-relative-to-fulvestrant-in-elain1-study-of-postmenopausal-women-with-locally-advanced-or-metastatic-er-her2-breast-cancer-and-an-esr1-mutation/

• https://www.uchicagomedicine.org/forefront/cancer-articles/lasofoxifene-found-to-be-a-promising-treatment-for-therapy-resistant-breast-cancer

• https://sermonixpharma.com/news/

• https://www.uchicagomedicine.org/forefront/cancer-articles/lasofoxifene-found-to-be-a-promising-treatment-for-therapy-resistant-breast-cancer

• https://breast-cancer-research.biomedcentral.com/articles/10.1186/s13058-021-01431-w 

• https://www.onclive.com/view/lasofoxifene-may-improve-vaginal-vulvar-symptoms-in-postmenopausal-er-her2-esr1-mutated-breast-cancer

Topical Arousal, in order 

Topical PDE5 Drugs

See above section

Topical Alprostadil / Prostaglandin E1 (PDE1) (available in EU and Canada as ED Drug for men)

Prostaglandin is a group of compounds that play various roles in the body, including regulating blood flow. Alprostadil is a specific type that is used medically for newborns with heart defects and also approved in Europe and Canada as a topical ED drug for men, under the brand name Vitaros.  It has been studied for topical vaginal application for women, with some success.  It has the same function as topical ED drugs, of increasing blood flow and thus orgasm. 

In the 2003-2013 period there was a company trying to develop a product called “Femprox”.  It had promising early results and seems to have gotten somewhere between Phase II and Phase III.  Then I’m not sure what happened. 

• https://www.nytimes.com/2003/01/27/business/patents-viagra-counterpart-for-women-its-way-it-addresses-clinical-condition-new.html

• https://academic.oup.com/jsm/article-abstract/5/8/1923/6862432?redirectedFrom=fulltext&login=false

• https://journals.sagepub.com/doi/10.2217/17455057.2.3.331

• https://www.sciencedirect.com/science/article/pii/S2050116116000581

• https://www.labourseetlavie.com/actualites-economiques-et-financieres-actualites/apricus-biosciences-to-present-poster-of-femprox-r-phase-iii-clinical-data-at-upcoming-industry-conference

• https://www.biospace.com/article/releases/apricus-biosciences-announces-it-is-seeking-a-global-partner-for-femprox-a-novel-treatment-for-female-sexual-dysfunction-/

• https://pubmed.ncbi.nlm.nih.gov/19017254/

• https://www.medscape.com/viewarticle/764590?form=fpf

• https://www.eurekalert.org/news-releases/882683

Note that you can get Alprostadil at various online pharmacies.  Seems to be cheaper in the UK.  This version of it is to inject into the penis (um, that’s a hard pass, so to speak).  Given give how invasive that is, and given the Femprox history, it must be safe to use topically. 

• https://www.invigoratemedspa.com/online-store/Trimix-Topical-Transdermal-Gel-p263826567

• https://onlinedoctor.superdrug.com/alprostadil-cream-or-injections.html

• https://onlinedoctor.superdrug.com/vitaros-cream.html

• https://www.bayviewrx.com/formulas/Alprostadil-1000-mcg-Papaverine-7-5-mg-Phentolamine-1-mg-ml-Urethral-Gel-Erectile-Dysfunction-Peyronie-s-Disease-Priapism-Hypogonadism-Post-Prostatectomy-Syndrome-

Topical Nitroglycerin (easily available with normal prescription)

Nitroglycerin is another topical substance that has been explored for both ED and women’s sexual pleasure and/or pain.  It is relatively easy to get with a prescription because it is often used for anal fissures.  There are also some Scream Cream mixes that have it. See some of the below pharmacy links. 

• https://pubmed.ncbi.nlm.nih.gov/12192883/

• https://nationalpharmacyrx.com/womens-health/sildenafil-cream-for-women/

• https://www.parkcompounding.com/scream-cream-female-viagra/

• https://nationalpharmacyrx.com/mens-health/nitroglycerin-cream-for-ed/

Carboxytherapy

Carboxytherapy seems to be the same idea as CO2LiftV, but it is CO2 injected with a needle.  Often used for men. I don’t think it’s common enough to even find. Pretty speculative.  

5. Ruled out or Not Considered

Estrogen and related substances, whether creams, pills, or pellets. The data are very clear about breast cancer risk and this is the point of my list. 

Osphena (Ospemefene)

This is not estrogen but it is estrogen adjacent and it is not advised for breast cancer survivors.  

But see above on Lasofoxifene, a different SERM.  

Tibolone

Tibolone is a menopause drug for hot flashes, bone density, atrophy, and sex drive.  While there is apparently evidence that it reduces breast cancer risk, there is other evidence that is less clear, or even that it increases it, and the negative evidence seems stronger.  So the consensus is not to use it if one has had breast cancer. For this reason, it is not approved in the US, and the UK NHS has a clear message that it is contraindicated for breast cancer survivors. 

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

But see below on Tamoxifen suppositories in section 5. 

DHEA

This is a supplement (in pill and cream form) that is sort of testosterone adjacent that seems to work for many women and men.  But to me it just seems far less controlled than the various studies with testosterone + estrogen blockers. There is also a connection between DHEA and breast cancer. 

Addyi (Flibanserin)

Addyi is the other drug that is FDA approved for HSDD. It’s a pill that balances serotonin and dopamine and is somewhat similar to Buspar.  But Addyi interacts badly with alcohol and you take it daily.  I don’t know why one would use Addyi before trying Wellbutrin/Buspar/Exxua and/or Vyleesi, or better yet trying my entire set of recommendations. Addyi is, of course, tailored for this purpose, but weigh that against the simplicity and long-term data of Wellbutrin/Buspar/Exxua or the ease of Vyleesi.  Addyi is really only superior to Vyleesi if you are afraid of needles and it may not be at all superior to Wellbutrin, Buspar, or Exxua. 

One notable fact about Addyi is that it is immediate release, but you take it every day, not as needed.  I do not know why it wouldn’t work as needed if there is some evidence that Buspar (and maybe Wellbutrin) works as needed.  Honestly it seems like it is worth a try as needed even if it is a higher bar to use it daily. 

The article below explains that libido is positively regulated by dopamine and negatively regulated by serotonin, consistent with the view I have outlined.   It seems to me that Addyi balances these out, in a way similar to the way Wellbutrin combined with Buspar would. 

Addyi agonizes 5-HT1A and antagonizes 5-HT2A.  This would be similar to Buspar+Trazodone and sort of similar to just Trazodone.  It is generally thought that this mix of effects causes an increase in dopamine too. 

I read the FDA application document below and it gives me two other reasons to be a little skeptical of this drug. First, while everyone says there is no increase in prolactin (see last link below) that is not quite what the document says. It basically says there is not much increase. Second, I am not sure how confident we can be on breast cancer and Addyi. The application notes an increase in mamary tumors in mice when they take a high dose and for their entire lives. That may be an extreme case, but remember, this drug is only technically approved for pre-menopausal women, and the original studies did not include women with breast cancer. One of the links below is a study that attempts to fill in the data gaps here, and results seem good. And various reputable organizations, including MSKCC, seem to have tacitly endorsed it. But so far, the relevant studies are small and it doesn’t even seem like they evaluated recurrence risk. So I’m sure this is fine for breast cancer, but I would have more confidence in Wellbutrin, Buspar, Apomorphine, Cabergoline, or any dopamine source. These have been around for much longer and the last two have been investigated for anti-cancer effects.

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198608/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9780775/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8847820/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741686/

• https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/022526Orig1s000MedR.pdf

• https://ascopubs.org/doi/pdf/10.1200/JCO.2022.40.16_suppl.e18761

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5358680/

  6. How Mood Drugs Work

Psychotropic drugs tend to work in one of four ways:

• Receptor Agonist:   Binds to a specific receptor and mimics the neurotransmitter, producing a biological response.  An agonist can be partial or full. 

• Receptor Antagonist: Binds to a specific receptor site and blocks the neurotransmitter, preventing a biological response. 

• Reuptake Inhibitor:  Prevents the reuptake of the neurotransmitter once it is in the synaptic cleft. This leaves more of the neurotransmitter available for use by all receptors. 

• Enzyme Inhibitor:  This inhibits the enzymes responsible for breaking down neurotransmitters, which leaves more of the neurotransmitter available. 

Libido is typically thought to be inhibited by serotonin and accelerated by dopamine and norepinephrine.  

The way that I think of this, as a layperson, is that serotonin drives higher brain functions like mood.  But too much serotonin in the wrong places can lead to rumination and anxiety, including a heightened aversion response to certain stimuli. 

Dopamine drives more base level functions like pleasure and reward. Too little of it and we do not receive the feedback we need from pleasurable activities.  Too much of it and we engage in overly risky, compulsive, or addictive behavior.  With dopamine, in order to increase libido, you either increase the general level or you target the D2 family of receptors.  Note that dopamine declines sharply when estrogen is cut off. 

Serotonin is a little more confusing. The simple version is that you want to agonize the 5-HT1A receptor and antagonize the rest, with the most important being 5-HT2A.   

I think part of what is literally going on here is that sex is both pleasurable and objectively kind of gross, as well as anxiety inducing for many complicated reasons (similar to the Dual Control Model). The key is to dial up the pleasure response and dial down the aversive responses.  

As you research drugs and supplements that have been found to increase libido, a consistent theme emerges:  most either adjust serotonin at those specific sites or they increase dopamine or dopamine sensitivity.  I initially started making a list of every drug that has been found to have positive libido effects.  But the reality is that anything that presses those buttons might work, depending on what is holding back libido. And if you press multiple buttons at once, the odds of success are much higher.  The only drugs that are really interesting are the ones that might target non-dopamine and non-serotonin areas, like melanocortin, oxytocin, or Alpha-2 adrenergic receptors.  Otherwise, just experiment with various mixes of the main dopamine/serotonin options and don’t worry about increasingly obscure drugs. And speak to your doctor. 

I think the ideal combination is probably Gepirone and Wellbutrin combined.  You could add a very low dose of Trazodone as needed.  That would partially agonize 5-HT1A, slightly antagonize 5-HT2A, and increase levels of both dopamine and norepinephrine.  Another approach would be to replace the Wellbutrin with Apomorphine as needed and / or take dopamine connected supplements.   But speak to your doctor. 

Dopamine D2, D3, D4

What it is:  There are five known Dopamine receptors, broken up into two (badly named) categories:  the D1 Family (receptors D1, D5) and the D2 Family (D2, D3, D4).  The D2 family has been linked to sex drive, in particular the D2 receptor. 

What you want:  Agonize the D2 Family of receptors and/or increase the availability of dopamine for all receptors

What works: 

• Reuptake inhibitor:  

• Wellbutrin is a NDRI, Norephrine Dopamine Reuptake Inhibitor. So it generally increases dopamine availability at all receptor sites. 

• Production increase / Supplemental: 

• L-Tyrosine and Phenylalanine are amino acids that are precursors to dopamine. People take them as supplements. Theoretically they can increase dopamine levels.  

• Mucuna Pruiens is about 20% L-Dopa.  L-Dopa is an even closer precursor to dopamine.  Higher than 20% L-Dopa is available, but only as a prescription for Parkinson’s. Take this 90 minutes before sex

• Phenylethylalamine (PEA) is the substance in chocolate that causes a release of dopamine.  It is short lived and should be taken just before sex.  It can also release serotonin, which runs counter to libido 

• Important vitamins:  Omega 3, D, magnesium, B5, B6

• Receptor Agonist:  

• Apomorphine is a dopamine agonist.  I have seen reference to it being a non-selective dopamine agonist and also to being “mostly” a D2 agonist.  Presumably by that they mean “D2 Family”.  

• Cabergoline is also a dopamine agonist, specifically D2.

5-HT1 Receptors

5-HT1A

What it is:  Serotonin receptors are a bit confusing because you want less overall serotonin, and yet agonizing this specific site can cause less serotonin in certain key parts of the brain. Honestly I don’t get this, but it seems clear from the evidence. 

“5-HT1A receptor activation has been shown to increase dopamine release in the medial prefrontal cortex, 

striatum, and hippocampus.”

https://en.wikipedia.org/wiki/5-HT1A_receptor

What you want:  Agonize

What works:  Buspirone, Gepirone, Addyi, Trazodone.  But note that Buspirone may have antagonistic activity at D2 and D3 and Addyi weak antagonistic at D4.  Gepirone has much less affinity for D2 and so it would almost certainly work better for libido than Buspirone. 

5-HT2 Receptors

5-HT2A

What it is:  Activating this receptor might negatively affect blood flow.  Its other effects are unclear (to me) but it does seem that antagonizing it improves sex drive by reducing serotonin. 

What you want:  Antagonize

What works: Trazodone, Addyi, Gepirone, Mirtazapine  (but research and anecdotes do not seem that positive on the latter)

5-HT2C

What you want:  Antagonize

What drugs work:  Agomelitine. But this has only been studied for SSRI induced sexual dysfunction.  When you switch to agomelitine as an alternative, it improves.  -Mirtazapine (but research and anecdotes do not seem that positive.  Mixed.)

https://go.drugbank.com/categories/DBCAT005169

5-HT3 Receptors

This group is less studied but might have an inhibitory effect on sexual behavior. It is antagonized by nausea meds like Ondansetron.  Any positive libido effect could partly come from an anxiolytic effect.  

What you want: Antagonize

What drugs work: Ondansetron, Granisetron, Mirtazapine  (but research and anecdotes do not seem that positive)

Ondansetron has never been found to have any effect on libido.  The other two have been researched more but still not much impact, or mixed. 

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5130128/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022722/

Alpha-2 adrenergic receptors

What it is:  Alpha-2 adrenergic receptors are targets for norepinephrine and epinephrine, important neurotransmitters for sexual function.   Agonizing them inhibits the release of epinephrine and thus lowers libido, and antagonizing them has the opposite effect, through a complex interplay with the serotonin and dopamine receptors covered here. 

What you want:  Antagonize

What works:

• Yohimbine, derived from bark from the Yohimbe tree. I do not like the side effects of this and I would use it sparingly. But it seems to work on this receptor site.  It is a selective antagonist, blocking only Alpha-2 .  Alpha-yohimbine/Rauwolscine is better tolerated

• Phentolamine, an anti-hypertensive blocks both Alpha-1 and alpha-2

• Buspar, Gepirone are also partial antagonists by way of metabolizing into metabolizes into 1-(2-pyrimidinyl)piperazine (1-PP)

• https://en.wikipedia.org/wiki/Gepirone

• https://books.google.com/books?id=g9NiQh7gleEC&pg=PA375#v=onepage&q&f=false

Note this excerpt from a great paper:

• “Drugs acting at the adrenergic α2 receptor  have been shown to alter sexual motivation in male rats. The antagonists yohimbine and RX821002 enhance sexual motivation, whereas agonists like dexmedetomidine and S18616 reduce it (Viitamaa et al., 2006; Chu and Ågmo, 2016). Curiously enough, the reliable motivational effects of drugs acting at the α2 receptor have not provoked the slightest interest.”

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10691110/#ref109

7. Random Notes

Random Gels etc 

Zestra and Other Gels

Zestra is a lubricant that you put on vagina that increases sensation. It’s basically herbal.  Who knows.   But it does have some studies supporting it, of unclear quality. There are lots of these types of products. Many reviews say it doesn’t work but many say that it does and that it increases arousal, not just sensation. 

Other gels or creams with some support include Chamomile Gel and Fennel Gel.  These two are for comfort where estrogen cannot be used. But it is important to ask whether they are mimicking estrogen, which I have not examined. 

• https://pubmed.ncbi.nlm.nih.gov/33832645/

• https://www.mskcc.org/cancer-care/integrative-medicine/herbs/zestra

• https://www.amazon.com/Semprae-Laboratories-Zestra-Essential-Arousal/dp/B0017DILCS/ref=cm_cr_arp_d_product_top?ie=UTF8

• https://pubmed.ncbi.nlm.nih.gov/29696061/

• https://pubmed.ncbi.nlm.nih.gov/35400624/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673442/

• https://www.vigorelle.com/#formulation

Acupuncture

There are a few studies that show acupuncture works. I am skeptical. I think it probably goes into the larger question is whether acupuncture is just placebo.  

• https://pubmed.ncbi.nlm.nih.gov/35738039/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5005297/

• https://pubmed.ncbi.nlm.nih.gov/37806029/

Cognitive Behavioral Therapy

“The results of the research, being presented Tuesday in Chicago at the annual meeting of the Menopause Society, suggest that cognitive behavioral therapy — a specific form of talk therapy — can significantly improve sexual dysfunction problems related to perimenopause and menopause. Earlier research has shown CBT to be effective for hot flashes and other symptoms of menopause.”

https://www.washingtonpost.com/wellness/2024/09/10/menopause-low-sex-drive-cbt/

Miscellaneous Articles

• https://pubmed.ncbi.nlm.nih.gov/29198512/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8673442/#R68

• https://www.uspharmacist.com/article/female-sexual-dysfunction

• https://www.timesofisrael.com/spotlight/4-best-sex-pills-for-women-top-instant-female-arousal-pills-libido-boosters/

• https://focus.psychiatryonline.org/doi/10.1176/foc.7.4.foc481

• https://www.uspharmacist.com/article/female-sexual-dysfunction-from-causality-to-cure?utm_source=TrendMD&utm_medium=cpc&utm_campaign=US_Pharmacist_TrendMD_0

• https://journals.sagepub.com/doi/pdf/10.1177/070674370204700502

• https://www.mayoclinicproceedings.org/article/S0025-6196(16)30596-1/fulltext

• https://www.revmed.ch/revue-medicale-suisse/2008/revue-medicale-suisse-150/dysfonctions-sexuelles-induites-par-les-antidepresseurs-et-les-antipsychotiques-et-leurs-traitements

• https://regendoctors.com/products/tadalafil-oxytocin-apomorphine-20mg-100iu-4mg-melts-3-pack/

• https://psychscenehub.com/psychinsights/sexual-dysfunction-with-antidepressants/

• https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907491/

• https://pubmed.ncbi.nlm.nih.gov/4717948/

• https://www.sciencedirect.com/science/article/abs/pii/S0278584605001260

• https://www.allohealth.care/healthfeed/erectile-dysfunction/antihistamine-erectile-dysfunction

• https://www.santacruzsentinel.com/2024/02/08/top-3-best-instant-female-arousal-pills-and-sex-enhancers-for-women/

• https://www.invigoratemedspa.com/patient-information

• https://alphahormones.com/sexual-wellness

• https://regendoctors.com/female-sexual-wellness/

• https://my.clevelandclinic.org/health/articles/22588-dopamine-deficiency

• https://academic.oup.com/smr/article/11/3/179/7128131

• https://www.psychiatrist.com/jcp/targeting-circuits-sexual-desire-treatment-strategy/

Notable Doctors

• https://vulvodynia.com/

• https://poynorhealthnewyork.com/

This looks very interesting but it is somewhat obscure and hard to source

Bromantane

https://everychem.com/product/buy-bromantane/

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

Probiotics

There are some studies suggesting probiotics helps. I suspect that this is only the case if there is a gut imbalance, but I don’t know and I have not really researched it.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10785460/#:~:text=Comparison%20of%20sum%20score%20of,group%20(p%20%3C%200.05).

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7952237/