Anhedonia & A Long List Of Potential Interventions

In my opinion, emotions are a major part of what makes life worth living. Unfortunately, there are some individuals with anhedonia, which is an inability to feel (and presumably also to generate) emotions.

In this article, I discuss the “brain disease”-anhedonia, that is, the type of anhedonia that is the cause of being a purposeless, directionless, and connectionless person, and not the consequence. Unfortunately, it is hard to figure out which type one is.

Furthermore, anhedonia needs to be differentiated from a “schizoid” personality. Being numb and disconnected is just part of the way some people are naturally and for those, there is quite little that can be done about it because their brain is “wired” that way. I discuss why large-scale changes in brain wiring are impossible in developed brains here.

Some general stuff

If I had a billion dollars, I would put a significant amount of money into researching anhedonia and how to treat it because anhedonia is a very under-researched and undertreated condition that currently has few satisfying treatment options.

It is a – if not the – core symptom of depression and it is thought that about 70% of people with MDD have it. However, it does not only show up in depressed individuals. In fact, there are a large number of non-depressed folks who feel emotionally blunted and mostly numb.

Even though often unnoticed, sometimes subjective experience is dull, grey, and far less rich than it used to be during childhood and adolescence. Emotions are what let people connect with others and with the world around them. Without them, humans feel, are, and stay mostly disconnected. Even the most understanding, patient, and caring person will only be able to love a robot for so long.

Anhedonia is quite hard to treat. Furthermore, the condition is likely quite heterogeneous and multifactorial, as so often in psychiatry. That is, my anhedonia is not your anhedonia in the same way my flu is your flu. The flu is a specific well-defined medical entity with a single cause. Anhedonia is not.

If we line up ten people with anhedonia, most will have a different combination of causes and contributing factors. Likely, there are even multiple neurological mechanisms that lead to anhedonia, in the same way that many ways lead to Rome.

Five neurotransmitter systems are of crucial importance for mediating different nuances of the “richness” of one’s moment-to-moment experience:

• Dopamine (“motivation”)

• Noradrenaline (“alertness”)

• Serotonin (“calmness”)

• Histamine (“wakefulness”)

• Endorphins (“pleasure”)

The current thinking is that the various aspects of anhedonia relate to endogenous opioid and dopaminergic activity. Using dopaminergic drugs to “target” anhedonia is a common practice whereas using opioids is rarely employed (and probably for a good reason) – though many anhedonic individuals self-medicate with weed (which temporarily enhances opioidergic pathways).

“Anticipatory anhedonia” is thought to be related to underactive dopamine pathways, while “consumptive anhedonia” is thought to be in part related to underactive opioid pathways (though all of the monoamine and non-monoamine neurotransmitter systems are interconnected, and changes in one system produce downstream changes in the others).

These neurotransmitters are discussed in more detail here: An Introduction to Neurotransmitters (and How to Modulate Them).

Promising research questions

• It seems that, on average, females are usually more emotional than males (possibly related to females needing to pick up on subtle emotional cues from offspring). That is, in general, female brains are capable of generating more and deeper emotions than male brains, manifesting in greater female emotionality & empathy. If this is indeed true, how much of this is due to circulating factors (e.g., estradiol, oxytocin, leptin – all of which are much higher in females), and how much is due to it being developmentally “constructed” into the nervous system?

• Children appear hypomanic at baseline compared to adults. Why is the intensity of emotions, for most people, greater during childhood and puberty than in adulthood? Hormones? Neurotransmitters? Neuroplasticity? Is this purely a function of alertness?

• How does ketamine improve anhedonia? Glutamate? Neuroplasticity?

• How exactly does GHB bring out deep emotions?

Treatment options

What follows is a list of things that may work for treating different aspects of anhedonia. However, few of these have been rigorously explored. The following list is in no way prescriptive but rather represents a “buffet” of possible things to try.

Lifestyle changes

Beating addictions (e.g., THC, sugar, food, porn)

One of the most important points on this list. Anhedonia is a core symptom of addiction, in part because addicts usually hyperstimulate the dopaminergic and opioidergic pathways, which results in functional counterregulation. Friends of mine reported greater emotional intensities at baseline after they stopped either THC, stimulants, or porn. I briefly discuss addiction, and potentially helpful agents, here.

Exercise

Exercise has incredible benefits for brain health, neuroplasticity, and neurotransmitter regulation, particularly high-intensity exercise. I discuss this in more detail here.

Treating nutrient deficiencies

Sometimes, micronutrient deficiencies cause problems with neurotransmitter synthesis and neuron health. In particular, vitamin B3, B6, B12, iron, magnesium, zinc. However, micronutrient deficiencies are rarely the main problem. I discuss nutrients in more detail here.

Lowering inflammation

Low-level inflammation can severely mess with brain function as cytokines act on many brain sites, including monoamine-producing neurons. Potential avenues to decrease sterile inflammation (or neuroinflammation) are rapamycin, cutting out inflammatory factors (e.g., dairy, mold, obesity, etc.), and getting properly checked out by a rheumatologist. Because this article is already long, I discuss inflammation, and how to lower it, in more detail here.

Ketogenic diet

Two friends had success with the ketogenic diet, and for a brief while, both of them reportedly felt on top of the world. However, this may be at least in part related to the greatly increased cortisol secretion (discussed shortly). Nonetheless, the ketogenic diet may help some, in part because it lowers inflammation and may help with energy levels.

Increasing caloric intake

Undereating can severely mess with energy levels, and energy levels are proportional to emotional intensity. For example, in states with very high energy levels (such as on stimulants or during hypomania/mania) the intensity of emotions is much higher. Conversely, in states of lethargy, emotions are usually of low intensity.

Gaining body fat if one has too little

Having very low levels of body fat adversely affects a variety of neurotransmitters and hormones. At the most extreme end are patients with anorexia nervosa, which are almost always emotionally numb. This is thought to be related to hormones, particularly leptin.

Losing body fat if one has too much

High levels of body fat decrease energy levels, mess with sex hormones, and cause low-level inflammation, all of which reduce the brain’s ability to generate deep emotions. GLP-1 agonists may be helpful.

Sleep deprivation

Sleep deprivation can induce a temporary hypomanic-like state, which is characterized by increased emotional intensity. This may be in part related to glutamate and cortisol. In fact, sleep deprivation is one of the most surefire ways known to induce states of hypomania, if one is prone to experiencing them.

No fap & semen retention

Interestingly, when I was engaging in semen retention, my overall emotional tone seemed to be greater, particularly (but not exclusively) the intensity of feelings related to love and romance. Two friends have reported something similar.

Blue light therapy

Exposing oneself to blue light in the morning increases cortisol levels and potentially stimulates a variety of neurotransmitters. Furthermore, blue light therapy can help with energy levels.

Treatment of depression

Quite often (but not always) anhedonia is a symptom of depression or dysthymia, sometimes without the user being “subjectively” depressed (but neurobiologically depressed). For more: What Kind of Antidepressant Should I Choose?

Treatment of ADHD

Similarly, anhedonia often shows up in untreated ADHD. I discuss ADHD in more detail here: ADHD – To Treat Or Not To Treat?

Hormones

People are generally more emotional during puberty. Hormones may be part of the equation. Hormones deeply affect brain activity and metabolism, and certain hormones also affect the functioning of various emotional centers.

Therefore, it is no surprise that hormone deficiencies can cause a state resembling anhedonia. Conversely, hormone modulation represents a powerful way to increase the brain’s capability to generate emotions. Unfortunately, there is little to no proper research on this – but there are loads of anecdotes on the internet.

Cortisol

Exogenous glucocorticoids are known for their ability to make people hyperemotional, and sometimes even hypomanic. Conversely, low cortisol levels are associated with low levels of emotional arousal. Cortisol increases the synthesis, release, and signaling of dopamine, noradrenaline, and glutamate, among others. Furthermore, it enhances the activity of many emotional brain centers such as the anterior cingulate cortex.

Anecdotally, as I was using low doses of hydrocortisone, I was more emotional – friends reported something similar. Relatedly, individuals with borderline personality disorders, who are known for being hyperemotional, have elevated levels of cortisol (among other things). Cortisol is discussed here.

Thyroid hormones

Thyroid hormones are major determinants of idle-state energy levels. Furthermore, thyroid hormones regulate neurotransmitter levels across the board. Both energy levels, as well as neurotransmitters, are crucial to “feeling” something. I discuss thyroid hormones here.

Sex hormones

Sex hormones play a pivotal role in managing a multitude of processes that are intrinsically linked to the evolution and generation of human emotions, particularly those related to love or social status. Sex hormones are discussed here.

A note on estradiol and emotionality

Why do women have the reputation that they are more emotional and empathetic than men? While sociocultural conditioning surely contributes, in my opinion, this is mostly due to the fact that women have more and stronger emotions than men.

That is, neurobiologically speaking, women’s brains are more capable of generating deep emotions because firstly, they are wired differently (genetics; hormones) and secondly, women have different levels of certain neurotransmitters (e.g., ADH) and also higher levels of oxytocin and estradiol (and perhaps other circulating factors) that increase activity in certain emotional brain centers.

I recently did a Reddit deep-dive on anecdotes regarding individuals on exogenous testosterone (who often manipulate estrogen levels pharmacologically with aromatase inhibitors) to get an impression of what high vs. low levels of estradiol “feel like”. Out of over 100 anecdotal reports of men who have experienced states of both low and high estradiol, the common theme is that, with high estradiol, men report feeling more “excitatory” – stronger emotions, more anxiety, greater joy, being more “bubbly”, being more prone to crying during sad movies etc. Conversely, in states of low estradiol, these same men report being more “flat”, rational, apathetic, and anhedonic.

My own experiences with sex hormone modulation (including self-experiments with topical estradiol) lead me to believe this to be true. Also, anecdotally, a friend of mine on TRT claims that when his estradiol levels run high there is a lot going on in his emotional universe, and if he then takes low doses of aromatase inhibitors the excitement and anxiety turn to low levels within a couple of days, during which he becomes gradually more rational.

SERMs

The selective-estrogen receptor modulator clomiphene seems to cause emotional rollercoasters for both men and women (“the clomid crazies”). Raloxifene has been shown to improve the negative symptoms of schizophrenia (a state resembling anhedonia). At the very least it is safe to say that estrogen signaling in the brain is somehow tied to the generation of emotions.

Leptin

Leptin receptors are expressed by many brain sites, including monoaminergic neurons, the cingulate cortices, and the insula. Furthermore, leptin is a master-control hormone regulating the synthesis of other hormones. Leptin is discussed here.

Growth hormone

GH and IGF-1 receptors are widely expressed throughout the brain. Given that levels of GH and IGF-1 are much higher during childhood and adolescence (a period characterized by heightened emotional intensity), and given their established role in promoting neurogenesis & neuroplasticity along with the production and release of various neurotransmitters, it’s plausible to suggest that growth hormone therapy could potentially improve certain aspects of anhedonia. It surely is no coincidence that both of these hormones are inversely correlated to developing dementia.

Oxytocin & ADH

Oxytocin & ADH are two neuropeptides known for enhancing prosocial emotions. Both but especially ADH are implicated in the development and treatment of autism, a condition in which individuals are emotionally detached. I tried injectable oxytocin a handful of times and the only thing I personally noticed were more intense feelings for my girlfriend and a higher libido. Of note, oxytocin synthesis and signaling are strongly stimulated by estradiol levels.

Neurosteroids

Neurosteroids are a poorly researched group of steroid molecules that affect a wide variety of brain processes, including the generation and regulation of emotions. Supplementing with pregnenolone (“the mother of steroid hormones”) may increase neurosteroid synthesis, whereas 5aR-inhibitors such as finasteride and dutasteride negatively affect the synthesis of a variety of neurosteroids, though whether that affects emotions in any meaningful way is unknown.

Pregnenolone itself modulates the NMDA receptor, which is implicated in (some aspects of) anhedonia. Furthermore, there is some data that pregnenolone and progesterone are neuroprotective and improve memory, neuron health, and well-being.

Pharmaceuticals

Psychedelics

A friend claims that psychedelics enhance the intensity of his emotions like nothing else, which is perhaps the thing he loves most about psychedelics. On psychedelics, he feels emotional nuances he is not able to feel otherwise. Unfortunately, they only work for as long as they are in the system. I discuss microdosing here and macrodosing here.

Ketamine

All antidepressants I have tried so far (e.g., vortioxetine, moclobemide, bupropion) blunted my emotions to some extent (Disclaimer: I was not depressed when I tried these interventions). The only thing that did not, but instead enhanced my emotions, was ketamine. After trying ketamine for the first time, I felt like I did during puberty.

Ketamine is one of the few agents that have been rigorously tested in anhedonia. Whether ketamine-induced amelioration of anhedonia is related to an uptick in glutamate signaling, neurogenesis, or something else, is unknown. Ketamine is discussed here.

Dextromethorphan

Anecdotally, for some people, dextromethorphan improves anhedonia, though unfortunately, usually only for a short period of time. The pharmaceutical industry picked up on what bluelighters had been doing for a long time and created the drug combination dextromethorphan + bupropion (Auvelity), which is thought to specifically help with anhedonia.

Dopaminergic drugs

Dopaminergic stimulants are quite effective when it comes to treating the low-excitement type of anhedonia. Unfortunately, stimulants lose most of their effectiveness over time and they may make matters worse. Stimulants include amphetamine, lisdexamphetamine, ephedrine, methylphenidate, modafinil, and caffeine. Furthermore, there are a couple of “obscure” stimulants stuck in the pharmaceutical pipeline.

I want to specifically mention bupropion, which is a dopaminergic and noradrenergic antidepressant (more noradrenergic than dopaminergic). Bupropion is the only non-serotonergic mainstream antidepressant and, anecdotally, it works well for light cases of anhedonia.

Dopamine receptor agonists

Agonists at the dopamine receptor D2 may help with certain aspects of anhedonia. These include the partial D2-agonists aripiprazole/brexiprazole, and the D2/D3 dual agonist pramipexole. Furthermore, there are a variety of “dirty” dopamine agonists such as ropinirole, cabergoline, pergolide, and bromocriptine.

Dopamine-release disinhibitors

Very low dose amisulpride and cariprazine, both of which are atypical antipsychotics, preferentially block D2/D3 autoreceptors and are therefore thought to disinhibit dopamine release. Some psychiatrists like to prescribe them for anhedonia and dysthymia. I discuss some of these drugs in more detail here.

SAMe

S-adenosyl-methionine helps methylation processes. Among other things, it increases dopamine synthesis and therefore helps with anhedonia in the short term. Whenever I tried SAM-e I felt hypomanic for a couple of days. I discuss SAMe in more detail here.

Noradrenergic drugs

Noradrenergic drugs such as reboxetine, atomoxetine, bupropion, and nortriptyline, may increase emotional intensity, particularly in the first couple of weeks.

MAO-inhibitors

For some people, MAO inhibitors such as moclobemide, phenelzine, and tranylcypromine increase emotional intensity for the first couple of months. However, eventually, they reportedly cause emotional blunting for many but not all people. The selective MAO-B inhibitors selegiline and rasagiline do not cause emotional blunting at low doses and may improve anticipatory anhedonia by way of increasing dopamine levels.

Opioids

In the short term, targeting the opioid system (“pleasure”) is remarkably effective for anhedonia, in part because opioidergic signaling seems to increase the “richness” of one’s experience. Most people who consume THC, which acts as an indirect opioidergic enhancer, can attest to this. However, similar to direct opioid agonists, because THC enhances opioidergic systems, counterregulation occurs and the user gets less pleasure whenever there is no THC in the system. In fact, opioids are known to cause emotional blunting eventually.

Furthermore, using opioids is hardly a productive long-term strategy that makes ethical or material sense. Weak and potentially useful opioids include kratom, tianeptine, tramadol, and buprenorphine – though even these opioids eventually produce almost complete tolerance and counterregulation.

Low-dose naltrexone

For some people, low doses of naltrexone, a mu-receptor antagonist, can increase emotional intensity, particularly after a couple of weeks (during which it may have the opposite effect). This may be related to an increase in baseline opioidergic tone, a decrease in neuroinflammation, or both. For me, low-dose naltrexone was scary and did the opposite, though I only took it for a couple of days. LDN is discussed in more detail here.

Serotonergic drugs

For some people, the 5HT1A-agonist buspirone increases emotions. As do the serotonin-receptor modulators vilazodone, nefazodone, and vortioxetine. For most people though, SSRIs and SNRIs eventually blunt emotionality (unless they help with neurobiological depression). 5HT2C-antagonists such as agomelatine and mirtazapine may increase prefrontal catecholamine levels and are reported to help with certain aspects of anhedonia.

Glutamatergic drugs

Racetams and ampakines may help with anhedonia by elevating glutamate levels. Unfortunately, no ampakines have been assessed regarding safety and efficacy for this indication.

Phenibut & GHB

Both phenibut and GHB increase emotional intensity, presumably through the same mechanism. Unfortunately, both are highly addictive if taken regularly.

Neurogenesis stimulators

Cerebrolysin is a cocktail of neural growth factors that is thought to stimulate neurogenesis. Likewise, NSI-189 was developed as a neurogenesis stimulator. Anecdotally, both seem to enhance emotions. However, for both, there is little efficacy and safety data.

Others

Antivirals, antifungals, antibiotics

For some people, anhedonia may be a consequence of “sickness behavior”. Some people may find that their anhedonia gets better after a short course on doxycycline (antibiotic and antiprotozoan) or itraconazole (antifungal that is capable of crossing the blood-brain barrier) aimed at eliminating unwanted coinhabitants.

Deep brain stimulation (DBS)

DBS directly stimulates the nucleus accumbens and is known to alleviate anhedonia in refractory major depression. However, this is by far the most radical option on this list.

Sources & further information

• Anecdotes: Reddit – r/anhedonia
• Scientific review: The Neurobiology of Anhedonia and Other Reward-Related Deficits
• Scientific review: Anhedonia as a central factor in depression: Neural mechanisms revealed from preclinical to clinical evidence

Disclaimer

The content available on this website is based on the author’s individual research, opinions, and personal experiences. It is intended solely for informational and entertainment purposes and does not constitute medical advice. The author does not endorse the use of supplements, pharmaceutical drugs, or hormones without the direct oversight of a qualified physician. People should never disregard professional medical advice or delay in seeking it because of something they have read on the internet.