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The clients of prostitutes are mostly sexually frustrated men The stereotype of the john The stigma of prostitution extends to their clients, even more so after the Nordic Model for persecuting prostitution focused law enforcement on johns and pimps. The stereotype of the john is a man who is lonely, antisocial, misogynistic, unable to form romantic relationships, and prone to physical violence and rape. It is hard to know to what extent this image correspond to reality, because research studies on men who buy sex are even more scarce than those studying sex workers. The few studies I could find usually focus on the treatment of sex workers by their clients and on behaviors that increase the risk of sexually transmitted diseases like avoiding condom use (Schei and Stigum, 2010; Jones et al., 2015), rather than on the johns themselves and their motives. Prostitution customers are sexually frustrated men The best study I could find (Deogan et al., 2021) was a randomized survey of 6048 Swedish men, using data from a population-based survey of both genders. It included men 16-84 years old. It found that 9.5% of the men had ever paid for sex, which is comparable to what was found in studies in Norway, 13% (Schei and Stigum, 2010), and Britain, 11% (Jones et al., 2015). Only 0.26% of the men said that they had purchased sex within the last year. Men younger than 29 were less likely to had bought sex, although this is likely a confound of the question - obviously, they had less time for having “ever” bought sex than older men. Otherwise, there was little correlation of buying sex with age, educational level and income. If anything, men of lower education and income were slightly more likely to buy sex. The study found that men who bought sex were dissatisfied with their sex lives, had less sex that they wanted, viewed more porn, and looked for sex partners online. This is hardly surprising. It shows that men buy sex because they are sexually frustrated and cannot get sex otherwise. It also suggest that men who are less educated, have less income and are older buy sex because they find it harder to date women. Rape myth acceptance Another study (Klein et al., 2009) used the Burt’s Rape Myth Acceptance Scale in men who had been arrested for soliciting prostitutes in British Columbia. It found that rape myth acceptance was lower in older and more educated men; and also in men who viewed more porn, wanted more frequent sex, and believed that purchasing sex is a problem. Rape myth acceptance correlated positively with sexual conservatism, sexual violence and coercion, and social desirability. This indicates that beliefs that reinforce rape and sexual violence are not related to porn use or sexual desire, but to conservative views of sex. Sex Work benefits disabled people A topic that is rarely discussed is that sex work can provide relief for the sexual desire and loneliness of disabled people. In fact, in Victoria, Australia, people with disabilities are entitled to hire a sex worker and have the National Disability Insurance Service (NDIS) pay for it. In Norway, men who pay for sex are more likely to be on a disability pension (Schei and Stigum, 2010). Conclusions These studies show that the clients of prostitution are most sexually frustrated men who have trouble finding sexual partners. Johns are no more inclined to rape or sexual violence than other men. However, criminalization of prostitution make sex workers vulnerable to attacks by those clients that are so inclined.

How biochemistry unravels the mystery of life When I was in my last year of college, I had an epiphany. As I was listening to a lecture on thermodynamics of irreversible processes, my eyes were opened and I suddenly understood what is life. This was not some kind of mystical revelation but the culmination of two years of hard work studying biochemistry and molecular biology. But all of a sudden it all came together, and I understood what life is at its essence. Vitalism Since antiquity, people have wondered what makes living beings different from inanimate objects. The fact that an animal can be alive and then dead, and still look pretty much the same, gave rise to the idea of vitalism, which sustains that life is caused by a non-material essence, life force or Elan Vital, that infuses organisms with life and leaves them when they die. This idea persisted until the 20th century when it was debunked by the development of biochemistry, a science that explains life in terms of chemistry. But it is not as simple as that. Schrödinger’s first hypothesis and the discovery of DNA A good place to start is a book titled What is life? written by a famous quantum physicist, Erwin Schrödinger. The book came out of three public lectures that Schrödinger gave at the Trinity College, Dublin, in February 1943, while being exiled from Nazi Germany. In them, Schrödinger put forward two daring hypotheses. The first, which he termed “order from order”, was a genial insight. It proposed that the genes used by living beings to pass information from one generation to the next were an “aperiodic crystal” that stored information as a code in its molecular structure. He was right. The aperiodic crystal was found a decade later: it was DNA. An explosion of scientific discoveries followed. They established the genetic code and the mechanisms of transcription of DNA into messenger RNA (mRNA) and the translation of mRNA into proteins. These discoveries confirmed the theory of evolution by explaining: the molecular identity of the genes, the link between genes and sexual reproduction, why genes last for many generations, how changes in the DNA molecule are the mutations that drive evolution. The gene-centric view of life The problem was that many scientists fell so in love with genes and DNA that they thought that reproduction is the defining characteristic of life and the DNA-RNA-protein encoding system is its core mechanism. Everything else in a living organism is at the service of them. This view reflects the centralized and hierarchical way in which our society is organized. DNA is the king or the president. It sits in his throne in the nucleus at the center of the cell, from where it gives orders that are transmitted by its ministers, the messenger RNAs, and are faithfully executed by the workers, the proteins. However, there are a few problems with the gene-centric view of life: Reproduction is not the fundamental characteristics of life, because an organism can be alive even if it is unable to reproduce. Reproduction serves to perpetuate life in the long term and to drive evolution. DNA is not essential to be alive. Red blood cells (erythrocytes) are alive even though they do not have a nucleus with DNA. In the lab, it is possible to keep alive cells without a nucleus or preparations like synaptosomes, presynaptic terminals pinched off neurons. Viruses contain DNA or RNA, but they are not alive and able to reproduce until they infect a living cell. How do we know that something is alive? How do we know that red blood cells are alive and viruses are not? Because living cells breathe, consuming oxygen and producing CO2. They have an electric potential across their membrane. They can absorb substances from the outside and expel others. They consume substances to produce energy. All these properties mean that living cells have a metabolism. Viruses do not breathe, have no membrane potential and do not move or consume substances. They have no metabolism. To take a closer look, let’s consider what happens when a cell dies. To find out if a cell is alive, one of the things a scientist would do is to measure the amount of calcium ions (Ca2+) that it has inside. Living cells maintain a steep gradient of calcium concentration across their membrane, so that the amount of calcium inside is 10,000 times less than the amount of calcium outside. Another way to know if a cell is alive is to look at the electrical potential across its membrane: it should be about -60 millivolts. This electrical potential is maintained by pumping sodium ions (Na+) to the outside and potassium ions (K+) to the inside, although their concentration gradient is not as dramatic. A dead cell has a large amount of calcium inside and no membrane potential. All of its ion gradients have collapsed. These are just two examples of things in a living cell that do not make sense from the chemical point of view. Things seem to be quite out of place. Ions should be equally distributed on both sides of the membrane. Unstable substances are present in large amounts. There is energy and chemical imbalance everywhere. But what is even stranger is that, despite all that chemical imbalance, things stay the same. For example, the concentration of calcium inside a cell is always close to 100 nano-molar. Calcium concentrations may increase 10 times to convey a signal, but they immediately return to normal. Likewise, the concentration of any other substance within the cells is kept within a narrow range. There is a word for this property of life: homeostasis. It means the ability of a living organism to maintain a stable internal environment. Entropy and Schrödinger’s second hypothesis Because chemical imbalances require energy to be maintained, to understand homeostasis we need to invoke some basics concepts of chemistry and thermodynamics. The second law of thermodynamics states that the amount of disorder in a closed system always increases over time. The precise term for disorder is ‘entropy’, which is a measure of all the possible configurations of a system. That means that a highly organized system, like a living cell, requires a lot of energy to stay that way. Schrödinger also had an insight concerning the role of entropy in life. Unfortunately, it is not remembered as well as his prediction that genetic information would be stored in an aperiodic crystal. In his book What is Life? Schrödinger called his second hypothesis order from disorder. He said that for a living organism to keep its low entropy state it had to absorb energy and pump entropy to the outside. He called that property negentropy (negative entropy), but the term never caught on. Homeostasis is a state far from chemical equilibrium From the chemistry standpoint, increasing entropy means that a chemical reaction would proceed until the state of the lowest energy is reached. If compound A reacts with B to generate energy and compound C, the reaction will proceed until A and B are exhausted and all that remains is C. In other chemical reactions, compounds A and B react to produce compounds C and D, but the inverse reaction in which C and D produce A and B can also take place. In this case, an equilibrium is reached at some particular concentrations of A, B, C and D that minimize entropy. This is called chemical equilibrium. A living cell is a vast network of interlinked chemical reactions. These reactions are constrained by barriers (membranes and the cytoskeleton) that create the external and internal structure of the cell. Remarkably, these chemical reactions never reach chemical equilibrium and, in fact, the concentrations of substances inside a living cell are far away from equilibrium. Still, their concentrations do not vary: this is what homeostasis means. It is easy to keep concentrations of compounds the same at equilibrium, but to keep them stable far from equilibrium requires a system that carefully regulates the rate of those chemical reactions, speeding them up if the concentrations of products are too low and slowing them down if they are too high. This is achieved by having each reaction catalyzed by a protein called an enzyme, which is like a nanomachine with little control buttons that can speed it up or slow it down. So what presses those buttons? Well, other enzymes and signal molecules inside the cell. DNA is not a king The production of enzymes is regulated by the DNA-mRNA-protein genetic mechanism that I described above. But the DNA is not the king but just another piece of the machinery. DNA does not give orders, it follows them. And who orders DNA around? Proteins and small signaling molecules that tell the DNA which genes get to be expressed and how fast. So proteins are not the proletariat of the cell, but they are not kings, either. They follow orders from other proteins. Living cells are not organized like our societies or even our computers, because there is no command center. The cell just keeps going by having its parts interact which each other and with the environment. The best way to understand this is to view the cell as an information processing system, computing endlessly the best way to keep its homeostasis going. If I were to use a computer metaphor, DNA would not be the central processing unit but the hard drive where information is stored long term and extracted when needed. And it is a read-only hard drive, because permanent changes in the DNA genetic information are not allowed. Only the twin processes of mutation and natural selection get to make permanent changes in the DNA. Prigogine, dissipative structures and intracellular signals The idea that a living system is a system far from equilibrium or, as he called it, a ‘dissipative structure’, was envisioned by Ilya Prigogine, who wrote mathematical equations explaining this behavior. Recent discoveries on cell biochemistry supported his ideas. They unraveled the complex networks of intracellular signals that maintain homeostasis. Not only that, they also explained how a cell reacts to its environment or signals from the rest of the body, if the cell is part of a multicellular organism. Systems that are far from equilibrium and yet keep their shape are all around us. For example, a river: the water that flows in it is never the same and yet the river keeps its shape. The river is part of a non-equilibrium system: energy from the sun evaporates water from the sea that rains in the mountains and flows back to the sea, forming the river. But while the river may be turbulent and uneven below its surface, in a living cell every molecule is precisely placed and controlled. A more apt metaphor for a living cell will be ten thousand people juggling balls and passing them to each other in a precisely coordinated way. How did life get started? The homeostatic view of life has profound implications in many fields of biology. Take the problem of the origin of life, for example. The most accepted view these days is that of the RNA-world, in which molecules of RNA interacted with proteins to catalyze the first reactions of life. However, before that, there had to be a long process in which chemical reactions became progressively interlinked to create the first self-sustained entities. Then a primitive form of natural selection favored the most stable of those entities, slowly encouraging internal control to finally giving raise to homeostasis. The tightly regulated homeostasis of modern organisms probably took a lot of trial and error to evolve. With it came the formation of proteins, catalysis of reactions by proteins or RNA and, finally, DNA and the genetic code. Life as information processing That day in my last year of college, while the professor explained Prigogine’s ideas, it all came together. I understood that life is really homeostasis. Over the years, as I studied cell signaling systems with my own experiments, I realized that there is something beyond homeostasis. What keeps the system together in all its delicate balance is the flow of information through its signaling systems. Although there is no central processing unit, there is a certain hierarchy of control. “Intracellular signaling systems”, as they are called, form pathways for the transmission, amplification and processing of information. For example, one of them is formed by the enzyme adenylyl cyclase, the small molecule cyclic-AMP and enzyme protein kinase A, which changes the functioning of many proteins by attaching phosphoric acid to them in a process called phosphorylation. Other enzymes, the phosphatases, remove the phosphate. But there are many other signaling pathways, forming all kinds of complicated branches and loops. We are still trying to classify them and understand them. Its essence, then, life is the processing of information with the goal of keeping itself going. Reproduction is just a way to prolong the process in the long term, thanks to the effectiveness of DNA in preserving information. A living organism, therefore, is something essentially different from a material object. An object keeps its shape because its atoms and molecules stay in the same place. Inside a living organism everything moves; matter and energy come in and out. Like the water that flows in the river, atoms are not there to stay, they are just passing by. What always remains, in the end, is the information.

And how to defend yourself against them. Yes, they can hurt you The first mistake we make is to think that we cannot be hurt by our interactions online. After all, they are two separate worlds: the real one, where we live under our real name and interact with our friends and families, and the one behind our computer screen. In it, we are anonymous or hidden under a nickname. The relationships we develop can be severed at our whim by blocking people or ghosting them. Anything they write about us is not really about us, but about our internet persona. We can safely walk away from the nastiness simply by turning off our computer or putting away our phone. Then we go back to our real selves in our real lives. But things are not like that. Our brains are programed to respond to shaming and blaming by other people, no matter if they are in the real world or behind a computer screen. The relationships and social networks we create online are as real as the ones in the physical world. Fooled by our anonymity, we share secrets online that we wouldn’t dare to tell to our best friends. And then those secrets can be thrown back at us to hurt us in the most intimate places of our psyches. Since other people in the internet are also cloaked behind nicknames, their social inhibitions are turned off, and they dare say things that they would never say in the physical world. Nice doctor Jekyll turns into nasty mister Hyde as soon as he touches that keyboard. He also believes that what he writes cannot really hurt us, so he pours his venom with complete abandon. But, yes, we can be hurt online. It happens all the time. People are thrown into anxiety, rumination, depression and even suicide. If, like I do, you go into the internet to share your knowledge and defend worthy causes, you should be aware of all the ways people can be dishonest and abusive. You need to fend off the bad guys and attract the good ones. You need to know how to stay on message and avoid being derailed into worthless arguments. In this article, I compile ten dishonest and abusive tricks that you may find on the internet, and what you can do about them. 1) The personal attack The most basic and frequent form of internet abuse is the personal attack. You are discussing a problem in general terms, and then somebody comment on it, making it all about your person. This is an informal fallacy called ‘ad hominem’, which in Latin means ‘to the person’. Ideas should be considered on their own value, not based on the person who expresses them. Attacking the person and not the idea is a distraction commonly used by people who don’t have solid arguments against that idea. This turns an intellectual argument into an emotional one, since it is very easy to escalate an ad hominem into all sorts of blaming and shaming. Then you find yourself defending your reputation, and not the idea that you wanted to express. Questioning your authority on the topic at hand is not always dishonest. People have legitimate reasons to want to know how educated you are on a subject. If you have some academic credentials or an education degree, you may want to give them. However, this is not always a good idea. For one thing, you may out yourself, so you are no longer anonymous while your opponent remains so. This puts you in a situation of vulnerability, open to further attacks based on the information they may find about you. You may also be forced into the converse fallacy of the ad hominem: the argument from authority. It consists of defending an idea on the basis of your authority on the matter, instead of giving evidence and rational arguments to support it. A better solution is to show your authority by demonstrating it, for example, by citing papers and books that support your position. Or you may explain obscure ideas and technical jargon in ways that make everybody understand them. This will make you more popular amongst people who are trying to learn something, at the same time that it shows that you really know what you are talking about. Just try not to sound condescending. The most important thing to keep in mind is that you are not trying to convince the person arguing with you. In most cases, that person would be so attached to his beliefs that it would be impossible to convince them. Who you are trying to convince is everybody else watching the discussion. “Abusive ad hominem argument (or direct ad hominem) is associated with an attack to the character of the person carrying an argument. This kind of argument, besides usually being fallacious, is also counterproductive, as a proper dialogue is hard to achieve after such an attack.” Wikipedia. If a personal attack raises to the level of insult, block that person without a second thought. Life is too short to deal with mean people. 2) Fishing for personal information Personal attacks take many forms. The most vile seek points of weakness in your past to make you ashamed of them. The problem is that your attacker doesn’t know much about you. Hence, they need to extract some personal information from you beforehand. They may do that by feigning genuine curiosity or sympathy. Only after they have gathered the information that they want they will start their attack. Another strategy is to write a wild assumption about you. When you correct them, you give them the information they want. For example, a woman recently responded to one of my comments by saying that surely I was single and had problems dating. She implied that I was a misogynist and, therefore, no woman would want to date me. I replied saying that I had been married for 30 years, what about her? That way, I gave a minimum of truthful information and turned the tables on her. Of course, she didn’t volunteer if she was single or married. She knew the rules of her own game. 3) The dog pile The dog pile is one of the most vicious internet attacks. It’s when a group of people collude to make a simultaneous personal attack on you. The term ‘dog pile’ existed in the English vocabulary long before the invention of the World Wide Web. The internet made it possible to take it from a physical attack to a verbal one. Here is an old Bugs Bunny cartoon perfectly illustrating how a dog pile work. https://www.youtube.com/watch?v=F7CtOgFYtu0 Often, the people making a dog pile are part of a clique that follow a dog whistle of one of their members to appear in the comment section of one of your posts. Other times, dog piles form spontaneously when you dare post a view the goes against the commonly held beliefs of a site - not a wise thing to do. Stay off that site. You won’t make any friends or convert anybody there. You’ll be like Bugs Bunny chewing his carrot in the dog’s neighborhood. Since in a dog pile a lot of people are posting simultaneously, it is nearly impossible to defend yourself by responding to each of their comments. You could write a collective response, but this would just emphasize the fact that there are a lot of people against you. People are cowards, so don’t expect anybody to rush to your defense - unless you have enough friends to form a counter-dog pile in response. But even that would have destroyed the comments to your article. I found that the best response to a dog pile is to individually block every individual participating in it. These people are mean, you won’t miss them as followers. If you detect the dog pile early enough, you can block the instigators, thus nipping the attack on the bud before it does too much damage. 4) Baiting Baiting is when somebody post something in a provocative tone to evoke an emotional response from you. Things tend to escalate and go downhill from there. Baiting achieves its objective by making you look like a nasty, emotional and aggressive person. The more you descend to the level of your provocateur, the more you drive the onlookers away from your position. Besides, some provocateurs are deftly enough to always look cooler than you. If you are responding to comments on your blog or to one of your articles, you are defending your home turf. An attacker looks like a daring outsider, which gives her an advantage. Always remember that you are not writing for the attacker, but for the onlookers. Think of how you appear to them. The best way to respond to baiting is with a rational, overly polite answer. Not answering is always a good option. At least, you won’t waste your time. The baiter will not get her reward and will probably look for better targets. And you will devote your time and energy to the good members of your audience. However, keep in mind that intelligent disagreeing comments are the best. Agreeing comments are nice but boring, because it is hard to reply to them with something entertaining. An opponent willing to argue honestly is the best thing that can happen to your article. Treat them with the utmost respect and give them your best. A smart, profound discussion will enthrall your audience in ways that your article could not. 5) Sidetracking Sidetracking is when somebody takes the discussion away from the man topic of your article. It’s a common and annoying practice. If you built the reasoning of your article in a way that is rationally waterproof and based on solid evidence, people who disagree with it will find it hard to argue against it. Instead, what they would do is to nitpick on an irrelevant detail or take the conversation away to a different topic. This may be a topic that they know better than you, where they can embarrass you and destroy your credibility. Don’t let yourself be sidetracked. Do not respond to sidetracking comments. If you do, bring the discussion back to the main topic by sidetracking the sidetracker. If people follow a sidetracking thread, do not participate in it. Do not complain that they are sidetracking, because that would make you look like a censor. If you do not participate, you would avoid risking your credibility and lending importance to the sidetracking topic. 6) The joke is on you Often, sidetracking is done by joking. This could signal the beginning of a personal attack or a dog pile. There may be a trick question that then turns you into the butt of a joke. But, if you don’t play along with a joke, this would make you appear straitlaced and humorless. You’ll have to use your best judgment about how to respond to a joke. If you are witty and appreciated for your sense of humor, you could outwit the joker. A friendly audience will often flock to your side. But beware that this may escalate and you may not keep up your smart responses for long. Do not turn your response into an attack on the outsider. Always be friendly and compassionate. Your success as a writer depends on making friends, not enemies. 7) The Kafka trap “A sophistical rhetorical device in which any denial by an accused person serves as evidence of guilt. […] Coined by American computer programmer, author, and advocate for the open source movement Eric S. Raymond in 2010 in reference to the book Der Proceß (The Trial, 1925) by the Bohemian author Franz Kafka (1883–1924), in which a man is accused of crimes that are never specified, and every defense is treated as proof of guilt.” Kafkatrap, Wiktionary. Somebody accuses you of being a misogynist, a racist, a communist, etc. When you deny it, this is taken as evidence that you are because that’s precisely what a misogynist, racist, communist, etc. would say. In its most elaborated forms, Kafka traps are constructed so that even good behavior in support of a cause is taken as evidence that you have a secret agenda. You are virtue signaling. Or, worse, planning some ultimate exploitative act. For example, nice guys are the worst misogynists. White men dating Black women are racists. Men dating trans women are abusing them. The underlying idea is that being part of an oppressor group is an irredeemable quality, so that every good deed from members of that group would eventually turn evil. That there are nasty motives behind every good intention, even if they are unconscious. Because nobody can escape the oppressor-victim dynamic at the core of postmodern ideology. “As almost any glance back in history will tell you, silencing a subsection of society simply encourages the pretence of compliance, a fostered resentment and a festering that will re-emerge at a later date. The Kafka Trap is an excellent way to keep the walls of an echo chamber solid and a bad way to promote social change.” @Argumentative Penguin. Verbal Prison: How To Spot and Escape The Kafka Trap https://medium.com/lucid-nightmare/verbal-prison-how-to-spot-and-escape-the-kafka-trap-e7ee4104dbc8 8) Arguments from gender, race, nationality, etc. This is a variant of the ad hominem attack that is worth mentioning because it has become so pervasive in identity politics that it is almost part of its ideology. A long time ago, conservatives used to say that women or Blacks couldn’t say anything worth hearing because they were of lesser intelligence and education. Perhaps this is still true today in some conservative circles. But, nowadays, this misogynistic and racist idea has been turned on its head by identity politics. What somebody says can be discounted solely because he belongs to the wrong gender, race or nation. Again, the underlying assumption is that whatever is said by a member of an oppressor group can be attributed to wanting to maintain the privilege of that group, and not to an honest opinion or an idea based on evidence and logic. This frees people who espouse ideological dogmas from having to defend them against powerful arguments. A variant of this is to imply that the subjective experience of somebody belonging to an oppressed group trumps any objective finding related to this group. For example, a woman mocked me for being a man writing about female orgasms. Since I could not experience them firsthand, it was impossible for me to know anything about them. No matter how many women I had sex with. No matter how many scientific papers about orgasms I had read. Taken to its logical conclusion, this attitude would invalidate any scientific evidence in favor of the subjective experiences of certain people. 9) Pearl-clutching This expression comes from the image of a Victorian woman in rich clothes clutching her pearl necklace while exclaiming “Good Heavens! I can’t believe you could say that!” Or something along those lines. It’s a shaming maneuver that invites indignation from the audience. It’s designed to put you in a defensive position by having to defend your right to express an idea before you can start actually defending that idea. You would need to argue that expressing that idea is not a moral outrage. Even if you manage to do that, it would put you in a weakened position by the time you get around to defend your idea. Even though the image of pearl-clutching evokes Victorian era puritanism, today this attitude is most commonly encountered in those defending the politically correct status quo. 10) The easily offended Recently, in a chat group, I defended a gay man against a dog pile. People were attacking him because he said that there was still homophobia in some kinky groups. Among other things, I pointed out that a group attack on somebody who was gay could be perceived as homophobic. A woman who had marginally participated in the dog pile took great offense at that, saying that I had accused her of being homophobic. Never mind that I didn’t accuse her, or anybody else, for that matter. I just pointed out that what they were doing was wrong. As I said above, personal attacks are against people. Attacking ideas should be part of the normal discourse; otherwise, there would be censorship. We should also be free to condemn some behaviors. In fact, this is what I am doing in this article. Criticizing behaviors is essential to fight for a just society. For centuries, taking offense by confusing an attack of an idea, an ideology or a religion with a personal attack has been a favorite strategy of the defenders of dogma. Thus, questioning the dogmas of Christianity was presented as an attack on Christians and got a lot of people tortured and killed. Today, the Left furiously condemns any criticism of Islam as a bigoted attack on Muslims. Never mind that Islam holds the same misogynistic and homophobic ideas that the Left has been fighting in conservative Christianity. Conclusion The only hope out of the cultural wars that are tearing Western societies apart is to establish a solid base of common norms for polite discourse, evidence and rationality. Unfortunately, the Left has become as guilty of poisoning the well of rationality as the Right. When signaling to what cultural group you belong to becomes more important that finding the truth, everybody becomes more mired in their common delusions. Ideological divisions become more profound until talking across them becomes impossible and they tear our society apart. In this light, perhaps the most worthwhile battle is to fight for rational discourse and a common base of shared knowledge.

Companies that publish scientific journals exploit scientist and the taxpayer. Scientists have to pay to publish their papers It is a true scandal how commercial publishers of scientific journals have been profiting by exploiting scientists. Scientist do all the work that goes into making a science paper. They do the research, analyze the date, create the figures and write the paper. Then other scientists work as editor for the journal and peer-review the paper. All this work is done for free. Sometimes, scientists even have to pay to get their paper published. Yes, you read that right. Scientists frequently have to pay to publish a paper. Some journals, like the Journal of Neuroscience, have a submission fee that is not refunded, even if the paper is rejected. Many other journals make authors pay to publish a paper. For example, the Journal of Neuroscience has a submission fee of $2,360 ($1,710 if the authors are members of the Society for Neuroscience). This could make sense when scientific articles were printed in glossy journals, which is expensive. But nowadays most papers are just published electronically in PDF format, which is much cheaper, so these high fees are no longer justified. Scientists have to pay to read scientific papers The publishing house that owns the journal pockets the submission fee and the publication fee. Then it charges scientists again to read the paper. Frequently, publishing houses like Elsevier negotiate contracts with the libraries of universities to sell them packages of many different journals for hundreds of thousands of dollars. Many smaller universities cannot afford the cost. Even UCLA recently had to stop their contract with Elsevier because it was too expensive. Adding insult to injury, publishing companies demand that scientist transfer to them the copyright of their papers. Scientists have no choice but to comply, because their academic careers depend on publishing in journals with high impact factor owned by these companies. The Cost of Knowledge boycott These exploitative practices of Elsevier got so onerous that scientists have orchestrated a Cost of Knowledge boycott against it, in which they refuse to submit papers to Elsevier, serve as editors of its journals and do peer-review for them. I signed for the boycott. The public has to pay to access the research that they pay with their taxes You may think that this is a problem for scientists and universities. However, the money that is used to pay for journals and publication fees comes from government grants. Scientists use the direct costs of the grant: money destined to pay for salaries, instruments and reagents. Libraries used the indirect costs that come with those grants: a fixed percentage that the university gets with each grant to pay for administrative costs. Hence, the money that publishing companies skim is your tax money! Hence, it is unfair that you have to pay to read a scientific paper. Typically, getting the PDF file of a science paper costs $32. The money that you pay doesn’t go to the authors of the paper, but to the publisher. To respond to increasing protests about this business model, publishers created the possibility for scientist to publish their paper ‘open access’, but the authors have to pay publication fees of thousands of dollars per paper to do that. Not surprisingly, many authors opt not to do that. You can get free papers in PubMed The USA government passed a law establishing that any scientific paper created with government grants had to be freely accessibly after a year of its publication: the NIH Public Access Policy. However, this doesn’t mean that the public has access to the paper published by the publishing company. The authors of the paper have to send a manuscript to PubMed, who publishes another version of the paper that is free to the public (but only one year after the paper was published). This means that the best way to find a free version of a paper is to look for it in PubMed. I explain how to do that in another article. In PubMed, you will find a purple button that says View PDF when the paper is available for free. Plan S is a similar initiative in Europe. Getting a preprint in BioRxiv Another way to get a paper for free is to find a preprint of it in BioRxiv. Preprints are scientific papers that have not passed peer-review yet. BioRxiv is a repository for preprints of science papers. Hence, what you will find here is different from the final version of the paper, which would be modified according to the demands of the reviewers. However, for most people, this is close enough. The good news is that, even after a paper has been published in a journal, the preprint version is still available in BioRxiv. The bad news is that many papers are not deposited in BioRxiv, particularly those published in the past. Research Gate Research Gate (https://www.researchgate.net/) is a social networking site for scientists where they are invited to share their papers. Many scientists do, so you can download the full text of their publications from there. Authors do not care if they appear to violate the copyright that the publishers wrestled out of them by posting the journal’s version of their paper. This is one more way in the which the stranglehold that publishing companies have on scientific publication is being slowly eroded. If you want to find a paper in Research Gate, just search for the name of one of the authors or for the title of the paper. What works best is to search for the name of the senior author, that normally is at the end of the list of authors. Sci-Hub You can also look for papers in Sci-Hub, a pirate repository of scientific papers run out of Kazakhstan by Alexandra Elbakyan. Needless to say, Sci-Hub is highly controversial and subject to a number of lawsuits in many countries. Ask the author It’s a time-honored practice to ask one of the authors for a copy of his paper. In the old times, authors bought from the journal a stack of reprints of the paper, which they will then mail to scientists who requested them. Nowadays, authors just email a PDF of the paper. This is not a violation of the copyright, since it forms part of the agreement between the authors and the journal. Every paper has a corresponding author, normally designated by an asterisk in the list of authors. The asterisk links to a footnote in the first page of the paper with the address and email of that author. This is the author to who you should write requesting the paper. Even if you are not a scientist, you are likely to get a response. A short note explaining why you want to read the paper might help. Authors are delighted to know that somebody cares about their work. Unfortunately, reading the footnote with the email address of the corresponding author sometimes requires having the full text of the paper. In that case, Google the name of the last author in the list, which would normally be the senior author. It is normally easy to find his academic email address.

Scientific studies disprove the belief that the clitoris is the only source of women’s orgasms The clitorocentric dogma It’s a controversy that has lasted a hundred years. Since the earliest studies on sexology, it was believed that the clitoris is the only source of women’s orgasms. That vaginal penetration produced orgasms only by indirectly stimulating the clitoris. Hence, the best way for women to achieve orgasm is to directly stimulate the clitoris. For example, Alfred Kinsey wrote: “The walls of the vagina are ordinarily insensitive. […] All of the clinical and experimental data show that the surface of the cervix is the most completely insensitive part of the female genital anatomy.” (Kinsey et al., 1953). However, Kinsey’s own data contradict these claims: 84% of the women he examined responded to pressure in their cervix, and 93% of them responded to pressure in the anterior wall of their vagina (Jannini et al., 2012). The idea that the vagina is not a source of pleasure was based on the observation that the clitoris has many nerve endings, while the vagina has fewer. However, the vagina has enough nerve terminals to participate in the sexual response, particularly is its most deeper parts. Besides, abundant innervation of a particular area of the body does not correspond with the intensity of the sensation elicited there, but with its accuracy. For example, the fingertips and the tongue are profusely innervated because they have fine tactile discrimination. A few nerve fibers can produce a strong sensation (pain, itch or pleasure) if their signal is amplified in the nervous system. “Ipse dixit is a term labeling a statement, asserted but not proven, to be accepted on faith in the speaker. After Kinsey, Masters and Johnson, and Hite, this was the case of the clitorocentric dogma of female orgasm. The growing fruits of research will definitively change this paradigm.” (Jannini et al., 2012). Vaginal orgasms and the G-spot A large group of women felt that the idea that orgasms come from the clitoris represented their own experience. But an even larger group of women felt that it did not. They preferred to have orgasms from penetration. “However, women anecdotally describe two types of orgasm. The clitoral orgasm obtained by the direct external stimulation is described as “warm” or “electrical,” and the vaginal one, obtained by a vaginal penetration, is depicted as “throbbing,” “deep,” and generally stronger.” (Jannini et al., 2012). Thus, as noted in a recent article about the orgasm gap, 69% percent of women prefer to achieve orgasm through penetration. The paper cited (Blair et al., 2018) attributed this to normative sexual experiences that emphasize the male orgasm. This just parrots some political beliefs presented as feminist but that, in reality, invalidate the feelings of a large group of women, who are deemed to be sexually uneducated and brainwashed by the patriarchy. Indeed, as I discuss in another article, the existence of vaginal orgasms is mired in political ideology. The controversy started with the claim by Sigmund Freud that women who orgasm from clitoral stimulation were psychosexually immature. In 1976, Shere Hite responded with The Hite Report, in which she used informal questionnaires to claim that the best way for women to achieve orgasm was by touching the clitoris. This eventually grew into the belief that the majority of women do not orgasm from penetration, which I debunked in a previous article. Some sexologists, however, grabbed the banner of the vaginal orgasm. By listening to women, Beverly Whipple and John Perry rediscovered a sensitive area in the anterior wall of the vagina that swells when stimulated and can trigger orgasm and female ejaculation (Addiego et al., 1981). They named it the Grafenberg spot, or G-spot, after Ernst Grafenberg, who described it back in 1950. In fact, the G-spot was described in the Kamasutra and in Taoist texts of the 4th century, and in documents of many other civilizations (Korda et al., 2010). Questions that need to be answered Given the political controversy that surrounds this issue, is it possible to find scientific evidence that puts it to rest? Since orgasm is a subjective experience, to compare orgasms form different women, or induced by stimulating the clitoris or the vagina in the same woman, looks like an insoluble philosophical problem. The subjective feelings of orgasms are qualia, conscious experiences that cannot be conveyed from one person to another. However, scientists do not give up as easily as philosophers. They know that subjective experiences can be studied by investigating their neuronal correlates in the brain. What we need is factual evidence that answers the following questions: Can vaginal stimulation alone trigger an orgasm? Is this orgasm different from the clitoral orgasm? There are other related questions, such as whether the G-spot really exists, what is its anatomy and function, the nature of female ejaculation, and the relationship of the internal clitoris with the vagina. However, in this article in will focus on these two questions. They would establish whether vaginal orgasms are real and different from clitoral orgasms. Functional magnetic resonance imaging (fMRI) Today, scientists have several methods to study the activity of the brain in awake humans while they engage in different activities. They include electroencephalogram (EEG), positron emission tomography (PET) and fMRI. fMRI is used to determine what parts of the brain are active in different conditions. When an area of the brain has increased neuronal activity, its cells consume more oxygen. This prompts an increased blood flow to this area to replenish the oxygen called the hemodynamic response. fMRI measures changes in the magnetic properties of the iron atoms in the molecule of hemoglobin of the blood when they bind and unbind oxygen. The activity of brain areas is then mapped in three dimensions. Unlike EEG, fMRI can image the activity of deep brain areas. Women with spinal cord section have orgasms An opportunity to answer the first question presented itself when doctor Beverly Whipple encountered the case of women with complete spinal cord transections. The nerves that gather sensations from the genital area - pelvic, pudendal, hypogastric and lower splanchnic - carry information to the brain by entering the spinal cord at its lower segments, and then running upwards in the spinothalamic tract. If the spinal cord is severed above these lower segments, the spinothalamic tract is interrupted. All sensations below the waist, including those from the clitoris, the vagina and the anus, cannot reach the brain. Therefore, women with complete spinal cord injuries should not be able to feel their genitals and, consequently, to have orgasms. And yet, they do! They can feel when they menstruate and when their vaginas are penetrated. They experience pleasure in their vaginas, sometimes leading to orgasm. But they cannot feel their clitoris. How is this possible? Their gynecologists told them that they were experiencing phantom pleasure, something similar to the phantom sensations that amputees feel as coming from their missing limbs. But these women were experiencing pleasure from real penises and dildos, not phantom ones. fMRI of women with spinal cord sections Doctor Barry Komisaruk hypothesized that the sensations from their vaginas was carried by the vagus nerve. Unlike the sensory nerves I mentioned above, the vagus carries sensation from the internal organs directly to the brain, not through the spinal cord. ‘Vagus’ means ‘errand’ in Latin, because this nerve meanders inside of the body, carrying information back and forth from the heart, stomach, intestines and other internal organs to the brain. The bodies of the neurons that send axons in the vagus nerve are in the nodose ganglion, situated near the base of the skull. The enter the brain in the nucleus of the solitary tract (NTS). To test this hypothesis, Komisaruk, Whipple and their collaborators carefully selected five women with complete spinal cord transections (Komisaruk et al., 2004; Komisaruk and Whipple, 2005). These unfortunate women had spinal cord injuries from bullet wounds, which provide a clean cut of the spinal cord without the messy compression produced by car crashes, falls and similar types of accidents. Compression injuries of the spinal cord make it difficult to determine if all the axons in the spinothalamic tract have been severed. Another criterion to select the women for this study was that their spinal cord injury was above the T10 (tenth thoracic vertebra) spinal segment, to completely rule out that some branches of the genital nerves could enter the spinal cord above the injury. First, Komisaruk and collaborators used fMRI to determine if the NTS was activated when these women self-stimulated their vagina with a dildo. If that happened, that would mean that the sensation from the vagina was carried by the vagus nerve and entered the brain at the NTS. Sure enough, the lower part of the NTS was activated during vaginal stimulation in all five women. The NTS is organized forming a rudimentary map of the body, so its upper part correspond to the mouth and its lower part to the genitals. When the women were given a beverage with a strong taste to provide a sensation to the mouth, the upper part of the NTS was activated. This confirmed the hypothesis that the vagus nerve carries information from the vagina to the brain independently of the spinal cord. As it turns out, the supposedly scant innervation of the vagina serves a powerful function. Vaginal orgasms: brain fMRI of women with spinal cord injury Three of the five women in this study experienced orgasms during vaginal self-stimulation. This offered an opportunity to use fMRI to determine the areas of the brain activated by vaginal orgasms. Since the orgasms in these women were triggered exclusively from the vagina, this may throw some light on the second of the questions above: are vaginal orgasms different from clitoral orgasms? The areas of the brain activated by vaginal orgasms were consistent amongst the three women. Here is a list, with a short explanation of the function of each area. Amygdala. This is the part of the brain that mediates fear and anxiety, but it is also involved in a range of other emotions, like anger and aggression. In one of the women who had multiple orgasms lasting 3 minutes, the amygdala was active only for these 3 minutes and not for the subsequent 2 minutes of fMRI recording. Nucleus accumbens. You may have heard that dopamine release occurs in the brain when we experience pleasure. What actually happens is the activation of a ‘reward pathway’ that goes from the ventral tegmental area (VTA) to the nucleus accumbens, where it releases dopamine. Opioids, nicotine, cocaine, amphetamine and other addictive drugs activate this pathway, leading to dependence. This study showed activation of the nucleus accumbens during vaginal orgasms, which is to be expected from a pleasurable stimulus. This doesn’t mean, however, that orgasms are addictive. Insular cortex. ‘Insula’ means ‘island’ in Latin. This is an area of the cortex that forms an island of grey matter inside the white matter of the cerebral hemispheres. The insula is associated with all kinds of emotions. It mediates the emotional component of pain that tells us that we don’t like it. It is also involved in itch, disgust, anger, trustworthiness and (of course!) sexual pleasure (Craig, 2002). Anterior cingulate cortex (ACC). The cingulate cortex is a part of the cortex located deep inside the fissure that separate the two cerebral hemispheres. It’s one of the targets of the dopamine pathways from the VTA. The ACC, together with the insula and the somatosensory cortex, is at the end of the neural pathways that transmit pain. Its main function is to motivate us to make decisions. Hippocampus means ‘sea horse’ in Latin because it is shaped like this peculiar fish. It is essential for memory formation and the storage of short-term memories. Its links to the amygdala mediate a role in emotions. Cerebellum. This ‘little brain’ in the back of the skull modulates muscular contraction during movement. Its activation during orgasm may reflect the general muscular contractions and spasms during orgasms. Paraventricular nucleus of the hypothalamus. The hypothalamus is the part of the brain that modulates the functions of the body, producing feelings like thirst, hunger and sexual desire. It is located above the pituitary gland, by which it controls the endocrine system that releases hormones in the body. Thus, the hypothalamus-pituitary-adrenal (HPA) system controls the release of adrenaline and cortisol during stress. The fact that the paraventricular nucleus is activated during vaginal orgasms is very important because it releases oxytocin into the blood. This mediates the contraction of the nipples, the uterus and the vagina during orgasm and could be responsible for the bonding effects of sex (Stein, 2009). The sequence of activation of these brain areas is as follows. The amygdala and the insula are activated during the buildup of orgasm. Then the ACC enters the game. At the point of orgasm, the nucleus accumbens, the paraventricular nucleus of the hypothalamus and the hippocampus become activated, while the activation of the insula increases. Clitoral orgasms: brain fMRI of healthy women In a later study (Wise et al., 2017), the group of Komisaruk studied ten healthy women while they reached orgasm through clitoral stimulation, given by themselves or by a partner. Since they found no differences between self-induced and partner-induced orgasms, they pooled both sets of data and analyzed them together. Unlike the study in women with spinal cord injury, the objective here was to get a fine time resolution of the events before, during and after orgasm. I wanted to compare this study with the one on vaginal orgasms to see if there are differences in brain activation between them. Disappointingly, the authors did not do that in their paper. Hence, the conclusions I draw below are mine and not the authors’. Not surprisingly, clitoral orgasms activated some of the same regions activated by vaginal orgasms. These include the amygdala, nucleus accumbens, insula, anterior cingulate cortex, hippocampus and cerebellum. But, in addition, there were brain regions not mentioned in the study on vaginal orgasms: the operculum, parts of the frontal cortex and the right angular gyrus. The operculum is the area of the cortex surrounding the invagination that produces the insula. It is the main area of the brain activated in masochists when they are shown images of masochistic pain (Kamping et al., 2016). It mediates emotional responses to pain and pleasure. The frontal cortex is the area of the brain involved in complex decision-making, setting goals and behavior inhibition. In particular, the study with clitoral stimulation mentions the orbitofrontal cortex, which is a “hedonic hot spot.” The angular gyrus is involved in processing visual information, particularly during reading and other spatial cognition taaks. It is also involved in memory retrieval, attention and theory of mind (the capacity to imagine the mental states of other people). The angular gyrus in the right hemisphere is associate with out-of-body experiences, which the authors relate to the altered states of consciousness produced by orgasm. One potentially interesting difference between clitoral and vaginal orgasms is in the hypothalamus. While vaginal orgasms in women with spinal cord transections activated the paraventricular nucleus of the hypothalamus, clitoral orgasms recruited the mammillary bodies instead. The mammillary bodies are involved in episodic memory. Since the paraventricular nucleus drives the release of oxytocin in the blood, this could mean that vaginal orgasms release more oxytocin and therefore leads to stronger pair-bonding. Mental orgasms Some women can also have orgasms with mental imagery alone, without any genital or body stimulation (Whipple et al., 1992). fMRI showed that these orgasms activated the nucleus accumbens, anterior cingulate cortex, hippocampus and the paraventricular nucleus of the hypothalamus, but not the amygdala or the cerebellum (Komisaruk and Whipple, 2005). This indicates that those four brain regions are specifically related to orgasm, while the amygdala may be related to genital sensation and the cerebellum to muscle tension. The great variety of orgasms The studies on women with spinal cord injury provide compelling evidence that exclusive stimulation of the vagina and the cervix can trigger orgasm. This indicates that women can orgasm from vaginal penetration alone. Whether the internal clitoris, the Skene glands, or the innervation of the vagina and the cervix are the trigger of these orgasms is an interesting question to be addressed in future articles. There is also some evidence that vaginal orgasms and clitoral orgasms activate a few different brain areas. This supports the experience of many women, who say that orgasms triggered from the clitoris and the vagina feel different. I am not saying that there are only two different types of orgasms, clitoral and vaginal. In fact, Komisaruk and his collaborators emphasize in their studies on vaginal orgasms that they are triggered by stimulating the vagina and the cervix, which some women consider different types of orgasms. Orgasms can also be elicited by anal intercourse. They feel different because the anus is a sensitive erogenous zone. Given that only two thin membranes separate the rectum from the vagina, anal intercourse stimulates the anterior wall of the vagina, which can trigger an orgasm in much the same as vaginal intercourse. Orgasms in women can also be triggered without any genital stimulation at all: by stimulating the nipples, by spankings and other forms of BDSM play, by exercise (Herbenick et al., 2021), and by mental imagery (Whipple et al., 1992). This shows that orgasms happen in the brain. Whether the stimulus comes from the clitoris, the vagina, the anus or other part of the body seems to be quite incidental. At least, in women. Could men also enjoy this wonderful variety of orgasms? Some men claim that they can orgasm from stimulating their prostate through anal intercourse, dildo insertion or pegging. Perhaps prostate orgasms are the male equivalent of the female vaginal orgasms. But, are men also able to climax from spankings, exercise or mental imagery? Perhaps there is an orgasm gap, but in the opposite direction of the usually proposed. While it is true that some women have difficulty achieving orgasm, others are able to climax repeatedly and with extraordinary intensity. They would make any man envious. Why is this important? We may have been doing sexual education wrong by teaching women that climax should be achieved primarily by stimulating their clits. A study using five national sex surveys in Finland (Kontula and Miettinen, 2016) found that the percentage of young women (18-34 years old) that reached orgasm during sexual intercourse decreased from 1999 to 2015. Ability to reach orgasm did not improve from the 70s to the present in any of the age groups. This is surprising, given that Finland is ranked as one of the leading countries in gender equality in the world, and that substantial advances have been made is the sexual education and liberation of women since the 70s. Why hasn’t this translated in a better ability of women to climax during sex? It is possible that this was caused by an increase in stress and mental pressures as women incorporated into the workforce and took over more demanding careers. However, the findings in the study with Finnish women point at causes directly related to sex. Surprisingly, women who masturbated more often had less frequent orgasms during intercourse than women to masturbate less often. This contradicts the common assumption that masturbation is the best way for women to teach themselves to climax. Perhaps too much emphasis on clitoral stimulation locks women into a single pathway to reach orgasm, instead of encouraging them to explore other erogenous zones and their great variety of possible orgasmic experiences. In this they have become similar to men, who have been taught to look at their penises as their only source of sexual pleasure. Here are a few things that contributed to frequent orgasms during intercourse: The importance given to orgasms. High sexual self-esteem (“I am good in bed”). High sexual desire and sexual motivation. Open and easy sexual communication with their partner. Ability to focus in the moment and mindfulness during sex. An appreciation for sex. Good sexual techniques. A talent to be aroused by sexual stimulation. Love-making sessions that are frequent and long-lasting. Novelty. Sexual fantasies and role-playing. Anal stimulation. Letting go of control. “Women need to be encouraged to feel good about the variety of ways they experience sexual pleasure, without setting up specific goals (such as finding the G-spot, experiencing female ejaculation, or experiencing a vaginal orgasm). Healthy sexuality begins with acceptance of the self, in addition to an emphasis of the process, rather than the goals, of sexual interactions.” Dr. Beverly Whipple (Jannini et al., 2012). References Addiego F, Belzer EG, Comolli J, Moger W, Perry JD, Whipple B (1981) Female ejaculation: A case study. The Journal of Sex Research 17:13-21. Blair KL, Cappell J, Pukall CF (2018) Not All Orgasms Were Created Equal: Differences in Frequency and Satisfaction of Orgasm Experiences by Sexual Activity in Same-Sex Versus Mixed-Sex Relationships. The Journal of Sex Research 55:719-733. Craig AD (2002) How do you feel? Interoception: the sense of the physiological condition of the body. NatRevNeurosci 3:655-666. Herbenick D, Fu T-c, Patterson C, Dennis Fortenberry J (2021) Exercise-Induced Orgasm and Its Association with Sleep Orgasms and Orgasms During Partnered Sex: Findings From a U.S. Probability Survey. Arch Sex Behav 50:2631-2640. Jannini EA, Rubio-Casillas A, Whipple B, Buisson O, Komisaruk BR, Brody S (2012) Female orgasm(s): one, two, several. The journal of sexual medicine 9:956-965. Kamping S, Andoh J, Bomba IC, Diers M, Diesch E, Flor H (2016) Contextual modulation of pain in masochists: involvement of the parietal operculum and insula. Pain 157:445-455. Kinsey AC, Pomeroy WB, Martin CE, Gebhard PH (1953) Sexual behaviour in the human female. Philadelphia: WB Sanders Co. Komisaruk BR, Whipple B (2005) Functional MRI of the brain during orgasm in women. Annu Rev Sex Res 16:62-86. Komisaruk BR, Whipple B, Crawford A, Liu WC, Kalnin A, Mosier K (2004) Brain activation during vaginocervical self-stimulation and orgasm in women with complete spinal cord injury: fMRI evidence of mediation by the vagus nerves. Brain Research 1024:77-88. Kontula O, Miettinen A (2016) Determinants of female sexual orgasms. Socioaffective neuroscience & psychology 6:31624-31624. Korda JB, Goldstein SW, Sommer F (2010) The History of Female Ejaculation. The journal of sexual medicine 7:1965-1975. Stein DJ (2009) Oxytocin and vasopressin: social neuropeptides. CNS spectrums 14:602-606. Whipple B, Ogden G, Komisaruk BR (1992) Physiological correlates of imagery-induced orgasm in women. Arch Sex Behav 21:121-133. Wise NJ, Frangos E, Komisaruk BR (2017) Brain Activity Unique to Orgasm in Women: An fMRI Analysis. The journal of sexual medicine 14:1380-1391. Copyright 2023 Hermes Solenzol.

Shame and pride produce an anxiety that can be relieved by sexual dominance or submission While sadomasochism can be justified by the ability of pain to enhance pleasure and by the happiness brought by the endorphin high, the dominance/submission side of the BDSM equation is not so easily explained. The standard answer to the question of why do we like to submit to or to dominate is still “because you are sick”. All the efforts of the BDSM community had barely managed to keep sadomasochism out of the psychology diagnosis books. We heartily reject the idea that the desire to submit or dominate comes from childhood trauma, but when asked for alternative explanations we have nothing to offer. The few studies that have been done revealed that people who practice BDSM are actually psychologically healthier than the average. We just don’t know why. Do we eroticize what we fear? One possible explanation is that we eroticize what scares us. For example, in his podcast, Dan Savage often talks about how self-assured gay men like to be called “faggots” during sex. Or how feminist women, who are all about female power in real life, like to be dominated in bed. This makes sense: after all, fear releases adrenaline, which is a great aphrodisiac. However, this idea takes us back to the trauma paradigm: we were scared by early events in our life and now we exorcise them by reproducing them in a controlled environment. I don’t find that explanation satisfactory. After all, most submissives are not scared of submitting, they see it as sexy and liberating. And Doms are certainly not scared of what they do. Shame and pride A few years ago, I found an explanation for dominance-submission that presents it as a healthy response to the normal pressures of life. It is based on two opposite emotions that play a large role in our lives: shame and pride. Shame is one of our most powerful emotions, so powerful that it can lead to suicide. We all have heard stories of how bullying or persecution for being gay lead teenagers to kill themselves. Shame is an emotion that seems to be uniquely human (it is still hotly debated whether dogs feel shame) and yet seems to be deeply rooted in physiological responses. It causes blushing, which is an involuntary vascular response, and a specific body position consisting of dropping the head and hunching the shoulders. It also leads to immobility and withdrawal. The opposite of shame, pride, makes us lift our head, engage socially and feel full of energy. It is likely that pride activates the reward system in our brain linking the ventral tegmental area (VTA) of the striatum with the nucleus accumbens, releasing dopamine there. This is the same response produced by addictive drugs like heroin and cocaine. It makes us feel good and to want to repeat the behavior that triggered this response. The evolutionary logic of shame and pride All this shows that shame and pride are an essential part of human nature. They likely evolved as indicators of social status: shame warns us that our social status has declined while pride tells us that our social status has increased. In the tribes in which we lived for hundreds of thousands of years before modern societies were formed, social status was a matter of life and death. High social status gave you preferential access to food, shelter, power and sex. Low social status could make you a castaway, condemning you to an almost certain death. According to the reasoning used by evolutionary psychology, we could see why this is so. The biggest advantage we humans have over other animals is our ability to cooperate. In a tribe, everything is shared: food, protection against predators, shelter and the care of children. This creates one strategic problem: how to avoid cheaters. The guy that falls behind in the hunting party, the gal that has a siesta instead of gathering berries, they would have an evolutionary advantage because they get the same amount of food with less energy expending. Computer models have shown that genes for free-riding would take over the population in just a few generations. We would have evolved back to the kind of societies that chimps have, where no food is shared (other than with infants) and there is very little cooperation. That is why we developed powerful drives to eliminate cheaters. One of them is called “altruistic punishment”: the desire to punish people that we see as behaving in an unethical way, even if that takes a lot of energy and it doesn’t benefit us personally (hence the qualifier “altruistic”). It is based on emotions like indignation and self-righteousness. However, if this was the only way to eliminate cheaters, we would have societies with lots of internal conflicts. And, while this strategy punishes cheaters, it does not reward cooperators. Thus, the emotions of shame and pride evolved as internal motivators for cooperative behavior. When you do something against the common good, or when you fail to do your duty, people around you will make you feel ashamed. Conversely, when you achieve something that increases the common good, you are praised and you feel pride. Guilt is the other emotion for social control. However, the key difference between guilt and shame is that you feel guilty when you do something bad, whereas shame comes also from failing to do something good. Guilt tells us “you are bad”, while shame tells us “you are not good enough”. Why is sex shameful? But then, why is sex shameful? Is this largely a cultural thing, driven by religion and cultural norms? Well, not completely. In practically all cultures, sex is done in private, and nakedness (at minimum, exposing the genitals) is also a universal taboo. Well, if shame is linked to social status, so is sex. And not just in humans, but also in our primate cousins. In chimp troupes, when a female comes in heat almost every male gets to mate with her, but it is the alpha male who decides in what order and how often. In some monkeys, mating with high-ranking individuals increases social status, regardless of whether you are male or female. And in many monkey species, sex is used to assert dominance: low-ranking individuals offer their backsides to appease dominant ones and avoid being beaten. And yes, they do get fucked. And then there are the bonobos, famous for being total sluts. They use sex for bonding and for resolving social conflicts. They are promiscuous, pan-sexual, and do manual, anal and oral, not just penis-in-vagina. Therefore, even in our primate ancestors sex has been hijacked away from mere procreation to be used for bonding and to establish social status. Sex can express different things, not just love and bonding, but also dominance. Ultimately, the pleasure (and sometimes pain) associated with sex makes us feel vulnerable and exposed. Because of that, getting fucked implies a loss of face and being put in a submissive role. That is probably what causes its association with shame. Shame and pride in modern society Managing shame and pride was a relatively simple matter in the tribal societies of our evolutionary environment, but it became hugely complicated once the agricultural revolution took place 10,000 years ago. Before, if you hunted a nice prey, scared the bear away or gathered a basketful of berries you could feel proud and enjoy the appreciation of your fellow tribe people. Afterward, the limits of what you could achieve were vastly expanded: you could own land and animals, you could command workers and soldiers. You could never be successful enough to feel proud; there was always somebody who was better than you. And there were also plenty more opportunities to fail and feel ashamed. In our modern industrial societies, things are becoming even direr. Since childhood, we are taught to be proud of our successes and ashamed of our failures. “The sky is the limit!” we are told, and it really is. There are so many things at which we can succeed or fail! Reading, math, sports, arts, getting money, being famous… We interiorized these cultural imperatives, so that nobody needs to tell us anymore; we are our harshest judges. Somehow, our failures seem to count more than our successes. We can never achieve enough; we live in a state of constant craving for success. Ultimately, the twin emotions of shame and pride join forces to bring about our sense of self-worth, our self-esteem. Over time, they create an internal narrative of who we are: our ego, which we try to protect by propping up our pride and hide our shame. This creates a strong psychological tension. It makes us unhappy because we are never enough. We need to keep running the rat race away from failure and shame and in search of success and pride. Dominance-submission relieves the anxiety produced by shame This is where dominance-submission can come to our rescue by providing a way out of the rat race. This is how I think it works… The submissive gives up all social status by assuming the lowest possible rank. On top of that, obeying takes away the pressure to make the right decisions. Conversely, high status is granted to the Dominant without the effort that it normally entails. He or she gets to feel all-powerful for free. Success and failure are taken out of the equation: the submissive handles power to the Dominant simply because this is mutually beneficial. This ties to sex because of the ability of sex to symbolize social status. The submissive is used sexually by the Dominant and, paradoxically, this is perceived as liberating because it breaks the interior psychological tension created by shame and pride. Shame is embraced, and this frees us from the struggle. This is why humiliation is perceived as liberating by the submissive. Moreover, since internalized repression is a barrier to sexual pleasure, when the constraints created by internalized cultural norms are broken by the D/S power exchange, pleasure and orgasm become easier to achieve. Conclusion In conclusion, dominance-submission unleashes powerful emotions anchored deep in our evolutionary past. This serves to de-program reactions that society has taught us since childhood and that have become so ingrained that we cannot escape them even when we realize how unhappy they make us. That is why we perceive submitting as so liberating and empowering.

The neuropeptides oxytocin and vasopressin drive altruistic punishment, social bonding and monogamy The faithful prairie vole and the promiscuous montane vole Let me introduce you to the prairie vole, a small mammal that has attracted considerable attention in scientific circles. They are rodents with short tails and small ears that are found in North America, from west of the Rockies to east of Appalachia. What is so notorious about them is that they are strictly monogamous: a male and a female form a bond for life. However, a very close cousin of the prairie vole, the montane vole, is completely promiscuous. Males mate with multiple females if they can. Females become fertile in the proximity of males. Oxytocin induces monogamy Some scientists decided to find out how the brain of the prairie vole is different from that of the montane vole (Young et al., 2011). They found that female prairie voles have more oxytocin and oxytocin receptors in the nucleus accumbens and the amygdala, which are areas of the brain important in emotions and decision-making. Oxytocin was first recognized as the peptide that induces uterine contractions during labor. More recently, it has been shown to be crucial for many forms of social bonding. For example, it increases in the blood when a dog is being petted, in both the dog and the human! Back to our friends the voles… scientists genetically modified montane voles by increasing the production of oxytocin in the brain. These montane voles became as monogamous as their cousins the prairie voles. What about the male voles? Well, in them monogamous behavior seems to be determined by another peptide, vasopressin (Gobrogge et al., 2009; Donaldson et al., 2010), which is quite similar to oxytocin. Altruistic punishment Oxytocin also attracted the attention of researchers of a totally unrelated field: economics. Some unconventional economists decided to put to the test a basic belief of capitalism: that market decisions are rational. They found that they are not. Human transactions are based more on trust and empathy that on dispassionate decisions on what is to lose and what is to gain. For example, in all cultures, people engage in something called altruistic punishment (Fehr and Gachter, 2002): they will go at great length to punish individuals that they perceive as being unfair and untrustworthy. The ultimatum game One way they determined this was with an experiment called the ultimatum game. There are two players. Player one is given a sum of money, say $10, of which he has to offer a certain amount to player 2. If player 2 takes the offer, both get to keep the agreed amount of money. However, if player 2 rejects to offer, both of them lose the money. The results of the ultimatum game are consistent between people of all sexes, religions and cultures. Below a certain amount (about $3-4 if the total amount is $10), player 2 decides that player 1 is not being fair and rejects the offer. That means that he is willing to lose 2, 3 or even 4 bucks to punish player 1 for being greedy. That’s why this is called “altruistic punishment”. When levels of oxytocin were increased, player 1 tended to be more generous in his monetary offers. Testosterone did the opposite of oxytocin (Burnham, 2007; Zak et al., 2009; Dreher et al., 2016). In fact, men are more inclined to altruistic punishment than women (Zheng et al., 2017). The female sex hormone estradiol had more complex effects. When offers in the ultimatum game were framed as fair, estradiol increases acceptance in men but reduced acceptance in women (Coenjaerts et al., 2021). Oxytocin, vasopressin and social bonding Oxytocin and vasopressin are now called the social hormones because they strongly influence social behaviors like bonding, trust and empathy (Stein, 2009). However, we should not fall into the simplistic belief that oxytocin makes us good. It has been observed that this neuropeptide is involved in some nasty human behaviors, like xenophobia and intolerance. This is because oxytocin increases both bonding with the members of our group and exclusion of anybody perceived as a stranger (Radke and de Bruijn, 2012). Monogamy entails both feeling close to our spouse and rejecting member of the opposite sex that are not our spouse: bonding and exclusion. On the other hand, the role of vasopressin in monogamy may be related with possessiveness and territoriality: the male perceives the female as part of his territory and defends her as such. Likewise, altruistic punishment has a good side - like deterring crime-, and a bad side -like road rage and other confrontation when we think that somebody is taking advantage of us. References Burnham TC (2007) High-testosterone men reject low ultimatum game offers. Proceedings Biological sciences 274:2327-2330. Coenjaerts M, Pape F, Santoso V, Grau F, Stoffel-Wagner B, Philipsen A, Schultz J, Hurlemann R, Scheele D (2021) Sex differences in economic decision-making: Exogenous estradiol has opposing effects on fairness framing in women and men. European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology 50:46-54. Donaldson ZR, Spiegel L, Young LJ (2010) Central vasopressin V1a receptor activation is independently necessary for both partner preference formation and expression in socially monogamous male prairie voles. Behav Neurosci 124:159-163. Dreher JC, Dunne S, Pazderska A, Frodl T, Nolan JJ, O'Doherty JP (2016) Testosterone causes both prosocial and antisocial status-enhancing behaviors in human males. Proc Natl Acad Sci U S A 113:11633-11638. Fehr E, Gachter S (2002) Altruistic punishment in humans. Nature 415:137-140. Gobrogge KL, Liu Y, Young LJ, Wang Z (2009) Anterior hypothalamic vasopressin regulates pair-bonding and drug-induced aggression in a monogamous rodent. Proc Natl Acad Sci U S A 106:19144-19149. Radke S, de Bruijn ER (2012) The other side of the coin: oxytocin decreases the adherence to fairness norms. Frontiers in human neuroscience 6:193. Stein DJ (2009) Oxytocin and vasopressin: social neuropeptides. CNS spectrums 14:602-606. Young KA, Gobrogge KL, Liu Y, Wang Z (2011) The neurobiology of pair bonding: insights from a socially monogamous rodent. Front Neuroendocrinol 32:53-69. Zak PJ, Kurzban R, Ahmadi S, Swerdloff RS, Park J, Efremidze L, Redwine K, Morgan K, Matzner W (2009) Testosterone administration decreases generosity in the ultimatum game. PLoS One 4:e8330. Zheng L, Ning R, Li L, Wei C, Cheng X, Zhou C, Guo X (2017) Gender Differences in Behavioral and Neural Responses to Unfairness Under Social Pressure. Scientific reports 7:13498.

Memory formation, inhibition of pain and anxiety, and other interesting facts about the brain’s own cannabinoids This is the second in a series of articles about the neuroscience of cannabis: Cannabinoid Receptors Cannabinoids and Endocannabinoids THC (trans-delta-9-tetrahydrocannabinol) THC, or trans-delta-9-tetrahydrocannabinol, is the main psychoactive compound in the cannabis or marihuana plants, Cannabis sativa and Cannabis indica - it is still debated if these are one or two species. In fact, the cannabis plant contains at least 113 cannabinoids, including THC, cannabidiol (CBD), cannabigerol (CBG), cannabinol (CBN) and trans-delta-9-tetrahydrocannabivarin (THCV) (Pertwee, 2008; Bow and Rimoldi, 2016). It is still unknown how many of these cannabinoids are psychoactive or able to bind to the cannabinoid receptors: CB1, CB2 and GPR55. Keep in mind that a compound may not be psychoactive and yet bind to the cannabinoid receptors, acting at only one of them, or behaving as an antagonist or inverse agonist. This explains why different strains of cannabis have different effects on the brain. The many cannabinoids that they contain modulate the actions of THC. THC is a partial agonist of CB1 and CB2 receptors. Full agonists are compounds that completely activate the G protein when they bind to the receptor. Partial agonists only partially activate the G protein associated with their receptor. Antagonists bind to the receptor and they do not activate the G protein at all. Since they occupy the agonist binding site, they prevent it from activating the G protein. Inverse agonists not only fail to activate the G protein, but decrease a basal level of G protein activation that the receptor has, called constitutive activity. Efficacy is the level of activation of the receptor produced by a partial agonist, which varies from 100% (full agonist) to 0% (antagonist). Inverse agonists have negative efficacies. Potency indicates the amount of a compound required to produce their full effect. It is measured as their concentration in water in moles per liter, or molar (M). Its numbers are usually micromolar (µM) - one millionth of molar or 10 to the -6 - or nanomolar (nM) - a thousandth millionth of a molar or 10 to the -9. It is expressed as the Ki, which is a chemical constant derived from the binding reaction of a drug to its receptor. The lower the Ki, the higher the potency. Compounds with smaller Ki will out-compete compounds with higher Ki at the receptor. Efficacy and potency are unrelated. A drug could have high potency by low efficacy - it would a potent partial agonist. Or it could have low potency and high efficacy - in which case it would be less potent full agonist. THC binds to CB1 and CB2 receptors with similar potencies (Ki of 41 nM at CB1 and 36 nM at CB2) (Pertwee, 2008), which are quite high compared to other cannabinoids. CBD (cannabidiol) CBD, or cannabidiol, is an antagonist of both CB1 and CB2 receptors (Pertwee, 2008). Since CB1 and CB2 receptors have constitutive activity (they are a bit active in the absence of an agonist), CBD could be an inverse agonist instead of an antagonist. This means that CBD would not only displace agonists - THC or endocannabinoids - from the receptors, but also inhibit their constitutive activity. CB1 receptors are the ones responsible for the psychoactive effects of THC, so CBD will decrease the effect of THC on these receptors. Therefore, the cannabis strains that have high CBD content produce milder psychoactive effects. CBD is also an antagonist of GPR55, the third cannabinoid receptor. This is why it can be used to treat epilepsy, as I will explain in another article. Endocannabinoids Endocannabinoids are compounds produced in the body that are able to activate cannabinoid receptors. That is, they are neurotransmitters that are the endogenous ligands of the cannabinoid receptors, just like the endorphins are the endogenous ligands of the opioid receptors. Endogenous means produced inside the body. The two main endocannabinoids are anandamide (N-arachidonoyl-ethanolamine) (Devane et al., 1992) and 2-arachidonoyl-glycerol (2-AG). They are synthesized from arachidonic acid, which is one of the lipids found in fat and in the cell membrane. Arachidonic acid is also converted into prostaglandins, which are inflammatory substances. The name ‘anandamide’ comes from the Sanskrit word Ananda, meaning joy and bliss. THC (Ki of 41 nM at CB1 and 36 nM at CB2) is more potent than anandamide (Ki of 61 nM at CB1 and 1930 nM at CB2) and 2-AG (Ki of 472 nM at CB1 and 1400 nM at CB2) (Bow and Rimoldi, 2016). The lower the Ki, the higher the potency. Compounds with smaller Ki will out-compete compounds with higher Ki at the receptor, so THC displaces the endocannabinoids from CB1 and CB2 receptors. Endocannabinoids are retrograde neurotransmitters Endocannabinoids are weird neurotransmitters. Everything about them is atypical. Instead of being stored and released from synaptic vesicles, like other neurotransmitters, endocannabinoids are synthesized on demand. Because they are soluble in lipids, they can just cross the cell membrane. No fusion of synaptic vesicles with the membrane is necessary. Endocannabinoids function as retrograde neurotransmitters: they carry signals from the postsynaptic terminals in the dendrites to the presynaptic terminals of axons. Postsynaptic terminals do not have synaptic vesicles, so this is consistent with the fact that they are not released from those vesicles. Depolarization of the postsynaptic dendrites triggers the entry of calcium, which activates the enzymes that make endocannabinoids. Then they cross the synapse, going backwards, to activate CB1 receptors at the presynaptic terminal. There, CB1 receptors decrease the release of GABA from inhibitory interneurons in the hippocampus (Wilson and Nicoll, 2001), a brain region critical for memory formation. This whole phenomenon is called depolarization-induced suppression of inhibition (DSI) and it is thought to be involved in synaptic plasticity and, therefore, the formation of memories. This is probably the reason why cannabis decreases memory. Later research (Iremonger et al., 2011) found that endocannabinoids released from neurons in the hypothalamus inhibit the release of glutamate, the main excitatory neurotransmitter. This is called depolarization-induced suppression of excitation (DSE). In these synapses, CB1 receptors prevent the development of long-term depression (LTD), a component of synaptic plasticity that makes synapses shrink. Interestingly, another retrograde transmitter in these synapses is dynorphin, and endogenous opioid, which activates presynaptic kappa opioid receptors. This shows how cannabinoid and opioid receptors can work together. Differences between THC and endocannabinoids THC is a partial agonist at both CB1 and CB2 receptors, while the endocannabinoids are full agonists. This means that the effect of THC depends on the amount of endocannabinoids that are being produced. If there are no endocannabinoids present, THC will behave as an agonist, activating CB1 and CB2 receptors, although not as effectively as the endocannabinoids. If there are endocannabinoids already activating the CB1 and CB2 receptors, THC will compete with them, displacing them from the receptors. Since THC is not as effective as the endocannabinoids, the end result will be a lowering of the activity of CB1 and CB2 receptors. This means that THC would act as an antagonist in this case. Different brain regions may be releasing different amounts of endocannabinoids, so that THC may increase cannabinoid receptor activity in some brain areas and decreasing it in some others. Endocannabinoids decrease anxiety For example, THC sometimes increases anxiety, explaining the paranoia often felt by people who consume cannabis. CB1 receptor antagonists also increase anxiety. In contrast, inhibiting endocannabinoid degradation decreases anxiety, as do synthetic full agonist of CB1 receptors (Patel and Hillard, 2006). Therefore, THC behaves like a CB1 antagonist, and not an agonist, when it comes to anxiety. Since the endocannabinoids are full agonists of CB1 receptors, they likely reduce anxiety. Whether THC does or does not trigger paranoia could depend on the amount of basal CB1 activation that a person is getting from their own endocannabinoids. If this sounds complicated, it’s because it is! It would be difficult to know where in the brain THC is activating cannabinoid receptors and where it is inhibiting them. What we need to remember, however, is that the effect of endocannabinoids may be quite different from the effect of taking cannabis. Pain inhibition by endocannabinoids The effects of endocannabinoids are rapidly terminated by two enzymes: fatty acid amide hydrolase (FAAH), which breaks down anandamide, and monoacylglycerol lipase (MAGL), which degrades 2-AG. Inhibiting FAAH (Ghosh et al., 2015) or MAGL (Ignatowska-Jankowska et al., 2015) decreases pain by allowing anandamide and 2-AG, respectively, to activate CB1 receptors for longer times. This shows that one of the effects of endocannabinoids in the central nervous system is to decrease pain. References Bow EW, Rimoldi JM (2016) The Structure-Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation. Perspect Medicin Chem 8:17-39. Devane WA, Hanus L, Breuer A, Pertwee RG, Stevenson LA, Griffin G, Gibson D, Mandelbaum A, Etinger A, Mechoulam R (1992) Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science 258:1946-1949. Ghosh S, Kinsey SG, Liu QS, Hruba L, McMahon LR, Grim TW, Merritt CR, Wise LE, Abdullah RA, Selley DE, Sim-Selley LJ, Cravatt BF, Lichtman AH (2015) Full Fatty Acid Amide Hydrolase Inhibition Combined with Partial Monoacylglycerol Lipase Inhibition: Augmented and Sustained Antinociceptive Effects with Reduced Cannabimimetic Side Effects in Mice. J Pharmacol Exp Ther 354:111-120. Ignatowska-Jankowska B, Wilkerson JL, Mustafa M, Abdullah R, Niphakis M, Wiley JL, Cravatt BF, Lichtman AH (2015) Selective monoacylglycerol lipase inhibitors: antinociceptive versus cannabimimetic effects in mice. J Pharmacol Exp Ther 353:424-432. Iremonger KJ, Kuzmiski JB, Baimoukhametova DV, Bains JS (2011) Dual Regulation of Anterograde and Retrograde Transmission by Endocannabinoids. The Journal of Neuroscience 31:12011-12020. Patel S, Hillard CJ (2006) Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther 318:304-311. Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153:199-215. Wilson RI, Nicoll RA (2001) Endogenous cannabinoids mediate retrograde signalling at hippocampal synapses. Nature 410:588-592.

The moving stories of the parents who gave their children cannabis to save their lives Today is April 20, a day when many people celebrate the wonderful properties of cannabis. For the last few days, I have been publishing one article a day about the neuroscience of cannabis and the endocannabinoid system: Cannabinoid Receptors (Medium) Cannabinoids and Endocannabinoids (Medium) Charlotte’s Web (this article) I heard the moving story of Charlotte Figi and Charlotte’s Web in the opening talk at the Winter Conference in Brain Research (WCBR), an annual meeting of neuroscientists held at a ski resort in North America. The talk was given by one of the scientists who found the connection between cannabis and epilepsy. Dravet Syndrome Dravet Syndrome is an epileptic disorder in children of genetic origin. The seizures are unpredictable, but often triggered by heat. It’s so severe that sometimes it can lead to death. It typically appears when the child is 6 months old and becomes worse as the child ages. Their seizures are terribly debilitating. Apart from them, the children affected show motor problems, autism, hyperactivity, impulsivity, somnolence and insomnia. These problems, together with the fact that a seizure represents a mortal danger, makes impossible for the child to attend school. He or she requires constant attention. It’s hard to imagine what it must be like to be the parent of a child with this disease. The story of Charlotte One of these children was a little girl named Charlotte Figi, who lived with her parents in Colorado. She had a twin named Chase, who was healthy. They were born on October 18, 2006. Charlotte’s seizures started when she was 3 months old. The first one lasted 30 minutes. Over the next few months, Charlotte had seizures lasting two to four hours. She was hospitalized, but the doctors could not find what was wrong with her. They put her on benzodiazepines and barbiturates, drugs that affect normal behavior and are addictive. Maybe it was these drugs, maybe it was the seizures, but by age two Charlotte started to decline cognitively. When she was two and a half, the doctors were finally able to diagnose her. She had the Scn1a mutation in the gene that encodes for the Nav1.1 voltage-gated sodium channel, one of the proteins in the axons of neurons that mediate action potentials. The Scn1a mutation is present in 80% of the cases of Dravet Syndrome. A Dravet specialist put Charlotte in a ketonic diet, because high levels of ketones suppress seizures. But they also caused bone loss and weakened Charlotte’s immune system. And then, after two years, the seizures came back. Charlotte’s father, Matt, looked on the internet for solutions. He found a boy in California with Dravet Syndrome who was being successfully treated with cannabis. At age 5, Charlotte couldn’t walk, talk or eat. She was having 300 seizures a week. She was taken to the hospital several times at the edge of death. Her parents hesitated to give her cannabis. Scientists had been cautioning parents that cannabis had nasty effects on the developing bodies of children, affecting the lungs, the heart and the brain. They consulted two more specialists. But, since Charlotte was at the edge of death, they finally decided to give her cannabis. They found a strain of marijuana called R4, which was low in THC and high on CBD. They gave it to Charlotte. Her seizures went away for seven days. The Charlotte’s Web strain of cannabis Looking for a consistent supply of cannabis with low THC and high CBD, Charlotte’s parents met the Stanley brothers, Joel, Jesse, Jon, Jordan, Jared and Josh, who were one of the largest legal growers of cannabis in Colorado. They had developed a strain of marijuana with low THC content and high in CBD. Because it didn’t get people high, they couldn’t sell it, so they initially called it Hippie’s Disappointment. When they saw what it did to Charlotte, they renamed it Charlotte’s Web, after the popular children’s book and little Charlotte. By age 6, Charlotte was thriving. She was walking and riding her bike. For the first time in years, her parents heard her laugh. Her seizures happened only two or three times per months, mostly while she slept. The Stanley brothers started the Realm of Caring Foundation, a non-profit dedicated to provide special strains of cannabis to children suffering from Dravet Syndrome, and also to adults suffering from Parkinson’s Disease, multiple sclerosis, epilepsy and cancer. It was 2012. Cannabis was already legal in many states of the USA, but moving it from one state to another was still illegal under federal law. That meant that you could not buy Charlotte’s Web outside Colorado. Parents of children with Dravet Syndrome starting moving to Colorado, so they could give their children the life-saving Charlotte’s Web strain of cannabis (Whiting et al., 2015). Unfortunately, Charlotte’s story doesn’t have a happy ending. She died of pneumonia with complications related to her disease on April 7, 2020. The neuroscience However, the connection between CBD and the mutated Nav1.1 sodium channel that causes Dravet Syndrome was still unknown. It was important to find it in order to give the treatment of children with cannabis a solid scientific basis. Besides, unraveling such a mechanism could lead to the discovery of other drugs to treat epilepsy. A team of scientist from the University of Washington in Seattle set to work on this (Kaplan et al., 2017). The first thing they did was to find a strain of mice with the mutation Scn1a, so that the mice would have the same defective Nav1.1 sodium channel as the children with Dravet Syndrome. These mice had epileptic seizures triggered by heat and deficits in social behavior that resemble autism. Previous work had shown that the Scn1a mutation caused the Nav1.1 sodium channels to stop working. These Nav1.1 channels are present in neurons that release the neurotransmitter GABA (GABAergic interneurons), which inhibits other neurons. When the GABAergic interneurons do not fire enough action potentials, they cannot oppose the build-up of excitation in the brain, and an epileptic attack ensues. When Kaplan et al. gave CBD to the mice with the Scn1a mutation, the severity, duration and number of their seizures were significantly decreased. CBD also reduced the autistic-like social behavior of the mutant mice. Moreover, CBD increased the excitability of the GABAergic interneurons in the hippocampus of the mutant mice, a part of the brain essential for memory formation and that is the origin of epileptic seizures. The effect of CBD was not mediated by CB1 receptors, which are the receptors responsible for the psychotropic effects of THC. Blocking CB1 receptors with their inverse agonist AM281 did not affect the increase in the activity of the GABAergic interneurons produced by CBD. However, blocking GPR55, the third cannabinoid receptor, with its antagonist CID16020046 increased the activity of the GABAergic interneurons, just like CBD. CBD did not increase the excitability of GABAergic interneurons over the increase already produced by the GPR55 antagonist. The investigators concluded that the effect of CBD was mediated by the cannabinoid receptor GPR55. What CBD does is to inhibit GPR55 because is an antagonist of these receptors. GPR55 receptors inhibit Nav1.1 channels. When CBD blocks GPR55, this restores the function of Nav1.1 channels, preventing the epileptic attacks in Dravet syndrome. Epidiolex: a new drug to treat Dravet Syndrome CBD is now sold as an oral solution by GW Pharmaceuticals as Epidiolex ™ (Gray and Whalley, 2020). It was approved by the Food and Drug Administration in 2018 to treat Dravet Syndrome and other epileptic disorders. In September 2019, it was approved for European consumption as Epidyolex. The parents of children with Dravet Syndrome no longer have to relocate to Colorado to buy Charlotte’s Web for their children. They can just give them Epidiolex. If President Nixon would not have declared cannabis a Schedule I drug with no therapeutic use for political reasons, the use of CBD to treat Dravet Syndrome may have been discovered much sooner. Perhaps even before Charlotte was born. References Gray RA, Whalley BJ (2020) The proposed mechanisms of action of CBD in epilepsy. Epileptic Disord 22:10-15. Kaplan JS, Stella N, Catterall WA, Westenbroek RE (2017) Cannabidiol attenuates seizures and social deficits in a mouse model of Dravet syndrome. Proc Natl Acad Sci U S A 114:11229-11234. Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, Keurentjes JC, Lang S, Misso K, Ryder S, Schmidlkofer S, Westwood M, Kleijnen J (2015) Cannabinoids for Medical Use: A Systematic Review and Meta-analysis. Jama 313:2456-2473.

A quick review of the receptors that mediate the effects of cannabinoids Cannabis or marihuana is one of the oldest known drugs. Its use goes back to the dawn of time. The cannabis plant has more than a hundred psychoactive compounds besides delta(9)-tetrahydrocannabinol (THC), the most potent of them. Another important cannabinoids are cannabidiol (CBD), cannabinol (CBN) and cannabigerol (CBG) (Pertwee, 2008). Cannabinoid receptors Cannabinoids bind to three receptors that mediate their effects: CB1, CB2 and GPR55. All three are G protein-coupled receptors (GPCRs). G proteins are proteins that serve to carry signals inside the cells. They are formed by three subunits, α, β and γ. Normally, the G protein is attached to the GPCR in the inside of the cell membrane. When the GPCR binds its neurotransmitter, the G protein dissociates, with the α and the βγ subunits going separate ways to carry signals inside the cell. There are different G proteins. They have the same βγ subunits but different α subunits. Each α subunit activates a different second messenger system. Like the opioid receptors, CB1 and CB2 act through the inhibitory αi G proteins, which decrease the synthesis of the second messenger cyclic AMP (cAMP). In neurons, this leads to a decrease in the firing of action potentials and a decrease in neurotransmitter release. CB1 receptors mediate most of the psychoactive effects of THC: analgesia, euphoria and sometimes paranoia. It is the most abundant GPCR in the brain, being found in most brain regions. CB2 receptors were initially thought to exist only in non-brain tissues, like immune cells. However, more recently it was found in the brain, where it modulates the actions of CB1. They have important functions in the immune system and other organs of the body. GPR55 was an ‘orphan’ receptor, that is, a receptor whose gene was found first, before its ligand was known (Lauckner et al., 2008). GPR stands for ‘G protein-coupled receptor’. It signals through Gq and G12 proteins, releasing calcium from intracellular stores and inhibiting M current potassium channels (Lauckner et al., 2008). All that means that it excites neurons, instead of inhibiting them like CB1 and CB2 receptors. GPR119 and GPR18 are other orphan receptors that may also be cannabinoid receptors. TRPV1 (the capsaicin receptor), TRPV2 and TRPV3 are other receptors that can be activated by cannabinoids and endocannabinoids (Santha et al., 2010). They act as heat sensors in the skin, with TRPV1 detecting burning temperatures and TRPV2 and TRPV3 detecting milder temperatures. But they are also present in neurons in the central nervous system, playing roles still not well understood. CB1 and CB2 agonists There are many synthetic compounds that are agonists of CB1 and CB2 receptors (Patel and Hillard, 2006; Bow and Rimoldi, 2016). WIN 55,212-2 is one of the oldest of these compounds. It is an agonist of both CB1 and CB2 receptors. Arachidonyl-2'-chloroethylamide (ACEA) is a selective agonist of CB1 receptors. CB 65, HU 308 and JWH 133 are selective agonists of CB2 receptors. Abnormal-cannabidiol, ML 184 and O-1602 are selective agonists of GPR55 (Ross, 2009). These compounds are important tools for discriminating the effects of these three receptors. Constitutive activity of CB1 and CB2 receptors Like the µ-opioid receptor, CB1 and CB2 receptors have constitutive activity. This means that they have a little bit of activity, even when they do not bind an agonist, activating their associated G proteins to a certain extent. Therefore, there are compounds that act as inverse agonists of these receptors, that is, not only they inhibit the effect of the agonists, but are also able to inhibit the constitutive activity. Most of the substances identified as CB1 receptors antagonist, like rimonabant (or SR 141716A), AM 251 and AM 281, are in fact inverse agonists. AM 630 and GP 1a are inverse agonists of CB2 receptors. What is important about these compounds is that scientists have the ability to selectively block each one of the three cannabinoid receptors in order to determine how they contribute to the effects of THC, CBD and the endocannabinoids. However, since these compounds are inverse agonists, they would also block the constitutive activity that CB1 and CB2 receptors may have in the absence of any agonist. References Bow EW, Rimoldi JM (2016) The Structure-Function Relationships of Classical Cannabinoids: CB1/CB2 Modulation. Perspect Medicin Chem 8:17-39. Lauckner JE, Jensen JB, Chen HY, Lu HC, Hille B, Mackie K (2008) GPR55 is a cannabinoid receptor that increases intracellular calcium and inhibits M current. Proc Natl Acad Sci U S A 105:2699-2704. Patel S, Hillard CJ (2006) Pharmacological evaluation of cannabinoid receptor ligands in a mouse model of anxiety: further evidence for an anxiolytic role for endogenous cannabinoid signaling. J Pharmacol Exp Ther 318:304-311. Pertwee RG (2008) The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin. Br J Pharmacol 153:199-215. Ross RA (2009) The enigmatic pharmacology of GPR55. Trends Pharmacol Sci 30:156-163. Santha P, Jenes A, Somogyi C, Nagy I (2010) The endogenous cannabinoid anandamide inhibits transient receptor potential vanilloid type 1 receptor-mediated currents in rat cultured primary sensory neurons. Acta Physiol Hung 97:149-158.

Market forces induce the over-exploitation of common resources The basic problems of capitalism This is the second in a series of articles about the fundamental problems of capitalism. These problems are intrinsic to the nature of capitalism. They cannot be solved by market forces. These problems are: Perverse incentives. The tragedy of the commons. Unequal wealth distribution. Exploitation of workers. Exploitation of consumers. The merging of corporations leading to monopolies. The political influence of the corporations. Conservatives and libertarians argue that these problems can be solved by the raw market forces of capitalism: the invisible hand. I want to analyze these problems, one by one, to see if this is true. Sheep pastures A small village of shepherds has pastures in common. Since the shepherds are highly individualistic and greedy, they all try to raise more sheep than their neighbors. As the result, the pastures are overgrazed and the sheep starve. The shepherds are ruined. This actually happened in the Sierra Nevada of California. Big flocks of sheep were brought in to graze on the rich meadows of the sierras. They promptly destroyed them, causing the native bighorn sheep and deer to starve and wreaking havoc on the entire ecosystem. The shepherds just moved the sheep to other meadows, extending the damage. The government banned grazing sheep in the mountains, but the shepherds knew the intricate geography of these high mountains and refused to leave. Ultimately, the army had to be brought in to dislodge them. But, by then, irreparable damage was done to this fragile ecosystem. One of the shepherds was John Muir. Witnessing the damage done by the sheep started his environmental activism. [Source: The High Sierra: Peaks - Passes - Trails, by RJ Secor.] These are textbook examples of an economic problem called the tragedy of the commons. When a certain resource is held as a community property, greed and competition drive individuals to disregard the common good and use as much of the resource as they can. Whoever wants to take care of the common good makes less profit, while cheaters benefit. Over time, competition drives those that try to take care of the common good out of business, in favor of the exploiters. The cod fishery of the North Atlantic Here is another example. There used to be an enormous cod fishery off the coast of Newfoundland in the North Atlantic. Fishermen from Spain, France and Portugal discovered it and sailed across the Atlantic to get the fish. To keep the fish from rotting during the long traverse back, they salted it. To this day, salted cod is a traditional dish in Spain and Portugal. Salted cod kept so well that it was used to feed the armies during the endless European wars. The North Atlantic cod fishery lasted until the 20th century, when it collapsed. A similar threat exists for fish in international waters, where fisheries cannot be regulated. Even the coastal fisheries of poor countries get poached by factory fishing boats from rich countries. Planet Earth Ultimately, there is one resource common to all Humanity: planet Earth. The current climate crisis shows that the ‘invisible hand’ of capitalism will exploit it until its destruction. When it comes to the health of the planet, nations have to join forces to create laws to regulate the exploitation of oceans, the composition of the atmosphere, and other key systems for the well-being of the planet. An international system able to enforce these laws against pariah states is necessary. Conclusion There is no way that market forces can self-regulate to avoid the tragedy of the commons. Consumers are too uninformed, powerless and poorly organized to do anything about it. Any corporation that tries to take care of the commons will lose money. Eventually, it will be taken over by corporations dedicated to mindless exploitation. As in the example with the shepherds, the ultimate disappearance of the common resource will mean the ruin of the corporations. Unfortunately, modern corporations have a limited time outlook. It’s years, even months. Plans for the future are limited by the human lifespan. Few people care to do something when they will not live long enough to see the outcome of their efforts. And those idealistic few are certainly not the CEOs of big corporations. Unfortunately, changes in the environment occur over very long timeframes. A hundred years is an eye blink. Changes in global weather patterns usually take tens of thousands of years. We are forcing a global climate change on Earth in barely a hundred years. It’s way too fast for the biosphere of our planet to manage it. And yet, few of us will live long enough to see its full consequences. As it happened with the sheep in the California sierras, the only solution for the tragedy of the commons is for the State to use its power to regulate the use of common resources.

Breath play, sexual predators, mental conditions, switching, domestic discipline, and other topics debated in the BDSM community. Controversies and debates are good. That’s how we learn from each other and reach a consensus on the important matters. Most of today’s BDSM culture arose from past debates. However, there are still some unresolved issues. I list here 12 of them, trying to present both sides fairly and to withhold my own position. Each one of these issues deserves an article for itself. However, I think that is nice to have them all in one place to decide on their relative importance. I put those that I think are more controversial towards the top of the list. 1) How to fight predators in the BDSM community I put this one at the top because it is so controversial that is tearing some BDSM communities apart. Fetlife.com, the gathering site of millions of kinksters around the world, is routinely accused of not being tough enough on sex predators. Of enabling them. Of silencing victims. Is this a Trojan Horse used by radical feminists to keep attacking BDSM, after being defeated in the Feminist Sex Wars? Or are there conspiracies to protect some powerful people so that they can continue to prey on unsuspecting victims? Have some people been falsely accused of breaking consent and being predators? Or is the BDSM community too soft on sexual predators? 2) Is breath play safe? Proponents of breath play say that it is perfectly safe when done the right way. It induces an altered state of consciousness that is very pleasurable and different from that produced by drugs. Asphyxiation also increases enormously the intensity of orgasm. Opponents say that breath play is the most life-threatening BDSM activity, by far. There is no really safe way to do it because it is impossible to predict how the cardiovascular system is going to react. Repeated asphyxia may cause hidden brain damage. The pleasure it provides can be reached by other means, and it is certainly not worth the risk. 3) SSC or RACK? SSC - safe, sane and consensual - is the old standard, created in 1983 to define the limits between ethical BDSM and abuse. It is defended as the clearer and safer standard. These are the best criteria to present to the vanilla society. If things go wrong in a scene, do you want to tell a judge and jury that you were practicing “safe, sane and consensual” or “risk-aware consensual kink”? RACK - risk-aware consensual kink - was proposed later (1990s?) by people who thought that BDSM could never be totally safe or sane. ‘Safe and sane’ provided an excuse to be judgmental about some of the more extreme BDSM practices. It is up to the participants to inform themselves and decide what risks they are will to take, i.e., be “risk-aware”. Informed consent should be the main, and perhaps the only, concern. 4) Should people with mental problems practice BDSM? What do we exactly mean by ‘sane’ in SSC? It is usually understood as being aware of the potential psychological trauma that can be caused by BDSM. But there are people who are more psychologically vulnerable. And there are those who argue that they should not play in the bottom or submissive roles, because this would be inherently unsafe for them. At the very least, they should disclose their mental problems to their scene partners. And aren’t people with mental problems disqualified to play as tops or dominants? On the other hand, isn’t excluding neurodivergent people from the BDSM community discriminatory and ableist? It is the prerogative of each person to decide what is safe for them. Besides, there are a multitude of mental diseases. If we started judging people because of that, we may end up excluding those that are aware of them and taking care of themselves with medication or therapy, while accepting those in denial about their mental problems. 5) Is BDSM therapeutic? A lot of neurodivergent people who practice BDSM will tell you that, in fact, BDSM is good for them and helps them deal with their problems. BDSM can also help with chronic pain by teaching people emotionally healthy ways to deal with pain. However, other bristle at the idea that BDSM can be therapeutic. ‘BDSM is not therapy!’ they say. Shouldn’t therapy be left to qualified psychologists? Should tops walk into a minefield of hidden traumas in their bottoms? 6) Drug use in BDSM There is a consensus that people should not be on drugs during a BDSM scene. Dominants cannot make safe decisions if they are high. Submissives cannot give full consent or use a safeword if they are on drugs. However, I suspect that there is a bit of hypocrisy in this. That, in reality, there are people who use drugs in BDSM scenes. Shouldn’t this be just another decision that people are allowed to make after informing themselves? We are just awakening from a lot of misinformation spread by the government during the War on Drugs. President Nixon imposed a classification of drug risks based on his political ideas, because he didn’t like “those hippies”. In doing that, he destroyed the therapeutic potential of cannabis and psychotropic substances, which was being investigated in the 60s and is back into consideration today. Not all drugs are the same. On the one hand, the USA has been having an opioid epidemic for two decades that has caused hundreds of thousands of deaths. However, it was not started by “those hippies”, but by the greed of Purdue Pharma and the wrongdoing of many American doctors that prescribed their product, OxyContin, without checking is addictive potential. The danger of opioid abuse in the BDSM community is very small. On the other hand, the legalization of cannabis in most of the USA has made us aware that it is not as dangerous as we were told. Famous podcaster Dan Savage often recommends cannabis to deal with sexual problems. It is certainly healthier than the long-held tradition of getting drunk to ease sexual inhibitions during sex. The argument that submissives shouldn't take drugs because it prevents them from consenting and using the safeword is weakened by the fact that endorphins released during a BDSM scene are just as potent as any opiate. When they enter the sub space, submissives become just as unable to make decisions and use a safeword as if they were high. Taking a little cannabis to relax and overcome inhibitions produces a much less altered state of mind. Today, many people take micro-doses of cannabis and psychotropics like Psilocybe mushrooms and LSD in their daily life. Then again, drugs can incapacitate you from entering the submission space. Or create unpredictable problems by interacting with it. Maybe is time to have an honest conversation about this? 7) Is BDSM a sexual orientation? The politically correct belief is that homosexuality is from birth and unchangeable. People are attracted to people of the same gender because they are born that way. But people who like spankings, bondage or submission, somehow, picked those sexual tastes later in life. Never mind that a lot of BDSMers had kinky fantasies early in their childhood. We cannot even suggest that children can be sexual, let alone be perverts! Maybe the problem is that ‘sexual orientation’ are words that convey a lot of political privilege these days. If BDSM was a sexual orientation, then we would have the same right not to be discriminated against that gays and lesbians have. And they would have to stop criminalizing BDSM, as still happens in many countries where gay sex has been legal for a long, long time. 8) Is domestic discipline part of BDSM? Most people who practice domestic discipline see themselves as different from BDSMers. They dislike the fetish clothes, the special furniture, the implements and the attitude of BDSM. They wear normal clothes and don’t go to kinky parties. They just have a person who is in charge, some rules that need to be followed, and punishments when those rules are broken. In particular, people who practice Christian domestic discipline are very adamant that they are not like ‘those perverts’. They are just following the will of God, clearly explained in the Bible, that a wife must obey and be disciplined by her husband. People into BDSM just shrug and say: “You have similar fantasies than us, just a different style. The basics are the same: submission and spankings. But it’s okay if you want to feel special. Everybody does.” 9) Are switches authentic dominants and submissives? Switches, in case you didn’t know, are people who like to change roles between dominant and submissive, or between top and bottom. They are BDSM sluts who want to have their cake and eat it, too. They don’t care if they are tops or bottoms, as long as somebody gets spanked. There always has been an anti-switch attitude in the BDSM community. Some people think that being dominant or submissive is something essential to their personality, so that they could never be in the opposite role. Which is fine. The unspoken corollary, however, is that switches do not have that essence, so when they are dominants or submissives, they are faking it. On the other hand, there are those who say that experiencing BDSM from both sides makes it possible to truly empathize with your partner. You know exactly how they feel. And, to truly master an implement like a cane or a whip, you need to know what it feels like. 10) Is BDSM a game or a lifestyle? This is an old debate of the 90s that seems to have largely died off. However, some of its undercurrents still persist. Lifestylers look down on ‘gamers’ as unauthentic. They feel that being dominant or submissive is something essential to their personalities, not an outfit that they put on and take off. BDSM is something that completely permeates their life, an attitude that is always present. They don’t have ‘roles’. They do not ‘play’. They do not have ‘scenes’. Most of us see BDSM as a game. Scenes that we play for a time, and then we go back to our egalitarian roles. Being dominant or submissive may be something that we feel deeply, but it is a role that we only adopt in appropriate times. And there is nothing wrong with that. 11) Is kink different from BDSM? It seems that all BDSM is kink, but not all kink is BDSM. However, it is not clear what are those kinky activities beside BDSM. Some people say that anal sex and even oral sex are kink. Others say that just wearing sexy clothes like leather or rubber is kinky. Have BDSM looks, like wearing a collar, come into fashion to the detriment of authentic BDSM? 12) Who is really in control, the submissive or the dominant? Some people say that the submissive is the one really in control in a BDSM scene, because negotiations, limits, and having a safeword determine that the scene really plays to their fantasies. Other people say that the dominant is, and should be, in control. He starts with the fantasies and desires of the submissive and gradually folds them to his/her will. Yet other people say that both the dominant and the submissive are in service to the scene, which is something beautiful that they create together and ends up enveloping them.