Posts Tagged ‘ neuropharmacology ’

Stress Intervention

Scientists have discovered a way to shut down the brain’s “stress process” before it gets going, says a new study.

Stress, or just a very acute case of the munchies? It's hard to say.

By blocking the brain’s ability to manufacture certain chemicals called neurosteroids, researchers have managed to temporarily cut off a biological process crucial for stressful behavior – and for many stressful feelings as well.

Animals from amphibians all the way up to humans produce a hormone called corticosterone in their adrenal glands. Corticosterone levels become elevated under stress, and this hormone is a major ingredient in a number of stress-related biological processes, from feelings of nervousness to aggressive behavior.

Corticosterone does most of its direct work within a brain pathway known as the hypothalamic-pituitary-adrenal axis (also called the HPA or HTPA axis). To be honest, the word “pathway” is a bit of an oversimplification – the HPA is actually a whole set of neurochemical feedback circuits involved in regulating digestion, immune response, and mood, among other things.

The HPA’s activity is mostly regulated by a neurotransmitter chemical called gamma-Aminobutyric acid (GABA to its friends). GABA is typically an inhibitory neurotransmitter, which means it prevents electrochemical signals from being passed beyond a certain point. It often works closely with a neurosteroid called tetrahydrodeoxycorticosterone (THDOC), which helps its inhibitory effects spread even more widely throughout the HPA.

But when we come under stress, everything changes: the adrenal glands start cranking out extra-large doses of THDOC and sending them up into the HPA. And here’s where things get weird – those conditions trigger a certain electrochemical shift that causes GABA and THDOC to activate the HPA rather than inhibit it.

As the Journal of Neuroscience reports, the discovery of that neurochemical mechanism is the first half of a two-part breakthrough made Jamie Maguire‘s team at Tufts University:

We have identified a novel mechanism regulating the body’s response to stress by determining that neurosteroids are required to mount the physiological response to stress.

But how did they discover this mechanism, you ask? Well, since the team suspected that neurosteroidogenesis – the production of neurosteroids like THDOC – was a crucial component in stress-related HPA activation, they got a bright idea: they wondered if a drug that blocked neurosteroidogenesis might be able to stop the brain’s stress response before it could even get into gear.

As it turned out, they were right – they cut off the THDOC rush by administering a drug called finasteride – which you might’ve heard of under the brand name Propecia. Yep, the baldness drug:

Blocking neurosteroidogenesis with finasteride is sufficient to block the stress-induced elevations in corticosterone and prevent stress-induced anxiety-like behaviors in mice.

In other words, the researchers found that finasteride does more than just control stress – it blocks the chemical cascade that causes stress-related feelings and behavior. As far as they can tell, it prevents animals from experiencing stress at all – at least temporarily.

This has the potential to develop into a far more powerful treatment than benzodiazepines like Xanax and Ativan, which work by helping GABA inhibit more activity than it normally would. By contrast, a finasteride-like drug would make it almost impossible to feel stressed, even if you tried – meaning this drug might also be used to treat diseases like epilepsy and major depression, which have been linked to excessive activation of the HPA.

Right now, Maguire’s team is focused on isolating more of the exact neural connections that play roles in disorders like these. That means it may be a few years before this “wonder drug” becomes available. In the meantime, I wouldn’t recommend swallowing handfuls of Propecia when you’re feeling stressed – the drug needs to be applied in a pretty targeted way to make this work, which means a major part of pharmaceutical development will be the creation of an effective chemical delivery system.

Even so, it’s exciting to think that before long, depression and anxiety may be as easy to prevent as, say, polio and malaria are today. The thought’s enough to get my hormones pumping, anyway.

Chemical Parasites

A certain brain parasite actually turns off people’s feelings of fear by increasing levels of the neurotransmitter chemical dopamine, says a new study.

T. gondii, gettin' ready to blow your %@&#$ mind.

Toxoplasma gondii, a parasitic protozoan (a kind of single-celled organism), mostly likes to live in the brains of cats – but it also infects birds, mice, and about 10 to 20 percent of people in the U.S. and U.K. This might sound like science fiction, but plenty of microbiologists will assure you it’s very real.

In fact, T. gondii isn’t the only parasite that controls its hosts’ behavior – a fungus called Ophiocordyceps unilateralis makes infected ants climb to the highest point they can find, sprout fungal spore pods from their heads, then stay there and starve to death; at which point the spores are unleashed to recruit more ants for the fungus’s zombie army. Other microbes force spiders to weave cocoons for them, or make roaches lay immobile while larvae grow inside their bodies, then chew their way out. Um, yeah, so… nature is pretty frickin’ hardcore.

Anyway, back to the parasite at hand. Throughout the past few years, a University of Leeds microbiologist named Glenn McConkey has worked at the forefront of T. gondii research – in 2009, his team made the astonishing discovery that the microbe’s genome encodes instructions for producing dopamine: in essence, this bug is living cocaine, and it’s bending the minds of millions of people at this very moment.

And now, as the journal PLoS ONE reports, McConkey’s team has made a breakthrough that is, if anything, even more incredible: once the parasite has taken up residence in a brain, it triggers the production and release of dopamine at a much greater level than normal, causing infected animals (including people) to engage in impulsive, compulsive and/or fearless behavior:

In this study, infection of mammalian dopaminergic cells with T. gondii enhanced the levels of K+-induced release of dopamine several-fold, with a direct correlation between the number of infected cells and the quantity of dopamine released … Based on these analyses, T. gondii orchestrates a significant increase in dopamine metabolism in neural cells.

In short, by changing the electrochemical properties of dopaminergic neurons (those that deal with dopamine transmission and reception), T. gondii basically causes its host’s brain to shout “I’m awesome!” ceaselessly at top volume. You can imagine the havoc this wreaks.

If the host is, say, a mouse or a bird, impulsive and fearless behavior will typically get it gobbled up by a predator, which allows the parasite to move into a new host and spawn a new generation. But if the host happens to be a human being – well, there’s no telling what might happen. For one thing, studies have found a strong link between T. gondii infection and schizophrenia.

Thanks to Science, though, there’s hope – McConkey’s team is optimistic that these new results will help doctors diagnose T. gondii infections more quickly and accurately, and perhaps use dopamine antagonists – drugs that block dopaminergic activity – to fight some of the psychotic symptoms these crazy little guys cause.

So, I guess one big question remains: why the hell isn’t this story making front-page news? Your guess is as good as mine. Kinda spooky, isn’t it?

Drugs, Neuroscience, and You

Let’s be honest here: if a person really wants to try an illegal drug, he or she is going to find a way to try it. To me, the most reasonable response to this fact seems to be to share clear, science-backed explanations of the effects and risks involved with each drug.

So today, I’m going to take a little break from my usual newsy reporting, and provide a condensed rundown on some drugs, in the style of my Memory Menagerie write-up.

First, just a couple quick notes about this summary. For one thing, it’s going to focus on drugs that are illegal in many places, for the simple reason that it’s (understandably) not easy to get clear scientific info about them. (If you’re interested in a similar write-up about psychiatric prescription drugs, though, drop me a comment and I’ll happily write one.) Anyway, my goal here is to inform and educate – not to advise or condone anything. To be annoyingly literal about this: I’m not suggesting that you take illegal drugs.

Second, I also can’t cover every drug that’s available today – spend a few minutes on, and you’ll see that there are dozens, if not hundreds of them. So I’m going to stick to the ones you’re most likely to hear about. And that brings up my final note: my main goal here isn’t to be exhaustive or in-depth, but to provide a quick overview of major “street drugs” on a single page, simply because one-page collections of quick scientific info on illegal substances are (oddly enough) hard to come by.

And now, without further ado…let’s talk about some drugs.

Cannabis (marijuana)1

What it is: A resin that grows on the female buds of plants in the genus Cannabis. The word “marijuana” seems to have first come into use as a slang term (of unknown origin) in Mexico in the 1800s.
What it does: Physically, ingestion of the drug causes bloodshot eyes, dry mouth, increased heart rate, and muscle relaxation. Mentally, it produces a “high” – a feeling of euphoria. Beyond this, its psychological effects vary widely from user to user. Some common effects, though, include reduction of stress-related feelings, increased appreciation of art and music, increased tendency to laugh, increased appetite, a distorted sense of time, a variety of degrees of amnesia, and a tendency toward metacognition (thinking about thinking) and introspection. Another notable aspect of the high is that certain internal thoughts – especially those linked with strong emotion – seem extraordinarily vivid. If someone with an anxiety-related disorder uses cannabis, these effects can become tinged with negativity, and paranoia may set in, sometimes leading to a panic attack. As with many drugs, the boundary between positive and negative effects is easily crossed, and constant careful monitoring of one’s set and setting is crucial. Depending on the dose, effects can last from 30 minutes to eight hours. Though this drug is not chemically addictive, a large number of users develop a psychological dependency on it.
How it does this: A variety of cannabinoids bind to a range of receptors involved in the body’s natural endocannabinoid system, which blocks communication between neurons within their own areas.  Most prominent among the cannabinoids in cannabis is Δ9tetrahydrocannabinol, often known as THC. It binds to CB1 and CB2 endocannabinoid receptors in a wide range of brain areas, including the amygdala, the hippocampus, and the nucleus accumbens. The exact relationship between the neurochemistry of the “high” and many of the side effects above remains poorly understood.

Cocaine (coke)

What it is: A crystalline alkaloid, a chemical compound found in the leaves of the Coca plant. It was first isolated by the chemist Friedrich Gaedcke in 1855.
What it does: Physically, cocaine acts as a stimulant, raising heart rate, increasing feelings of energy, raising confidence and enthusiasm, and providing an otherwise euphoric and alert “high.” Cocaine also acts as a mild to moderate local anesthetic. In many users, the drug also greatly reduces patience and attention span, and contributes to feelings of anxiety or paranoia, especially after repeated use. Effects usually last from 15 minutes to an hour. This drug is highly addictive – withdrawal symptoms can include irritability, anxiety, fatigue, anhedonia (inability to feel pleasure) and insomnia.
How it does this: Cocaine molecules bind to sites on neurons called dopamine transporters, which normally help reabsorb dopamine – a neurotransmitter involved in feelings of reward – for future use. When the cocaine molecules bind to the dopamine transporters, they block these transporters’ function, keeping dopamine in the synaptic clefts much longer than usual. The result is that many brain pathways – in regions like the nucelus accumbens, the ventral tegmental area, and the prefrontal cortex – are bathed in dopamine, raising reward feelings far above the norm.

Psilocybin (mushrooms)

What it is: A chemical produced by more than 200 species of mushrooms – but mainly associated with the mushroom Psilocybe mexicana.
What it does: Physically, the drug tends to cause lethargy and drowsiness, disorientation, intensified reflexes, pupil dilation, and increased heart rate. As with most psychedelics, psychological effects vary widely from person to person, and depend heavily on set and setting. Feelings of euphoria or depression are common, as are enhanced appreciation of colors or shapes, and a distorted sense of time. Closed- and open-eye hallucinations vary from mild to intense depending on the dose, and can range from simple moving colors, shapes and patterns all the way to entheogenic experiences and dialogues with hallucinated beings. Effects can last from six to twelve hours, or possibly longer.
How it does this: The human body rapidly converts psilocybin to psilocin, a chemical that acts as a partial agonist to several types of serotonin receptors, especially the 5-HT2A receptor (serotonin is also known as 5-hydroxytryptamine, or 5-HT). Serotonin’s exact role in psychedelic effects remains poorly understood, but it’s known that this neurotransmitter is involved in regulating moods, and increasing feelings of well-being.

LSD (acid)

What it is: A semi-synthetic chemical originally derived from ergotamine, a substance found in ergot, a fungus that often grows on rye grain. It was first synthesized by the chemist Albert Hofmann in 1938, but he didn’t make his first (self-administered) test of LSD until 1943.
What it does:
Physically, the drug raises alertness, causes pupil dilation, raises or lowers body temperature, and increases or decreases appetite. As with most psychedelics, LSD’s psychological effects vary widely from person to person, and depend heavily on set and setting. Many users perceive movement of static surfaces like walls, as well as intensified perception of colors, brightness, iridescence, and shininess. Higher doses can trigger closed- or open-eye hallucinations of geometric patterns, echo-like distortion of sounds, and synaesthesia. Because the drug often intensifies emotions, some users can descend into “bad trips” involving panic attacks or even fragmentation of identity. However, the overall euphoric “high” sustained by LSD means a calming friend can sometimes help turn a bad trip back into a positive one. Effects usually last from four to twelve hours.
How it does this: LSD binds to many types of serotonin receptors, including 5-HT1A, 5-HT2A, 5-HT2C, 5-HT5A, and 5-HT6. At 5-HT2A, in particular, it acts as a strong partial agonist, helping trigger the release of glutamate throughout the cerebral cortex. Some research suggests that LSD may preferentially bind to less-used 5-HT receptors, triggering synaptic activity along little-used pathways. Exactly how all this contributes to the drug’s psychedelic effects remains poorly understood, but it’s likely to be linked with serotonin’s excitatory effects in the prefrontal cortex.

Salvinorin A (salvia)

What it is: A chemical found in the plant Salvia divinorum, a member of the sage family.
What it does: As with most psychedelics, salvinorin’s psychological effects vary widely from person to person, and depend heavily on set and setting. Some common effects include uncontrollable laughter, sensations of movement, distortions of time, distortions of body boundaries and perceived location, closed- or open-eye hallucinations of membranes or geometric patterns, vivid reliving of memories, synaesthesia, and glossolalia. Some users report feelings of euphoria, while others descend into fits of rage or panic attacks. Length of effects varies widely depending on the dose and method of ingestion – the experience can last from one minute to several hours.
How it does this: Salvinorin is a strong agonist for the κ-opioid receptor, and an even stronger partial agonist for the D2 dopamine receptor – thus, it increases availability of opioids and dopamine. Research on where this activity is mainly targeted, and what its relationship is to salvinorin’s psychedelic effects, remains in very early stages. Interestingly, though, salvinorin has no affinity for the 5-HT2A serotonin receptor, which is heavily affected by drugs like psilocybin, LSD, and mescaline – so salvinorin’s effects may be produced via entirely different neurochemical pathways.

MDMA (ecstasy)

What it is: A chemical first synthesized in 1912 by Merck chemist Anton Köllisch; its original intended use was to stop abnormal bleeding. It was derived from safrole, an oil extracted from the sassafras plant.
Important note: The term “MDMA” refers to the pure chemical; many tablets described as “ecstasy” also contain other substances, such as dextromethorphan or amphetamine.
What it does: Both physically and psychologically, the effects of the drug are more similar from user to user than those of many psychedelic drugs. Physically, it causes loss of appetite and exerts tension on muscles, which often results in behaviors like mild twitching or jaw-grinding. Psychologically, its most notable effect is that it raises alertness and produces a euphoric mental state, characterized by high energy, strong feelings of empathy and intimacy, heightened self-confidence, and sexual arousal. Effects last from 1.5 to 3 hours. The “comedown,” (i.e., aftereffects) of ecstasy can include dysphoria (feelings of unpleasantness), anxiety, and – in some cases – even prolonged depression.
Why it does this: MDMA triggers neurons to release serotonin, dopamine and norepinephrine. By blocking the actions of the vesticular monoamine transporter protein, which normally would help reabsorb norepinephrine, MDMA prolongs and heightens the availability of this neurotransmitter. It also acts as a weak agonist at 5-HT1 and 5-HT2 serotonin receptors, which increases the concentration and availability of serotonin – LSD acts as a partial agonist at some of these same receptors. Some scientists have suggested that MDMA also increases availability of oxytocin, the hormone present in high concentrations in a mother’s body during childbirth.

Nitrous oxide (balloons)

What it is: A chemical compound composed of sets of two nitrogen atoms bonded to one oxygen atom, usually in gas form.
What it does: At low doses, nitrous oxide has an anti-anxiety effect. It also produces dizziness, euphoria, and a feeling of being intensely in tune with somatosensory sensations. Effects often last only a few minutes, though they can be prolonged by repeated doses over a given time period.
How it does this: Nitrous oxide activates dopaminergic neurons in the ventral tegmental area and nucleus accumbens – areas known to be involved in addiction and reward. It also moderately blocks NMDA glutamate receptors, which play crucial roles in memory and learning, as well as β2-subunit-containing nicotinic acetylcholine (ACh) channels,which respond to nicotine-like chemicals. Meanwhile, it weakly inhibits AMPA and kainate glutamate receptors, GABAC receptors, and 5-HT3 serotonin receptors, while potentiating GABAA and glycine receptors – all of which modify synaptic likelihood and range in a wide variety of ways.


What it is: An acid that naturally occurs in small amounts in the central nervous systems of most animals. Synthesis of the chemical was first reported in 1874 by chemist Alexander Zaytsev.
What it does: Though it’s sometimes described as “liquid ecstasy” (i.e., MDMA), GHB can produce a much broader range  of effects than MDMA does, depending on the dosage. At low to moderate doses, its effects are indeed very similar to MDMA: it acts as a stimulant and produces euphoria, decreased anxiety, and increased sociability – often with a more serene emotional tenor than the typical MDMA experience. At higher doses, though, it can act as a dissociative or a sedative, and has even been reported to trigger “blackout” fugue states in some users. Depending on the dose, effects may last from 1 to 5 hours.
How it does this: GHB is an agonist at the excitatory GHB receptor, and it’s a weak agonist at the GABAB receptor, which is inhibitory. GHB induces the accumulation of either a derivative of tryptophan or tryptophan itself in the extracellular space, possibly by increasing tryptophan transport across the blood-brain barrier. Activation of the GHB receptor in some brain areas seems to contribute to the release of the excitatory neurotransmitter glutamate. Interestingly, low concentrations stimulate dopamine release via the GHB receptor, while higher concentrations inhibit dopamine release via GABA(B) receptors.

2C-B (nexus)

What it is: A chemical first synthesized as an anesthetic by chemist Alexander Shulgin in 1974.
What it does: At low doses, many users experience aphrodisiac effects, increased energy, and euphoria. Moderate to high doses can result in jittery feelings, a tendency toward “giggliness,” increased attention to one’s body and thought processes, and difficulty holding one’s concentration on a task (executive attention). Higher doses can produce unique visual and auditory hallucinations – objects can take on “runny” shapes or “watercolor-like” colors. At high doses, these may become full-blown hallucinations; i.e., independent of the user’s actual visuals. Depending on the dose, these effects can last from 1 to 5 hours – but the drug is known to leave residual effects with some users (i.e., the effects of the drug may still be experienced for several hours after the user’s body has metabolized the entire dose); this seems to be more common with higher doses. The “comedown” period has been associated with irritability, headaches, etc., but not all users report these symptoms.
Why it does this: Unlike most hallucinogens, 2C-B has been shown to be a low efficacy serotonin 5-HT2A receptor partial agonist or even full antagonist. This means its effects are produced by other neurochemical pathways than the serotonin pathway used by drugs like LSD and mescaline. Though it’s known that 2C-B contributes to the formation of several chemicals in the liver, their role in its effects is still poorly understood.

Ketamine (special K)

What it is: A chemical first synthesized as an anesthetic by pharmaceutical company Parke-Davis in 1962.
What it does: The drug produces a feeling of “dissociative anesthesia” – a sense of depersonalization or detachment from one’s body. As with other dissociatives, this state is often accompanied by a feeling of euphoria – the tendency of users in dissociative states to report decreased fear responses may also contribute to this feeling. At higher doses, ketamine can result in hallucinations (typically simple closed- or open-eye visuals), and sometimes in the strong dissociation commonly known as a “K-hole,” which is thought to mimic the psychological effects of schizophrenia. Effects often last 60 minutes or shorter.
How it does this: Ketamine acts as an NMDA receptor antagonist. At high, fully anesthetic level doses, ketamine has also been found to bind to type 2 opioid μ receptors, both of which contribute (along with its general tendency to block sodium channels) to its anaesthetic and analgesic effects. It acts as a dopamine reuptake inhibitor, increasing the availability of that neurotransmitter. Effects seem to be primarily focused in the hippocampus and the prefrontal cortex.

PCP (angel dust)

What it is: A chemical first synthesized as a surgical anesthetic in 1926.
What it does: Physically, low doses produce numbness, loss of balance, and slurred speech, while higher doses have analgesic and even anesthetic effects. Psychologically, users report euphoria, increased self-confidence, feelings of invulnerability, changes in body image, and loss of ego boundaries. Higher doses have been reported to lead to paranoia, hallucinations, depersonalization, and suicidal impulses. Depending on the dose, effects may last from 1 to 6 hours.
How it does this: PCP’s primary action is as an antagonist at on glutamate receptors, such as the NMDA receptor – this inhibits the release of the excitatory neurotransmitter glutamate, which is likely a cause of effects like loss of ego boundaries and depersonalization. PCP also inhibits nicotinic acetylcholine receptors – and, like ketamine, it acts as a partial agonist at D2 dopamine receptor sites, contributing to feelings of reward and euphoria.

Mescaline (peyote)

What it is: An alkaloid that occurs naturally in several types of cactus, most notably the peyote cactus (Lophophora williamsii).
Important note: the terms “mescaline” and “peyote” aren’t strictly synonymous; the peyote cactus contains a large spectrum of psychoactive  phenethylamine alkaloids, of which the principal one is mescaline.
What it does: The visual distortions produced by mescaline are somewhat different from those of LSD – rather than perceptions of non-existent objects or persons, they tend to enhance subjective perceptions and modify them in ways that many users find difficult to describe in words. Color and shape are greatly enhanced, and users report experiencing an overwhelming sense of the unique “is-ness” of individual objects. As with LSD, synesthesia is also common. Effects typically last for 12-18 hours.
How it does this: Neurochemically, mescaline acts similarly to other psychedelic drugs like LSD and DMT – it binds to and activates the serotonin 5-HT2A receptor with a high affinity as a partial agonist. How this leads to psychedelic effects is still poorly understood, but it likely involves excitation of neurons in the prefrontal cortex. Mescaline also activates the 5-HT2C serotonin receptor. In addition to serotonin receptor activity, the drug also stimulates dopamine receptors.


What it is: A chemical compound that naturally occurs in small quantities in the central nervous systems of many animals, and is often made from the bark resin of Virola trees. It was first synthesized in 1936 by chemist Richard Manske.
Important note: Although 5-Me-O DMT is often referred to as “DMT,” the two terms are actually not synonymous: 5-Me-O DMT is a close relative  of the chemical DMT, but it’s approximately 4 times as potent. Still, the pharmacology and range of potential effects for both chemicals are highly similar.
What it does: At low doses, DMT and its relatives produce somewhat similar effects to those of psychedelics like LSD and 2C-B – increased appreciation for light, color, and sound, and enhanced brightness and “watercolor-like” colors. At higher doses, the drug can produce powerful entheogenic experiences including intense visuals, euphoria and hallucinations. Effects often last only 5 to 10 minutes, but users have reported that a full-blown “trip” can be shocking in its alienness and intensity.
How it does this: Like other hallucinogens such as LSD and mescaline, a large part of DMT’s psychedelic effects are linked to the drug’s activation of the 5-HT2A serotonin receptor – though, as with these other drugs, the exact linkage between 5-HT receptors and psychedelic effects is poorly understood. Psilocin, an active chemical in many psychedelic mushrooms, is structurally similar to DMT.


What it is: A chemical stew of various psychoactive substances prepared from the South American Banisteriopsis caapi jungle vine. Its usage in certain tribal rituals dates back hundreds – if not thousands – of years.
What it does: Ayahuasca is essentially a preparation specially crafted to allow DMT to be deliverable to the brain when taken orally – so most of its effects are highly similar to those listed in the “5-MeO-DMT” entry above. The chemicals harmine and harmaline – other ingredients in the brew – can cause severe nausea and vomiting, which some users say enhances the intensity of the psychedelic experience.
How it does this: Ordinarily, the chemical MAO-A prevents DMT from crossing the blood-brain barrier – but the chemicals harmine and harmaline are selective and reversible inhibitors of MAO-A, while tetrahydroharmine is a weak serotonin uptake inhibitor. This inhibition of MAO-A allows DMT to diffuse unmetabolized past the membranes in the stomach and small intestine and eventually get through the blood-brain barrier (which, by itself, requires no MAO-A inhibition) to activate receptor sites in the brain.

Methamphetamine (meth)

What it is: A chemical first synthesized from the herb ephedrine by chemist Nagai Nagayoshi in 1893. Fun fact: in World War II, the Japanese military stockpiled vast amounts of this drug, and handed it out to soldiers before battles.
What it does: Physically, the drug often increases heart rate, raises body temperature, and causes tremors or twitching. Psychologically, it creates euphoria and aids concentration – especially on menial and repetitive tasks – increases libido, and raises self-confidence and feelings of power. Higher and/or repeated doses can lead to dermatillomania (compulsive skin picking), hallucinations, paranoia, and sometimes even psychosis. Depending on the dose, effects can last from 3 to 12 hours. This drug is highly addictive, and many former users experience anhedonia (inability to feel pleasure).
How it does this: Methamphetamine causes the norepinephrine, dopamine, and serotonin (5HT) transporters to reverse their direction of flow, leading to a release of these neurotransmitters into the synaptic cleft. The drug also indirectly prevents the reuptake of these neurotransmitters, causing them to remain available for a prolonged period. This leads to feelings of euphoria and reward – and, over time, also contributes to paranoia and addiction.


What it is: A chemical first synthesized from the opioid drug morphine by C. R. Alder Wright in 1874. The usage of opium dates back at least to the third millennium BCE, if not earlier.
What it does: Because heroin is essentially a concentrated form of morphine, which in turn is essentially a concentrated form of opium, this entry will deal with the similar effects of these three related drugs. Users of all three report an intense “rush,” and an acute, transcendent state of euphoria. Many users also report anesthetic and analgesic effects. Depending on the dose and the method of administration, effects may last from 30 minutes to 3 hours. This drug is highly addictive – withdrawal symptoms include dysphoria (feelings of displeasure), anxiety, nausea, diarrhea, fever, restlessness, and insomnia.
How it does this: When taken orally, heroin is metabolized in the digestive tract, delivering morphine to the body and brain. When injected, the drug quickly crosses the blood-brain barrier and is converted into morphine there. In either case, morphine binds to μ-opioid receptors, creating euphoria, analgesia, and anti-anxiety effects. It also stimulates histamine release, leading to a “body high” for many users.

…and there you have it. I’ll do my best to keep updating, refining, and adding to this over time; but for now, I just wanted to make sure it’s available.


1. For all these drugs, I’m going to provide the “real” name, and the most common “unofficial” name. Every drug is known by loads of other slang terms, and more are being coined all the time. My goal isn’t to list them, but simply to make it clear what drug I’m talking about.

Pain on the Brain

Men and women experience pain in different ways, a new study shows.

"Aaaagh, my KORs are killing me!"

The behavior of opioids – chemicals that suppress pain – differs between men’s and women’s bodies. This is because the three main types of opioid receptors in the brain and spinal cord interact very differently, depending on whether their owner is a man or a woman.

See, scientists have known for years that certain kinds of narcotic analgesics – a certain class of pain relieving drugs – are much more effective on women then on men. It was hard to understand why, though, because both men and women have mu (MOR), delta (DOR), and kappa (KOR) opiate receptors – the three main kinds – and these receptors work in essentially the same way in either gender.

But now, scientists have found that the spinal cords of female animals have almost five times as many kappa-mu heterodimers – complex molecules formed by combining KORs and MORs (commonly called KOR/MOR heterodimers) – as those of males. And not only that – the number of KOR/MOR heterodimers climbs four times higher when a woman’s body is pumping with estrogen and progesterone – two hormones crucial for regulating female body chemistry:

Spinal synthesis of estrogen is critical to the processes [of forming and using KOR/MOR heterodimers], and blockade of either estrogen receptor (ER) α-, β-, or G-protein-coupled ER1 or progesterone receptor (PR) substantially reduces KOR/MOR and eliminates mediation by KOR of spinal morphine antinociception.

In other words, a squirt of estrogen causes a sharp increase in the number of KOR and MOR receptors that get formed. This is a Big Deal, because some previous research suggests that in men, KORs and the chemicals that activate them may actually promote pain – and that their attachment to a MOR converts them to part of a pain-relieving system:

The research suggests that kappa-mu opioid receptor heterodimers could function as a molecular switch that shifts the action of kappa-opioid receptors and endogenous chemicals that act on them from pain-promoting to pain-alleviating.

To figure out what was going on with all these receptors, a team led by Alan Gintzler, a SUNY biochemist, first did some research to show that KOR and MOR opioid receptors join to form KOR/MOR heterodimers, the Journal of Neuroscience reports. This research was the first step toward understanding how these receptors interacted in the body’s pain system.

For this new study, though, the scientists injected estrogen and progesterone into the spinal cords of test animals, and determined that both chemicals were critical for the formation or KOR/MOR heterodimers, and these heterodimers’ activity in suppressing pain, as opposed to spreading it.

This discovery could go a long way toward explaining why certain pain-suppressant drugs that target MORs and KORs – such as pentazocine and nalbuphine – work well on women, but poorly on men: in spinal cords that lack the KOR/MOR heterodimer, the drugs might be activating the lonely little KORs, which – without their MOR friends, would help promote pain instead of relieving it. How rude of them.

Anyway, this new data looks like it’ll provide some encouraging ideas for future pain relief research:

The activation of the kappa-opioid receptor within the kappa-mu-opioid receptor complex could provide a mechanism for recruiting the pain-relieving functions of spinal kappa-opioid receptors without also activating their pain-promoting functions.

The researchers also point out that doctors should talk with women about where they are in their menstrual cycle before prescribing them medications like these – when estrogen and progesterone levels drop, pain relievers might turn into pain promoters.

So the moral of the story is, if you’re a guy (or a women who’s low on estrogen), some things really are gonna hurt me more than they hurt you.


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