Welcome to Huberman Lab Essentials, wherewe revisit past episodes for the most potent and actionable science-based toolsfor mental health, physical health, and performance.

 I'm Andrew Huberman, and I'm a professorof neurobiology and ophthalmology at Stanford School of Medicine.

 Today, we continue our discussion of thesenses, and the senses we are going to discuss are pain and pleasure.

 Pain and pleasure reflect two oppositeends of a continuum, a continuum that involves detection of things in our skin,and the perception, the understanding of what those events are.

 Our skin is our largest sensory organ andour largest organ indeed.

 It is much larger than any of the other organs in ourbody.

 And it's an odd organ if you think aboutit.

 It has so many functions.

 It acts as a barrier between our organs and theoutside world.

 It harbors neurons, nerve cells that allowus to detect things like light touch or temperature or pressure of various kinds.

 And it's an organ that we hang ornamentson.

 People put earrings in their ears.

 People decorate their skin with tattoosand inks and other things.

 And it's an organ that allows us to experience eithergreat pain or great pleasure.

 So, it's a multifaceted organ, and it's one that ourbrain needs to make sense of in a multifaceted way.

 I think we allintuitively understand what pleasure and pain are.

 Pleasure generally is a sensation in thebody and in the mind that leads us to pursue more of whateveris bringing about that sensation.

 And pain is also a sensation in the body and in the mind that, ingeneral, leads us to want to withdraw or move away from some activity orinteraction.

 Scientists would call this appetitive behaviors, meaning behaviorsthat lead us to create an appetite for more of those behaviors, and aversivebehaviors, behaviors that make us want to move away from something.

 The organ thatwe call the skin, as I mentioned earlier, is the largest organ in our body, and throughout that organ, we haveneurons, little nerve cells.

 Now, to be really technical about it, and the way I'dlike you to understand it, is that the so-called cell body, meaning the locationof a cell in which the DNA and other goodies, the kind of central factory ofthe cell, that actually sits right outside your spinal cord.

 So, all up and downyour spinal cord, on either side, are these little blobs of neurons, littlecollections of neurons.

 They're called DRGs, dorsal root ganglia.

 A ganglion is just acollection or a clump of cells.

 And those DRGs are really interestingbecause they send one branch that we call an axon, a little wire, out to our skin,and they have another wire from that same cell body that goes in the oppositedirection, which is up to our brain, and creates connections within our brain, inthe so-called brain stem, okay? These wires are positioned withinthe skin to respond to mechanical forces, so maybe light touch.

 Some will only sendelectrical activity up toward the brain in response to light touch.

 Others respond to coarse pressure, to hardpressure, but they won't respond to a light feather.

 Others respond totemperature, so they will respond to the presence of heat or the presence of cold.

And still others respond to other types of stimuli, like certain chemicals on ourskin.

 So, these neurons are amazing.

 They're collecting information ofparticular kinds from the skin throughout the entire body and sending thatinformation up toward the brain.

 And what's really incredible, I just wantyou to ponder this for a second, what's really incredible is that the languagethat those neurons use is exactly the same.

 The neuron that responds to lighttouch sends electrical signals up toward the brain.

 The neurons that respond tocold or to heat or to habanero pepper, they only respond to the particular thing that evokes the electrical response.

 I shouldsay that they only respond to the particular stimulus, the pepper, the cold,the heat, et cetera, that will evoke an electrical signal, but the electrical signals are a commonlanguage that all neurons use.

 And yet, if something cold is presented to yourskin, like an ice cube, you know that that sensation, that thing is cold.

 You don'tmisperceive it as heat or as a habanero pepper, okay? So, that's amazing.

 Whatthat means is that there must be another element in the equation of what createspleasure or pain, and that element is your brain.

 Your brain takes these electrical signalsand interprets them, partially based on experience, but also there are someinnate, meaning some hardwired aspects of pain and pleasure sensing thatrequire no experience whatsoever.

 A child doesn't have to touch a flame but once,and the very first time, they will withdraw their hand from the flame.

 Thepain and pleasure system don't need prior experience.

 What they need is a brain thatcan interpret these electrical signals and somehow create what we call pleasureand pain out of them.

 So, what parts of the brain? Well, mainlyit's the so-called somatosensory cortex, the portion of our neocortex, which is onthe outside of our brain, the kind of bumpy part.

 And in your somatosensory cortex, you have amap of your entire body surface.

 That map is called a homunculus.

 It's yourrepresentation of touch, including pleasure and pain.

 But it's not randomly organized.

 It'shighly organized in a very particular way, which is that the areas of your skin thathave the highest density of these sensory receptors are magnified in your brain.

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 what arethe areas that are magnified? Well, the lips, the face, the tips of thefingers, the feet, and the genitals.

 And that's because the innervation, thenumber of wires that go into those regions of your body, far exceeds the number ofwires for sensation of touch that go to other areas of your body.

 You can actually experience this in realtime right now, by doing a simple experiment that we call two pointdiscrimination.

 Two point discrimination is your abilityto know whether or not two points of pressure are far apart, near each other, or you actually could perceive incorrectly asone point of pressure.

 You might want a second person to do thisexperiment.

 That person would take two fine points, so it could be two pencils orpens, or the backs of pens.

 If you were to close your eyes and I were to takethese two pens and put their points close together about a centimeter apart, andpresent them to the top of your hand, you, even though your eyes were closed, youwould be able to perceive that that was two points of pressure presentedsimultaneously to the top of your hand.

 However, if I were to do this to themiddle of your back, you would not experience them as two points of pressure.

You would experience them as one single point of pressure.

 In other words, yourtwo point discrimination is better, is higher, on areas of your body which have many,many more sensory receptors.

 Most of us don't really appreciate how important andwhat a profound influence this change in density of receptors across our body'ssurface has.

 So, you've got sensors in the skin, and you've got a brain that's goingto interpret what's going on with those sensors.

 And believe it or not, yoursubjective interpretation of what's happening has a profound influence on your experience of pleasure or pain.

There's several things that can impact these experiences, but the main categoriesare expectation, if someone tells you this isgoing to hurt, I'm going to, you know, give you an injection right here, it mighthurt for a second, that's very different and your experience of that pain will bevery different than if it happened suddenly out of the blue.

 There's also anxiety.

 How anxious or howhigh or low your level of arousal, autonomic arousal.

 That's going to impact your experience ofpleasure or pain.

 How well you've slept and where you are in the so-calledcircadian or 24-hour cycle.

 Our ability to tolerate pain changesdramatically across the 24-hour cycle, and as you can imagine, it's during thedaylight waking hours that we are better able to tolerate, we are more resilient topain, and we are better able to experience pleasure.

 At night, ourthreshold for pain is much lower.

 In other words, the amount of mechanicalor chemical or thermal, meaning temperature stimuli that can evoke a painresponse and how we would rate that response, is much lower at night, and in particular, inthe hours between 2:00 AM and 5:00 AM if you're on a kind of standard circadianschedule.

 And then the last one is our genes.

 Pain threshold and how long a painresponse lasts is in part dictated by our genes.

 So, we have expectation, anxiety, how wellwe've slept, where we are in the so-called 24-hour circadian time, and ourgenes.

 So, let's talk about expectation andanxiety, because those two factors can powerfully modulate our experience of bothpleasure and pain in ways that will allow us to dial up pleasure, if we like, andto dial down pain, if indeed that's what we want to do.

 So, let's talk aboutexpectation and anxiety, because those two things are somewhat tethered.

 There are now a number of solidexperiments that point to the fact that if we know a painful stimulus is coming, that we can better prepare for itmentally, and therefore buffer or reduce the pain response.

 Essentially if subjectsare warned that a painful stimulus is coming, their subjective experience of that pain is vastly reduced.

 However, if they are warned just twoseconds before that pain arrives, it does not help.

 It actually makes itworse.

 And the reason is they can't do anything mentally to prepare for it inthat brief two-second window.

 Similarly, if they are warned about painthat's coming two minutes before a painful stimulus is coming, that also makes itworse, because their expectation ramps up the autonomic arousal, the level ofalertness is all funneled toward that negative experience that's coming.

 So, how soon before a painful stimulus should we knowabout it if the goal is to reduce our level of pain? And the answer is,somewhere between 20 seconds and 40 seconds is about right.

 This can come inuseful in a variety of contexts, but I think it's important because what itillustrates is that it absolutely cannot be just the pattern of signals that arearriving from the skin.

 There has to be a subjective interpretation component,because we are all different in terms of our pain threshold.

 First of all, what ispain threshold? Pain threshold has two dimensions.

 The first dimension is theamount of mechanical or chemical or thermal stimulation that it takes for youor me or somebody else to say, "I can't take that anymore.

 I'm done.

" But there's another element as well, whichis how long the pain persists.

 And to just really point out how varied we allare in terms of our experience of pain, let's look to an experiment.

 There have been experiments done atStanford School of Medicine and elsewhere, which involved having subjects put theirhand into a very cold vat of water and measuring the amount of time that theykept their hand in that water, and then they would tell the experimenter how.

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painful that particular stimulus was on a scale of one to 10.

 That simpleexperiment revealed that people experience the same thermal, in this case cold,stimulus vastly different.

 Some people would rateit as a 10 out of 10, extreme pain.

 Other people would rate it as barely painful atall, like a one.

 Other people, a three.

 Other people, a five, et cetera.

 In fact,there is no objective measure of pain.

 Similarly, pleasure is something that weall talk about, but we have no way of gauging what other people are experiencingexcept what they report through language.

 So, rather than focus on just thesubjective nature of pain, let's talk about the absolute qualities of pain, andthe absolute qualities of pleasure, so that we can learn how to navigate thosetwo experiences in ways that serve us each better.

 First of all, I want to talk about heatand cold.

 We do indeed have sensors in our skin that respond to heat and cold, andone of the best tests of how somebody can handle pain is to ask them to just getinto an ice bath.

 Some do it quickly, some do it slowly.

 Others find the experienceof cold to be so aversive that they somehow cannot get themselves in.

 I thinkit can be helpful to everyone to know that even though it feels better at a mental level to get into the coldslowly, it is actually much worse from a neurobiological perspective.

 The neurons that sense cold respond towhat are called relative drops in temperature.

 So, it's not about the absolutetemperature of the water, it's about the relative change in temperature.

 Therefore,you can bypass these signals going up to the brain with each relative change,one degree change, two degrees change, et cetera, by simply getting in all at once.

 In fact,it is true that if you get into cold water up to your neck, it's actually muchmore comfortable than if you're halfway in and halfway out.

 And that's because ofthe difference in the signals that are being sent from the cold receptors on yourupper torso, which is out of the water, and your lower torso.

 Now, I wouldn't wantanyone to take this to mean that they should just jump into an unknown body ofwater.

 People can have heart attacks from getting into extremely cold water.

 But itis absolutely true that provided it's safe, getting into, uh, cold water is always going to be easier todo quickly, and is going to be easier to do up to your neck.

 Now, heat is theopposite.

 Heat is measured in absolute terms by the neurons.

 So, gradually movinginto heat makes sense, and finding that threshold which is safe and comfortablefor you, or if it's uncomfortable, at least resides within that realm of safety.

 One of the most important things tounderstand about the experience of pain, and to really illustrate just howsubjective pain really is, is that our experience of pain and thedegree of damage to our body are not always correlated.

 A classic example ofthis was published in the British Journal of Medicine in which a construction workerfell from, I think it was a second story, which he was working, and a nail went up and through his boot.

 And he looked down, and he saw the nailgoing through his boot, and he was in absolute, excruciating pain.

 They took him to the hospital, and because the nail was so long, andbecause of where it had entered and exited the boot, they had to cut away the bootin order to get to the nail.

 And when they did that, they revealed thatthe nail had passed between two of his toes.

 It had actually failed to impale his body in any way, andyet the view, the perception of that nail entering his boot at one end, and exitingthe boot at the other was sufficient to create the experience of a nail that hadgone through his foot.

 And the moment he realized that that nail had not gonethrough his foot, the pain completely evaporated.

 And I want to make sure that Iemphasize the so-called psychosomatic phenomenon.

 Ithink sometimes we hear psychosomatic and we interpret that as meaning all in one'shead.

 But I think it's important to remember that everything is neural,whether or not it's pain in your body 'cause you have a, a gaping wound andyou're hemorrhaging out of that wound, or whether or not it's pain for which youcannot explain it on the basis of any kind of injury.

 It's all neural.

 So, sayingbody, brain, or psychosomatic, it's, it's kind of irrelevant, and I hope someday wemove past that language.

 So, when we hear syndrome, and a patient comes into a clinic and says, uh, that they suffer, for instance,from something which is very controversial, frankly, like chronicfatigue syndrome.

 Some physicians believe that it reflects a real underlying medicalcondition, others don't.

 However, syndrome means we don'tunderstand, and that doesn't mean something doesn'texist.

 Fibromyalgia, or whole body pain, for along time was written off or kind of explained awayby physicians and scientists, frankly, my community, as one of these syndromes.

 It couldn't beexplained.

 However, now there is firm understanding of at least one of the basesfor this whole body pain, and that's activation of a particular cell typecalled glia.

 And there's a receptor on these glia, forthose of you that want to know, called the Toll-4 receptor.

 And activation of the Toll-4 receptor isrelated to certain forms of whole body pain and fibromyalgia.

 Now, what treatments exist forfibromyalgia? There are clinical data using aprescription drug.

 The drug is called naltrexone.

 Naltrexoneis actually used for the treatment of various, uh, opioid addictions and thingsof that sort.

 But it turns out that a very low dose.

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 has been shown to havesome success in dealing with and treating certain forms of fibromyalgia.

 And it hasthat success because of its ability to bind, to unblock these toll4 receptors onglia.

 There's another approach that one could take, and that compound isacetylcarnotine.

 There is evidence that acetylcarnotine canreduce the symptoms of chronic whole-body pain, and other certain forms of acutepain at dosages of somewhere between one tothree and sometimes four grams per day.

 Now, acetylcarnotine can be taken orally.

It's found in 500 milligram capsules, as well as by injection.

 There are a largenumber of studies on acetylcarnotine.

 You can look those up on PubMed if you like,or on examine.

com.

 So, it appears that L-carnitine is impacting a number ofdifferent processes both to impact pain and perhaps, and I want to underscoreperhaps, but there are good studies happening now, perhaps accelerate wound healing as well.

Now, I'd like to turn our attention to a completely non-drug, non-supplementrelated approach to dealing with pain, and it's one that has existed for thousandsof years, and that only recently has the Westernscientific community started to pay serious attention to.

 And there isterrific mechanistic science to now explain how and why acupuncture can workvery well for the treatment of certain forms of pain.

 Now, first off, I want to tell you whatwas told to me by our director or chief of the pain division at Stanford School ofMedicine, Dr.

 Sean Mackey, which was that a fraction of people experience tremendouspain relief from acupuncture, and others experience none at all or very little.

 Anumber of laboratories have started to explore how acupuncture works, and one ofthe premier laboratories for this is Qiufu Ma's lab at Harvard Medical School.

 Now,the form of acupuncture that they explored was one that's commonly in use calledelectroacupuncture.

 So, this isn't just putting little needles into differentparts of the body.

 These needles are able to pass an electrical current, notmagically, but because they have a little wire going back to a device and you canpass electrical current.

 So, what Qiufu Ma's lab found was that ifelectroacupuncture is provided to the abdomen, to the stomacharea, it creates activation of what are calledthe sympathetic ganglia, and the activation of these neurons involvesnoradrenaline and something called NPY, neuropeptide Y.

 The long and short of it is thatstimulating the abdomen with electroacupuncture was either anti-inflammatory or it couldcause inflammation.

 It could actually exacerbate inflammation, depending onwhether or not it was of low or high intensity.

 Now, that makes it a veryprecarious technique, and this may speak to some of the reason why some peoplereport relief from acupuncture and others do not.

 However, they went a step furtherand stimulated other areas of the body using electroacupuncture, and what theyfound is that stimulation of the legs caused a circuit, a neural circuit to beactivated that goes from the legs up to an area of the base of the braincalled the DMV, and activated the adrenal glands which sit atop your kidneys, and re- caused a release of what are calledcatecholamines, and those were strongly anti-inflammatory.

 In other words,electroacupuncture of the legs and feet can, if done correctly, beanti-inflammatory and reduce symptoms of pain, and perhaps accelerate woundhealing, because activations of these catecholaminergic pathways can acceleratewound healing as well.

 Now, let's talk about a phenomenon that has long intriguedand perplexed people for probably thousands of years, and that's redheads.

 You may have heard before thatredheads have a higher pain threshold than other individuals, and indeed, that istrue.

 There's now a study that looked at thismechanistically.

 There's a gene called the MC1R gene, and this MC1R gene encodes for a number ofdifferent proteins.

 Some of those proteins, of course, arerelated to the production of melanin.

 This is why redheads often, not always, butoften are very fair-skinned, sometimes have freckles, not always, and of course,have red hair.

 This gene, this MC1R gene is associated with a pathway that relates to something that I've talked about onthis podcast before during the episode on hunger and feeding, and this is POMC.

 POMCstands for proopiomelanocortin, and POMC is cut up,it's cleaved into different hormones, including one that enhances painperception.

 This is melanocyte-stimulating hormone.

 And another one that blocks pain, betaendorphin.

 The endorphins are endogenously made, meaning made within our body.

Opioids, they actually make us feel numb in response to certain kinds of pain.

Now, not completely numb, but they numb or reduce our perception of pain.

 We allhave beta endorphins, we all have POMC, et cetera, but redheads make more of theseendogenous endorphins.

 Now this, of course, should not be taken to mean thatredheads can tolerate more pain and thereforeshould be subjected to more pain.

 All it means is that their threshold for pain onaverage, not all of them, but on average, is shifted higher than that of otherindividuals.

 And I should mention, because I mentioned the ice bath, that of course pain threshold is something that can bebuilt up, but it does seem that certain patterns of thinking can allow us tobuffer ourselves against the pain response, and that should not be surprising.

 Certain forms of thinking are associatedwith the release of particular neuromodulators, in particular dopamine,and dopamine.

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And it may seem, is kind of the thing that underlies everything, butit's not.

 Dopamine is a molecule that's associated with novelty, expectation,motivation, and reward.

 We talked about this at the beginning of the episode.

 Andthe ways in which dopamine can modulate pain is not mysterious.

 It's reallythrough the activation of brain stem neurons that communicate with areas of ourbody that deploy things like immune cells.

 So for instance, we have neurons inour brain stem that can be modulated by the release ofdopamine, and those neurons in the brain stemcontrol the release of immune cells from tissues like the spleen, or organs likethe spleen.

 And those immune cells can then go combat infection.

 We've heardbefore that when we're happy, we're better able to combat infection, deal with pain, deal with all sorts ofthings.

 It essentially makes us more resilient, because dopamine affectsparticular circuits and tells, in a very neurobiological way and abiochemical way, tells those cells and circuits that conditions are good, and itreally does allow for more resilience.

 So along those lines, let's talk aboutpleasure.

 With all the cells and tissues and machinery related to pain, you mightthink that our entire touch system is designed to allow us to detect pain and toavoid tissue damage.

 And while a good percentage of it is devoted to that, agood percentage of it is also devoted to this thing that we call pleasure.

 And that should come as no surprise.

Pleasure serves an adaptive role, and that adaptive role relates to the fact thatevery species has a primary goal, which is to make more of itself, otherwise itwould go extinct.

 That process of making more of itself,sexual reproduction, is closely associated with the sensation and the perception ofpleasure.

 And it's no surprise that not only is the highest density of sensoryreceptors in and on and around the genitalia, butthe process of reproduction evokes sensations and molecules and perceptionsassociated with pleasure.

 And the currency of pleasure exists in multiple chemicalsystems, but the primary ones are the dopamine system, which is the anticipationof pleasure, and the work required to achieve theability to experience that pleasure, and the serotonin system, which is moreclosely related to the immediate experience of that pleasure.

 And fromdopamine and serotonin stem out other hormones and molecules, things likeoxytocin, which are associated with pair bonding.

 Oxytocin is more closelyassociated with the serotonin system, biochemically and at the circuit level,meaning the areas of the brain and body that manufacture a lot of serotonin usually, not always, but usually containneurons that also manufacture and make use of the molecule oxytocin.

 Those chemicals together create sensationsof warmth, of, uh, wellbeing, of safety.

 The dopamine molecule is more closelyassociated with hormones like testosterone and other molecules involved with pursuitand further effort in order to get more of whatever could potentially cause morerelease of dopamine.

 So, if levels of serotonin and dopamine are too low, it becomes almost impossible to experiencepleasure.

 There's a so-called anhedonia.

 This is also described as depression,although it needn't be long-term depression.

 So, certain drugs likeantidepressants, like Wellbutrin, bupropion, as it's commonly called, or the so-called SSRIs, the serotoninselective re- top- reuptake inhibitors, excuse me, like Prozac, Zoloft, andsimilar, will increase dopamine and serotonin respectively.

 They're notincreasing the peaks in those molecules, the, what we call the acute release of those molecules.

 What they'redoing is they're raising the overall levels of those molecules.

 They're raisingthe sort of foundation or the tide, if you will.

 Think about it as your mood, oryour pleasure rather, is like a boat, and if it's on the shore and it can't get outto sea unless that tide is high enough.

 That's kind of the way to think aboutthese tonic levels of dopamine and serotonin.

 Now, most of us, fortunately,do not have problems with our baseline or our tonic levels of dopamine and serotoninrelease.

 The brain and body use these common currencies for differentexperiences.

 So yes, if your dopamine and serotonin, or o- or I should say, if yourdopamine and/or serotonin levels are too low, it will be very hard to achieve pleasure,to experience physical pleasure or emotional pleasure of any kind.

 That's whytreatments of the sort that I described a minute ago, um, might be right for you.

Obviously we can't determine if they're right for you.

 It's also why they haveside effects.

 If you artificially increase these molecules that are associated withpleasure, oftentimes you get a lack of motivation to go seek things like food.

People don't get much interest in food, 'cause why should they if their serotoninlevels are already up? Again, there's a ton of individual variation.

 I don't wantto say that these antidepressants are always bad.

 Sometimes they've saved lives.

They've saved millions of lives.

 Sometimes people have side effects thatmake them not the right choice.

 So, it has to be determined for the individual.

 Justbriefly, 'cause it's relevant to the conversation that we've been having, you might want to be wary of anyexperience, any experience, no matter how it arrives, chemical, physical, emotional,or some combination, you might want to be wary of letting yourdopamine go too high, and certainly you want to be wary of it going too low,because of the way that these circuits adjust.

 Basically, every time that thepleasure system is kicked in in high gear, an absolutely spectacularevent, you cannot be more ecstatic, there is a mirror symmetric activation of the painsystem.

 And this might seem like an evil curse ofbiology, but it's not.

 This is actually a way to protect this whole system of rewardand motivation that I talked about at the beginning of the episode.

And it mightsound great to just ingest substances or engage in behaviors where it's justdopamine, dopamine, dopamine, and just constantly be motivated.

 But the system will eventually crash.

 Andso what happens is when you have a big increase in dopamine, you also will get abig increase in the circuits that underlie our sense of disappointment, andreadjusting the balance.

 And with repeated exposure to high levels of dopamine, notnaturally occurring, wonderful events, but really high chemically induced, uh, peaks in dopamine, high magnitude chemically induced peaks indopamine, what happens is those peaks in dopamine start to go down, and down, anddown in response to the same what ought to be incredible experience.

 We start towhat's called habituate or attenuate, and yet the pain increases in size.

 And this has apreservative function in keeping us safe, believe it or not.

 But what I just described is actually thebasis of most, if not all, forms of addiction, something that we will dealwith in a future episode in depth.

 So, today we talked about the pathways in theskin and in the brain, and elsewhere in the body that control our sense ofpleasure and pain.

 We described a number of different tools ranging from differentsupplements to, uh, electro-acupuncture and various other tools that one could useto modulate your sense of pleasure or pain.

 And of course, in thinking aboutpleasure, we have to think about the dopamine system and the serotonin system,and some of the related chemical systems.

 I realize that today's podcast had a lotof scientific details.

 I don't expect that everyone would be able to understand allthese details all at once.

 What's more important really is to understand the general principles ofhow something like pleasure and pain work, how they interact, and the variouscells and systems within the brain and body that allow them to occur, and thatmodulate or change their ability to occur.

 And of course, your subjective experienceof pleasure or pain.

 So, I do hope that this was on whole more pleasureful than painful foryou.

 And last but not least, I thank you for your time and attention, and thank youfor your interest in science.