Drug

A drug (from French drogue "supply") is a chemical substance (other than food) that changes the structure or function of the body of an organism when administered. The United States `Food and Drug Administration`_ considers cosmetics_ containing drug ingredients drugs as well, e.g. an anti-dandruff shampoo, toothpastes with fluoride, deodorants that are also antiperspirants, and sunscreen. [10]

The most widely used drug is caffeine, followed by nicotine_, and alcohol. Other examples of drugs include alclometasone dipropionate, acetaminophen, albuterol_, alprazolam_, amphetamine, `anabolic steroids`_, aspirin, benzodiazepine, bismuth subsalicylate, bupropion, cannabis, cocaine, codeine_, creatine_, dextromethorphan, fluoride, flunitrazepam, guaifenesin, ibuprofen, kava_, ketamine, lysergic acid, MDMA, melatonin, methamphetamine, modafinil, morphine_, opium, ondansetron, prednisone, promethazine, phenylephrine hydrochloride, pseudoephedrine hydrochloride, psilocybin, sildenafil, tretinoin, and `triamcinolone acetonide`_.

There is no simple way to divide chemical substances into drugs and poisons. So many factors influence the action of chemicals and whether or not they will be therapeutic or toxic, including most obviously dosage, that there is no distinction between the sciences of pharmacology and toxicology. [19]

Drugs are studied as part of biochemistry_ and neuroscience_. Pharmacology is the branch of biology specifically concerned with the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function.


The FDA regulates drugs separately from dietary supplements, which refers to vitamin and mineral formulas, and substances derived from herbs, glands, amino acids, and enzymes. Dietary supplements are not intended to treat, diagnose, cure, or alleviate the effects of diseases. Dietary supplements do not have to be proven safe to the FDA's satisfication before they are marketed, nor prove to FDA's satisfaction that claims are accurate or truthful before they appear on the product.

The term "dietary supplement" means a product (other than tobacco) intended to supplement the diet that bears or contains one or more of the following dietary ingredients:

[17]

https://www.cancer.org/treatment/treatments-and-side-effects/complementary-and-alternative-medicine/dietary-supplements/fda-regulations.html

In 1994, the Dietary Supplement Health and Education Act (DSHEA) defined dietary supplements as a category of food, which put them under different regulations than drugs. They are considered safe until proven otherwise.

A dietary supplement is considered “new” if it contains an ingredient not recognized as a food substance, unless it was sold as a supplement before October 1994. If it is new, the manufacturer must provide the FDA with reasonable evidence that the new ingredient is safe before the supplement is marketed to the public.

But manufacturers are not required to test new ingredients or supplements in clinical trials, which would help find risks and potential interactions with drugs or other substances. The DSHEA gives the FDA permission to stop a company from making a dietary supplement, but only when the FDA proves that the product poses a significant risk to the health of Americans. This means they are found unsafe only after they cause harm. This is the reverse of the way prescription and non-prescription drugs are handled.

Products like herbs are sometimes tainted with germs, pesticides, or toxic heavy metals. Other supplements do not contain what’s listed on the label. Still others contain more or less than the amount of the herb listed on the label. And many have ingredients that aren’t listed on the label at all.

This problem extends beyond the supplement makers and sellers. Some herbal suppliers (those who grow, harvest, or sell the crops) may mix or even substitute their crops with less expensive or more readily available plants. There’s also the problem of accidental contamination, when one plant grows in with others, as well as cases of mistaken identity (when one plant looks like another).

In 2013 researchers in Toronto published a report in which they sampled and analyzed 44 herbal supplements. The supplements were sold in both the US and Canada, and labeled as containing single herbs. Using DNA bar coding analysis, less than half the supplements (48%) contained any of the herb listed on the label. More than half of the supplements contained something that wasn’t on the label (substitutions or fillers). Even among the samples that contained the herb on the label, many also contained fillers or contaminants.

A more serious trend today is extra ingredients in supplements. Some “herbal” supplements have been found to contain prescription drugs or other compounds that are not listed on their labels.

There are also times that new ingredients with little-known effects are slipped into supplements. In one situation, supplements were labeled as being made from geranium but turned out to contain the stimulant drug dimethylamylamine (DMAA). This type of supplement was sold as a “natural stimulant,” but it contained DMAA, a man-made drug. The DMAA-containing supplements were exposed after some serious events, including several deaths, leading the FDA to send warning letters to US manufacturers in 2013.

.

Federal law does not require dietary supplements to be proven safe to FDA's satisfaction before they are marketed.

For most claims made in the labeling of dietary supplements, the law does not require the manufacturer or seller to prove to FDA's satisfaction that the claim is accurate or truthful before it appears on the product.

In general, FDA's role with a dietary supplement product begins after the product enters the marketplace. That is usually the agency's first opportunity to take action against a product that presents a significant or unreasonable risk of illness or injury, or that is otherwise adulterated or misbranded.

Dietary supplement advertising, including ads broadcast on radio and television, falls under the jurisdiction of the Federal Trade Commission.

It is not legal to market a dietary supplement product as a treatment or cure for a specific disease, or to alleviate the symptoms of a disease.

Many dietary supplements have clean safety histories. For example, millions of Americans responsibly consume multi-vitamins and experience no ill effects.

Some supplements have had to be recalled because of proven or potential harmful effects. Reasons for these recalls include

microbiological, pesticide, and heavy metal contamination

absence of a dietary ingredient claimed to be in the product

the presence of more or less than the amount of the dietary ingredient claimed on the label

In addition, unscrupulous manufacturers have tried to sell bogus products that should not be on the market at all.

[18]

Contents

1   Function

An effect is a change in the structure or function of the body of an organism. Most drugs induce multiple behavioral and physiologic effects. Some effects are desirable, some are neutral, and some are adverse. Effects which are desirable are called therapeutic effects. An adverse effect refers to harmful or undesired responses. What constitutes a therapeutic or adverse effect depends on the goal of treatment. A side effect is any effect, whether therapeutic or adverse, that is unintended.

People administer drugs to induce certain effects. Effects include:

The exact effects that ingesting a chemical substance will cause depend on four sets of factors: 1) the subject, 2) the substance, 3) external conditions e.g. the method of administration, the presence of sunlight, meteorlogical conditions and 4) time. [19]

The action of chemicals in part depends on features of the subject. Some example:

The action of chemical in parts also depends on the substance itself.

2   Mechanism of action

Most drugs are administered orally. They are absorbed by the `gastrointestinal tract`_ into the blood. Drugs which affect the brain must cross the blood-brain barrier. Drugs have a half-life which causes their effects to end?

Most drugs achieve their effects by binding to or blocking `receptor proteins`_ for certain hormones or neurotransmitters. A chemical that binds to a receptor is called a receptor agonist. A chemical that blocks a receptor is called a receptor antagonist.

3   Properties

Potency.

Selectivity. Drugs that are not selective usually have undesirable side effects. For example, first-generation antihistamines were not selective, and would cause sedation.

4   Classification

There are multiple ways to classify drugs:

4.1   By use

Drugs can be classified by how people use them.

What about when people are addicted?

4.1.1   Doping agents

In 1962, the International Olympic Committee listed caffeine as a "doping agent". Removed in 1972, then re-added in 1984.

4.1.2   Nootropic

A nootropic (from Greek nous "mind") is a chemical substance that may improves performance on cognitive tasks. For example, Adderall, caffeine, methamphetamine, methylphenidate_ (Ritalin), modafinil, or piracetam_.

The word "nootropic" was coined in 1972 by Romanian psychologist and chemist, Corneliu E. Giurgea, from the Greek words nous "mind" and trepein meaning "to bend or turn".

Nootropics are thought to work by modulating neuronal metabolism, cerebral oxygenation, neurotransmitter availability, increasing neurotrophic factors and by affecting other cellular processes. The exact mechanism of action will depend on the compound.

Some substances are unclear if they actually do anything: L-theanine, taurine.

Ritalin increases focus and energy through inhibiting the re-uptake of both dopamine and norepinephrine in the brain. These neurotransmitters then remain in the synapse longer, and their effects are felt in the form of heightened focus and awareness. Adderall, however, works via a slightly different mechanism. While it's postulated that Adderall also inhibits the re-uptake of these same neurotransmitters, amphetamines also trigger the release of dopamine. This affects the brain's reward mechanisms, so it's not only easier to focus on mundane or repetitive tasks, it can also feel positively delightful to do so. [8]

4.2   By therapeutic effect

Drugs can be grouped by therapeutic effect resulting in roughly eighty groups. A subset are presented here.

Analgesics

An analgesic (= painkiller; from Greek an- "without" + algos "pain") is any member of the group of drugs used to relieve pain without causing loss of consciousness. For example, acetaminophen, aspirin, ibuprofen, and morphine_.

The two main categories of commonly used pain relievers (analgesics) are acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs), which include aspirin and drugs known as COX-2 inhibitors. [22] NSAIDs ease pain, lower fever, and turn down inflammation. They can be very helpful for pain arising from inflammation-related conditions such as arthritis. Acetaminophen eases pain and fever, but does not affect inflammation. [22]

NSAIDs include aspirin, ibuprofen, and naproxen (Aleve). [22]

NSAIDs treat inflammation by blocking the production of prostaglandins_. This can have the side effect of disrupting the upper digestive tract, which may upset stomach or heart burn.

"Ibuprofen s considered a nonselective NSAID because it blocks both COX-2 enzymes (involved in pain signaling and inflammation) and COX-1 enzymes (associated with a protective effect on stomach lining)."

Because all pain medications have side effects, they should be taken at the lowest effective dose for the shortest possible time.

Anesthetic
Causes loss of sensation. Examples include lidocaine_ and procaine_.
Antacids
Neutralize stomach acid. Examples include bismuth subsalicylate (Pepto-Bismol), `calcium carbonate`_ (Tums), and Alka-Seltzer (combination of aspirin, `sodium bicarbonate`_, and `citric acid`_).
Anxiolytics
Inhibit anxiety. For example, alprazolam_ and other benzodiazepine tranquilizers.
Antibiotics
Destroy or inhibit growth of microorganisms. Examples include penicillin_.
Anticoagulants
Prevent blood from clotting.
Antidepressants
Prevent or relieve symptoms of depression. For example, escitalpram_, fluoxetine_, and sertraline_. Possibly ketamine and psilocybin.
Antidotes
Counteract poisons and their effects. Examples include naloxone_ (antidote of opioids).
Antifungals
Kill or inhibit growth of fungi_.
Antihistamines
An antihistamine (from anti- + "amine produced by the decomposition of histidine") is a drug that prevents the action of histamine, thereby suppressing allergies. Many antihistamines are also sedative. Examples include cetirizine, diphenhydramine hydrochloride, fexofenadine, loratadine, and promethazine.
Anti-inflammatory
Prevent inflammation_. For example, aspirin and ibuprofen.
Anti-impotence
Treat `erectile dysfunction`_. For example, sildenafil.
Antitussive
Prevent or relieve cough. Includes codeine_, dextromethorphan, and guaifenesin.
Aphrodisiacs
Increase libido. For example, amphetamine.
Contraceptives
Prevent conception.
Corticosteroids

Prevent normal immune response. Includes prednisone.

The topical corticosteroids constitute a class of primary synthetic steroids used as an anti-inflammatory and anti-pruritic agents. Topical corticosteroids share anti-inflammatory and anti-pruritic and vasoconstrictive actions. The mechanism of the topical corticosteroids is unclear. Various laboratory methods include vasoconstrictor assays are used to compare and predict potencies and clinical efficacies of the topical corticosteroids.

The extent of percutaneous absorption of topical corticosteroids is determined by many factors including the vehicle, the integrity of the epidermal barrier, and the use of occlusive dressing.

Topical corticosteroids can be absorbed from normal intact skin. Inflammation and/or other disease processes in the skin increase percutaneous absorption.

Occlusive dressing substantially increase the percutaneous absorption of topical corticosteroids.

Once absorbed through the skin, topical corticosteroids are handled through pharmacokinetic pathways similar to systematically administered corticosteroid. Corticosteroids are bound to plasma proteins in varying degrees. Corticosteroids are metabolized primarily in the liver and are then excreted by the kidneys. Some of the topical corticosteroids and their metabolites are also excreted into the bile.

Decongestants
Reduce nasal congestion and or swelling. Includes pseudoephedrine hydrochloride.
Diuretics
Increase the excretion of urine_. For example, caffeine.
Expectorants
Facilitates the remove of mucous_. Includes guaifenesin.
Euphoriants
Includes amphetamine.
Hypnotics
A hypnotic (from Greek Hypnos "sleep") (= soporific = "sleeping pills") is a `psychoactive drug`_ that initiates, sustain, or lengthens sleep. For example, Ambien_, Lunesta_, diphenhydramine_, doxepin, lorazepam, melatonin, temazepam.
Immunosupressants
Prevent rejection of transplanted organs.
Laxatives
Relieve constipation_. For example, caffeine.
Muscle relaxants
Relax skeletal muscle.
Weight control
pass

4.3   By action location

4.3.1   Nervous system

static/images/nootropics_overview.gif

A psychoactive drug is a drug that affects the function of the central nervous system, altering perception, mood, consciousness, cognition, or behavior. These drugs are broadly divided into stimulants, depressants, antidepressants, and hallucinogens.

4.3.1.1   Stimulants

A stimulant is a drug that increases the activity of specific neurotransmitters. Stimulants include amphetamine (and MDMA), caffeine, cocaine, nicotine_, pseudoephedrine_.

4.3.1.2   Depressants

A depressant (= "downer") is a drug that lowers the activity of specific neurotransmitters. Depressants are further classified as hypnotics_, opioids, and sedatives.

4.3.1.2.1   Opioids

An opioid (1957, from "opium" + -oid meaning "opiate-like") is a substance, either natural or synthetic, that binds to opioid receptors within nerve cells to produce euphoria_ and reduce pain. Examples of opioids include codeine_, fentanyl_, heroin_, and morphine_.

The medical community uses opioids to treat pain.

Opioids can be classified by source as endogenous (endorphins, enkephalins, dynorphins), opium alkaloids (morphine, codeine), semisynthetic (oxycodone), or synthetic (methadone, fentanyl).

The euphoria makes them more addictive than painkillers?

Opioids can cause fatal overdoses when combined with other sedatives. [11] Overdose can be reversed by agents such as naloxone_. [11]

The poppy Papaver somniferum is the source for all natural opioids.

4.3.1.2.2   Sedatives

A sedative (= tranquilizer) is a drug that reduces irritability or excitement. For example, alcohol and ketamine.

4.3.1.3   Antidepressants

An antidepressant is a drug that treats depression.

Antidepressants can be classified by mechanism of action into SSRIs and SNRIs. SSRIs are more common.

A selective serotonin reuptake inhibitor (SSRI) is a drug that ... SSRIS are prescribed to people who have depression. This include escitalpram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), Clexa (citalopram), Cymbalta, and Luvox (fluvoxamine).

SSRIs work by increasing the neurotransmitter serotonin in your brain. This has the side effect of decreasing libido.

Increasing the amount?

For men, SSRIs more often affect libido and orgasm rather than actual performance, says Sadock. So you'll probably get an erection just fine, but it takes forever to orgasm — or you can't finish at all. Some may also experience erectile dysfunction, though that's a less common side effect.

The complicating thing here is that depression also affects libido and depresses it. It's important to look at what your sex drive was like before your symptoms hit, what it was like when you were experiencing symptoms, and what it's like now that you're taking medication.

Even leaving aside withdrawal effects, there is now a large pile of evidence suggesting—in line with those early studies of the ineffectiveness of Prozac and Paxil—that SSRIs may not work terribly well. In January 2010, almost exactly 20 years after hailing the arrival of SSRIs with its cover story “Prozac: A Breakthrough Drug for Depression,” Newsweek published a cover story about the growing number of studies that suggested these and other antidepressants are barely more effective than sugar pills. A large-scale study from 2006 showed that only about a third of patients improved dramatically after a first cycle of treatment with antidepressants. Even after three additional cycles, almost a third of patients who remained in the study had not reached remission. After reviewing a host of studies on antidepressant effectiveness, a paper in the British Medical Journal concluded that drugs in the SSRI class—including Prozac, Zoloft, and Paxil—“do not have a clinically meaningful advantage over placebo.” [2]

A serotonin and norepinephrine reuptake inhibitors (SNRI) is ...

5   Substance

Features:

5.1   Composition

An active ingredient is the ingredient in a drug that is biologically active. Some products may contain more than one active ingredient.

6   List

This section lists drugs by alphabetical order. This is simplest given there are multiple ways to build taxonomies of drugs, and some drugs fit into multiple categories.

6.1   Acetaminophen

Brand names:Tylenol

Treats pain and fever. It is the most commonly used medication for pain and fever in both the United States and Europe.

  • Can help with the pain from inflammation (e.g. that caused by arthritis_) but it does not treat the inflammation itself. Best for other types of pain such as a headaches.
  • Acetaminophen reduces fever via the hypothalamus_.
  • Should never be taken when consuming alcohol.
  • Taking large amounts or small amounts over a long period of time can damage the liver_.

6.2   Adderall

Aderall ("A.D.D. for All" [6]) is a brand name for a mixture of amphetamine salts. The active ingredients are 75% dextroamphetamine and 25% levoamphetamine. Adderall is a stimulant that increases the activity of the neurotransmitters norepinephrine and dopamine.

The United States classifies adderall as a Schedule II substance. The FDA approved Adderall for the treatment of `Attention Deficit Hyperactivity Disorder`_ and narcolepsy in 1996. It is only available by prescription.

static/images/Adderall_XR_pills.jpg

Adderal XR capsules.

Adderall XR is formatted in a capsule form containing pellets. Half of the pellets are immediate-release and half of them are delayed-release. [4]

Adderall comes in two forms: Adderall Instant Release (Adderall IR) and Adderall Extended Release (Adderall XR). Adderall XR was launched in 2001.

By comparison, the immediate-release pellets are comprised of a bead in the center of a drug layer, followed by an overcoating. The delayed-release pellets are comprised of a bead in the center of a drug layer, with an overcoating covered in a release-delaying polymer, covered with a second overcoating. [4]

The combination of immediate and delayed release pellets results in a bimodal distribution of effect that could be achieved by simply taking 2 properly-timed immediate-release tablets. For the sake of convenience, many people like the Adderall XR format. However, if you don’t always need a “second wind” after your first 4 to 6 hours, Adderall IR may be preferred. [4]

Adderall is manufactured in six dosage options ranging from 5 mg to 30 mg.

The effects of Adderall IR last 4 to 6 hours. The effects of Adderall XR last up to 12 hours, nearly twice as long. Therefore, Adderall IR users must take twice as many pills for the same effect. And Adderall XR users typically take doses twice as large as Adderall IR users since the dose is spread out over more time.


.

Think about how wasteful all of this is. We throw people in jail for using Adderall without a prescription. We expel them from colleges. We fight an expensive and bloody War on Drugs to prevent non-prescription-holders from getting Adderall. We create a system in which poor people need to stretch their limited resources to make it to a psychiatrist so they can be prescribed Adderall, in which people without health insurance can never get it at all, in which DEA agents occasionally bust down the doors of medical practices giving out Adderall illegally. All to preserve a sham in which psychiatrists ask their patients “Do you have ADD symptoms?” and the patients say “Oh, yeah, definitely,” and then the psychiatrists give them Adderall. It’s like adding twenty layers of super-reinforced concrete to a bunker with a wide-open front door.

Trying to discover the risks of Adderall is a kind of ridiculous journey. It’s ridiculous because there are two equal and opposite agendas at work. The first agenda tries to scare college kids away from abusing Adderall as a study drug by emphasizing that it’s terrifying and will definitely kill you. The second agenda tries to encourage parents to get their kids treated for ADHD by insisting Adderall is completely safe and anyone saying otherwise is an irresponsible fearmonger. The difference between these two situations is supposed to be whether you have a doctor’s prescription. But what if you are the doctor, trying to decide who to prescribe it to? Then what? All they tell you in medical school is to give it to the people who actually have ADHD – which, I repeat, is kind of meaningless.

Concerns about side effects that permanent and dangerous. How common are they?

The best source for exact numbers is the guidelines by sinister-sounding European organization EUNETHYDIS. I’ll use US medical database UpToDate as a secondary source. Both lump together Adderall and Ritalin – something I’ll be doing too throughout most of this essay, except where it becomes important to distinguish them.

Seizures

EUNETHYDIS doesn’t believe this happens at normal doses. They write:

There are occasionally concerns that, as with other psychotropics, ADHD medications may lower the seizure threshold so as to cause seizures in previously seizure-free individuals. However, in prospective trials, retrospective cohort studies and post-marketing surveillance in ADHD patients without epilepsies, the incidence of seizures did not differ between ADHD pharmacotherapy and placebo [relative risk (RR)] for current versus non-use for methylphenidate, 0.8; RR for atomoxetine, 1.1

Hypertension

Broad agreement from both sources that stimulants cause hypertension. EUNETHYDIS says 1-4 mm systolic, UpToDate says 3-8 mm.

The main problem with hypertension is that it increases risk for things like heart attacks. I calculated an average 40 year old’s risk of heart attack and got 1% over 10 years. Adding on an average Adderall-related increase in blood pressure, I got 1.1%.

Heart Attack and Stoke
The main problem with hypertension is that it increases risk for things like heart attacks. I calculated an average 40 year old’s risk of heart attack and got 1% over 10 years. Adding on an average Adderall-related increase in blood pressure, I got 1.1%.
Psychosis

I saw this a lot when I worked in inpatient. Somebody would take five times the recommended dose, or take more Adderall every time they felt tired until they hadn’t slept for a week, and then they would start hearing voices or feeling like something was crawling on their skin. After a day or two off Adderall, and a night or two getting a normal amount of sleep, they’d be fine. Take enough stimulants and you will become psychotic – but it’s rare on prescribed doses, and it usually resolves pretty quickly.

What dose can cause psychosis? Amphetamine-Induced Psychosis says:

Early studies demonstrated that amphetamines could trigger acute psychosis in healthy subjects. In these studies, amphetamine was given in consecutively higher doses until psychosis was precipitated, often after 100–300 mg of amphetamine. The symptoms subsided within 6 days.

Compare this to the standard daily dose of Adderall of about 10 – 60 mg.

Can psychosis ever happen at normal doses? EUNETHYDIS is skeptical. They write:

Data from population-based birth cohorts indicate that self-reported psychotic symptoms are common and may occur in up to 10% of 11-year-old children. In contrast, the prevalence of psychotic symptoms in children treated with ADHD drugs from RCTs is reported as only 0.19%. While this very low observed event rate in trials is likely to reflect a lack of systematic assessment and reporting, there is no compelling evidence to suggest that the observed event rate of psychotic symptoms in children treated with ADHD drugs exceeds the expected (background) rate in the general population. In the US FDA analysis, ADHD drug overdoses did not contribute significantly to reports of psychosis adverse events.
In General

Probably the most informative passage I’ve seen on the medical risks of stimulants is this one from Misuse Of Study Drugs:

In 1990, there were about 271 emergency room reports involving methylphenidate, 1,727 in 1998, and 1,478 in 2001 [32]. The total number of emergency department visits resulting from use of all psychotherapeutic CNS stimulants was 4091 in 1998, 3644 in 1999, 3336, in 2000, 3146 in 2001 and 3275 in 2002 [33]. There are approximately 25 emergency room deaths per year among up to 3 million users of prescription stimulant drugs (including both those medically prescribed and not prescribed these drugs). Thus, the likelihood of dying from such drugs appears to be approximately 1 in 120,000.

Here’s another passage from the same source:

Intravenous use of prescription stimulants is particularly dangerous. In particular, intravenous (IV) abuse of methylphenidate may result in talcosis. Talcosis is a reaction to talc, a filler and lubricant in methylphenidate and other oral medication. This inflammation reaction occurs in the lungs and related consequences include lower lobe panacinar emphysema.

People aren’t dying because their psychiatrist gave them Adderall 10 mg bid. They’re dying because they ground it up, injected it into their bloodstream, and had their lungs turn into talc. The people dying of stimulant use are doing things so horrifying you could not possibly imagine them even if you took ten times your prescribed dose of Adderall and used all of it to focus on writing a report on the most horrifying ways you could possibly use Adderall.

Scott doesn't have data about addiction, but is skeptical.

I don’t think there are good data here, but my intuitions and personal experience is that “addiction” of the sort you get with heroin or tobacco is very rare, at least when responsible people without a personal or family history of addictive behavior take stimulants as prescribed. Most people agree the risk is lower for extended-release stimulants (eg Adderall XR), and very low for Vyvanse.

Tolerance

Tolerance is when you keep needing more and more of a drug to get an effect. In the worst cases, your baseline changes so that you need the drug to feel normal. The concern is that long-term use of Adderall will make your attention naturally worse, so that medicated-you is only as good at concentrating as unmedicated-you was before, and unmedicated-you is even less attentive.

We know tolerance occurs over the short-term, and we encourage patients to take a few days off Adderall every week or two to let their bodies reset. More concerning is whether it happens over the space of years, where people’s bodies adjust in a more permanent way.

For the first year, the kids getting stimulants did much better on all metrics than behavioral-therapy-only. For the second year, they did a little better. By the third year, they were the same. In the eighth year, which was as long as anyone kept checking, they were still the same.

This is pretty concerning. It sounds like over three years people’s bodies built up some tolerance to stimulants, after which they provided no further benefit. The only saving grace is that there’s no evidence of stimulants ever making people worse than normal (even on people who stopped the medications later).

People have critiqued this study on the grounds that although they started off giving the experimental group stimulants vs. the control group behavioral therapy, any patient could switch treatments at any time and many of them did. By year three when the groups equalized, only 66% of the medication group was on medication, and a full 43% of the therapy-only group was. So maybe this just drowned out any original effect?

The authors of the study are not convinced:

It is tempting to conclude that intensive medication management beyond 14-months could have resulted in continued differences between the randomly assigned treatment groups…In a previous multimodal treatment study where medication was carefully titrated and monitored for two years, treatment gains were maintained for the entire period. However, after 14 months the MTA became an uncontrolled naturalistic follow-up study and inferences about potential advantages that might have occurred with continued long-term study-provided treatment are speculation. Moreover, with one exception (math achievement), children still taking medication by 6 and 8 years fared no better than their non-medicated counterparts despite a 41% increase in the average total daily dose, failing to support continued medication treatment as salutary (at least, continued medication treatment as monitored by community practitioners)…Finally, a previous analysis of the MTA data through 3 years did not provide evidence that subject selection biases towards medication use in the follow-up period accounted for the observed lack of differential treatment effects.

Thus, although the MTA data provided strong support for the acute reduction of symptoms with intensive medication management, these long-term follow-up data fail to provide support for long-term advantage of medication treatment beyond two years for the majority of children—at least as medication is monitored in community settings.

As far as I can tell, pretty much everyone has ignored this, using the usual range of meaningless excuses like “Well, treatment must be individualized to the patient”.

So: there’s no good evidence that taking Adderall will actively make your ADHD worse in the long run. There is good evidence from clinical trials that benefits will decrease to zero over the space of a few years, apparently contradicted by the personal experiences of doctors and patients. Overall not sure what to do with this one.

6.2.1   Crashes

Some users of Adderall experience a physical and mental "crash" after the effects wear off.

6.2.2   History

Roger Griggs introduced Adderall in 1994. [6]

Modern marketing of stimulants began with the name Adderall itself. Mr. Griggs bought a small pharmaceutical company that produced a weight-loss pill named Obetrol. Suspecting that it might treat a relatively unappreciated condition then called attention deficit disorder, and found in about 3 to 5 percent of children, he took “A.D.D.” and fiddled with snappy suffixes. [6]

Richwood Pharmaceuticals first got its patent in 1996. Adderall has been on the market since 1996.

Generic pills cost $25 to $40 for 30 pills (roughly $1/pill).

6.3   Albuterol sulfate

Brand name:Ventolin

Albuterol is a bronchodilator. It helps open up the airways in the lungs. It is used to treat bronchospasm_.

Oral inhalation for treating asthma.

6.4   Alclometasone dipropionate

Skin cream for treating facial eczema.

6.5   Amphetamine

Effects:Wakefulness, suppressed appetite, aphrodesiac, euphoriant, improved cognition, enhanced athletic performance :Medical uses: Treats ADHD, narcolepsy, and obesity_

Amphetamine (a contraction of alphamethyl-phenethylamine) refers to two enantiomers_, levoamphetamine and dextroamphetamine, in any combination.

Amphetamine stimulates the central nervous system.

Adderall works by stimulating the release of dopamine and related neurotransmitters. Their effect is to activate the brain's reward system, which is the mechanism responsible for making you want to keep doing whatever it is that you're doing. The reward system is normally activated by actions which we have evolved to instinctual recognize as advantageous: eating, drinking, fucking, taking care of your kids.

Adderall and amphetamines in general) forces the reward system to activate on command, making you interested in any arbitrary activity. In other words, it hacks your brain chemistry to make you want to perform any arbitrary task, giving you artificial discipline. The effect is potent and general: the task doesn't have to be actually useful or sensible for you to want to do it, on Adderall; amphetamine users could be put to digging a trench and they'd work away at it as if that were the most interesting project they've ever worked at.

Don't know if this is credible:

In 2015, a systematic review and a meta-analysis of clinical trials found that when used at low (therapeutic doses), amphetamine produces modest yet unambiguous improvements in cognition, including working memory, long-term episodic memory, inhibitory control, and some aspects of attention, in normal healthy adults.

-- Wikipedia

It is a `prescription drug`_ in many countries due to the significant health risks associated with recreational use. Addiction is a serious risk with heavy recreational use, but is unlikely to occur from long-term medical use at therapeutic doses. Very high doses can result in psychosis_.

6.5.1   Effects

6.5.1.1   Cognition

It would be another few years before studies appeared showing that Adderall’s effect on cognitive enhancement is more than a little ambiguous. Martha Farah, a cognitive neuroscientist at the University of Pennsylvania, has conducted much of this research. She has studied the effect of Adderall on subjects taking a host of standardized tests that measure restraint, memory and creativity. On balance, Farah and others have found very little to no improvement when their research subjects confront these tests on Adderall. Ultimately, she says, it is possible that “lower-performing people actually do improve on the drug, and higher-performing people show no improvement or actually get worse.” [7]

6.5.2   Methamphetamine

Methamphetamine (= "meth" = "crystal meth" = "speed") is a form of amphetamine that has similar effects to amphetamine, but is both more dangerous and easier to manufacture.

Methamphetamine was the subject of `Breaking Bad`_.

6.5.3   History

Amphetamine was first synthesized in 1887 in Germany by Romanian chemist Lazar

Edeleanu. Its stimulant effects unknown until 1927 when it was independently re-synthesized by Gordon Alles. Amphetamine had no medical use until late 1933 when `Smith, Line, and French`_ began selling it as an inhaler under the brand name Benzedrine as a decongestant.

During World War II, amphetamine and methamphetamine were used extensively by both the Allied and Axis forces for their stimulant and performance-enhancing effects.

As the addictive properties of the drug became known, governments began to place strict controls on the sale of amphetamine. During the early 1970s in the United States, amphetamine became a schedule II controlled substance under the Controlled Substances Act.

Many famous people have used amphetamines.

  • `Paul Erdos`_, one of the most prolific mathematicians in history. Erdos began using them at age 58, when a doctor prescribed them to him to ally the depression with his mother's death. A friend once challenged Erdos a $500 wager to see if Erdos could abstain for 30 days. Erdos won, but complained "Mathematics was set back a month".
  • Jack Kerouac.

Adderall as we know it today owes its origins to accident. In the late 1920s, an American chemist named Gordon Alles, searching for a treatment for asthma, synthesized a substance related to adrenaline, which was known to aid bronchial relaxation. Alles had created beta-phenyl-isopropylamine, the chemical now known as amphetamine. Injecting himself to test the results, he noted a “feeling of well being,” followed by a “rather sleepless night,” according to “On Speed: The Many Lives of Amphetamine,” by Nicolas Rasmussen. By the 1930s, the drug Benzedrine, a brand-name amphetamine, was being taken to elevate mood, boost energy and increase vigilance. The American military dispensed Benzedrine tablets, also known as “go pills,” to soldiers during World War II. After the war, with slight modification, an amphetamine called Dexedrine was prescribed to treat depression. Many people, especially women, loved amphetamines for their appetite-suppressing side effects and took them to stay thin, often in the form of the diet drug Obetrol. But in the early 1970s, with around 10 million adults using amphetamines, the Food and Drug Administration stepped in with strict regulations, and the drug fell out of such common use. More than 20 years later, a pharmaceutical executive named Roger Griggs thought to revisit the now largely forgotten Obetrol. Tweaking the formula, he named it Adderall and brought it to market aimed at the millions of children and teenagers who doctors said had A.D.H.D. A time-release version of Adderall came out a few years later, which prolonged the delivery of the drug to the bloodstream and which was said to be less addictive — and therefore easier to walk away from. In theory. [7]

6.6   Aspirin

Aspirin, also known as acetylsalicylic acid (ASA), is a medication used to treat pain, fever, or inflammation. It is a `nonsteroidal anti-inflammatory drugs`_ (NSAID) similar to ibuprofen. Unlike acetaminophen, it treats inflammation.

6.7   Beclomethasone dipropionate

Brand names:QVAR

Beclomethasone dipropionate is a drug used as a maintenance treatment for the prevention and control of asthma. QVAR is an inhaled corticosteroid_. medicine.

QVAR comes in two strengths: 40 and 80 mcg.

Rinse your mouth with water without swallowing after each dose. This will help lessen the chance of getting a yeast infection in your mouth and throat.

6.8   Benzodiazepine

Brand names:Xanax, Valium

Benzodiazepine is a class of psychoactive drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. They function as a tranquilizer_, and have sedative, hypnotic, and anxiolytic effects.

Benzodiazepine stimulates `gamma-aminobutyric acid`_ receptors.

6.9   Bismuth subsalicylate

Bismuth subsalicylate, sold under the brand name Pepto-Bismol, is an antacid_ medication.

6.10   Bupropion

Bupropion is a drug used to treat anxiety and depression.

6.11   Caffeine

Discovery:1820
Effects:appetite suppressant, anxiety, diuretic, laxative, vasoconstriction, wakefulness, increased heartbeat, stimulates respiration
static/images/caffeine.jpg

A caffeine molecule under a microscope.

Caffeine (from French cafe "coffee") is a drug. Its effects are biphasic, first behaving as a stimulant and then as a depressant_. Many people use caffeine as a nootropic.

Caffeine is the most widely consumed psychoactive substance in history. [23]

6.11.1   Effects

  • Caffeine increases physical endurance. In Tibet, horses and mules working at high elevations are often given large vessels of tea to increase capacity for work.

    It is well known that caffeine increases performance for running and cycling.

  • Increase sleep latency and reduces duration and quality of sleep.

  • May improve cognition

    So the Trust Me team asked Professor Peter Rogers of Bristol University to put caffeine to the test. He recruited a group of 20 people, 10 of whom never normally touch caffeine. The other 10, regular caffeine imbibers, were asked to turn up for testing having abstained for at least 12 hours.

    Both groups were measured for mental agility, concentration and dexterity. Then they got a drink with a good jolt of caffeine in it. I found the results surprising, not to mention disappointing.

    "Overall, regular caffeine consumers who'd been without caffeine overnight, were slower on the reaction time task, were sleepier and were less mentally alert than non-users," Professor Rogers said.

    They did improve after they got a caffeine drink, but only up to the level the non-users had achieved without caffeine.

    When the non-users were given caffeine to drink their reaction times increased but they also became more jittery and anxious.

    Professor Rogers says that, contrary to what most people believe, drinking lots of coffee on a regular basis won't enhance your mental performance. Part of the problem with caffeine is we quickly develop dependency.

6.11.2   Mechanism of action

Caffeine is a receptors antagonist for adenosine. The body adapts by increasing the total number of adenosine receptors, which causes tolerance to develop over time.

Does blocking adenosine just postpone the effects (ie, just letting the adenosine buildup)? Or when caffeine binds to a receptor, does it actually "knock that one out"?

Drinking caffeine triggers the release of adrenaline.

6.11.3   Structure

static/images/caffeine_molecule.png

Structurally, caffeine is a purine_, an organic compound built around a basic structure of two interconnected "rings" of alternating carbon and nitrogen atoms. More specifically, caffeine is a xanthine_ in which a pair of oxygen atoms is tightly bound to the hexagonal component of the basic purine ring structure. Xanthines turn up often in vegetable tissues, including seeds and berries. They seem to correspond to uric acid in animals: metabolic end products that play no further active role in the plant's life cycle. But many xanthines become chemically active if ingested by an animal. Some are potent poisons; most are diuretics, encouraging excretion; in higher animals, many also cause temporary relaxation of the circulatory system, lowering blood pressure by enlarging vessel capacity. [11]

6.11.4   Delivery

Caffeine is commonly ingested orally as part of food or drink, but caffeine pills are available as well.

  • A typical cup of coffee contains about 100 milligrams of caffeine. The exact amount varies depending on the origin and composition of blend (i.e. Robusta has twice as much caffeine as Arabica), the method of brewing (drip method (115mg), percolator (80mg), and instant (65mg)), and the amount (per 5oz cup)
  • Tea has more caffeine than coffee by weight, but less weight is used. The amount of caffeine varies based on method and steep time, but is usually less than 60mg.
  • A 12oz soda contains 30-60mg of caffeine
  • A 1-ounce piece of chocolate can be said to have the stimulating power of roughly 40 milligrams of caffeine. (In reality it has only 20, but it has 130mg of theobromine, a weaker stimulant)

6.11.5   Onset & Duration

Caffeine is absorbed by the `small intestine`_ within 45 minutes of ingestion and then distributed throughout all tissues of the body. Peak blood concentration is reached within one hour and remains stable for around 1 hour before gradually clearing in the following 3-4 hours.

The liver_ disposes of caffeine by undoing the steps that led to its formation in plants: methyl groups are plucked off one at a time. This is an important point: depending on _which_ methyl group is removed, caffeine is transformed into theophylline, theobromine, or paraxanthine.

70 percent of a given dose of caffeine is converted to paraxanthine, which is actually slightly more potent than coffee. Exactly how paraxanthine affects the brain is not clear, though it seems to mimic caffeine.

As more methyl groups are removed the chemicals lose their stimulating effects and the products are removed in urine.

Half-life:

  • In healthy adults, caffeine's half-life is approximately 4.9 hours.
  • Heavy cigarette smokers show a decrease in half-life of 30-50%, oral contraceptives can double it, and pregnancy can raise it even more, to as much as 15 hours during the last trimester.
  • In newborn infants the half-life can be 80 hours or more; however it drops very rapidly with age, possibly to less than the adult value by the age of 6 months.

6.11.6   Sources

  • Coffee beans

  • Leaves of tea shrubs

  • Kola nuts

    The word "cola" comes from "kola", the name of the African tree that produces the caffeine-containing seeds from which a flavor extract is made. (Hence "Cola" in "Coca-Cola".) For other soft drinks, much of the caffeine comes from the caffeine extracted from decaffeinated coffees and teas.

  • Yerba mate


Caffeine emerged independently in several parts of the world as a natural insecticide. However, it is likely that it confers additional to the plants that have yet to be discovered.

Caffeine starts out in coffee plants as a precursor compound called xanthosine. The coffee plant makes an enzyme that chops off a dangling arm of atoms from the xanthosine; a second enzyme adds a cluster of atoms at another spot. The plant then uses two additional enzymes to add two additional clusters. Once the process is complete, they’ve turned xanthosine into caffeine. [13]

The caffeine-building enzymes belong to a group of enzymes called N-methyltransferases. They’re found in all plants, and they build a variety of compounds. Many of these molecules serve as weapons against enemies of the plants. Sometimes, those weapons turn out to be valuable to us. Salicylic acid, first discovered in willow trees, became the basis for aspirin, for example. [13]

The evolution of caffeine in coffee started when the gene for an N-methyltransferase mutated, changing how the enzyme behaved. Later, the plants accidentally duplicated the mutated gene, creating new copies. Those copies then mutated into still other forms. [13]

When coffee leaves die and fall to the ground, they contaminate the soil with caffeine, which makes it difficult for other plants to germinate. Coffee may thus use caffeine to kill off the competition. [13]

Coffee plants also use caffeine to ward off insects that would otherwise feast on their leaves and beans. At high doses, caffeine can be toxic to insects. As a result, insects have evolved taste receptors that help them avoid ingesting caffeine. [13]

Coffee and a number of other plants also lace their nectar with low doses of caffeine, and in that form, it seems to benefit the plants in a different way. [13] Plants make nectar to feed insects and other animals so they’ll spread their pollen. When insects feed on caffeine-spiked nectar, they get a beneficial buzz: they become much more likely to remember the scent of the flower. This enhanced memory may make it more likely that the insect will revisit the flower and spread its pollen further. [13]

6.11.7   Interactions

  • For reasons that remain obscure, caffeine significantly increases the analgesic effectiveness of both aspirin and aspirin substitutes. On average, painkillers without caffeine had to be about 40 percent large to obtain the same degree of relief.
  • The antidepressant Fluvoxamine (Luvox) reduces the clearance of caffeine by more than 90%, and prolongs its elimination half-life more than tenfold; from 4.9 hours to 56 hours.

6.12   Cannabis

Effects:Increased appetite, dry mouth ("cotton mouth"), red eyes, paranoia_
Onset:Minutes when smoked, 30-60 minutes when eaten
Duration of effects:2-6 hours

See cannabis.

6.13   Cetirizine

Brand names:Zyrtec
Medical uses:Antihistamine, sedative

6.14   Cocaine

6.14.1   Crack cocaine

Crack cocaine (= crack) is a form of cocaine that offers a short but intense euphoria. It is usually ingested by smoking.

Crack cocaine can be produced from cocaine by combining it with `baking soda`_.

6.15   Dextromethorphan

Cough suppressant. However, controlled studies have found the symptomatic effectiveness of dextromethorphan similar to placebo.

DXM is also used for recreation. When exceeding approved dosages, dextromethorphan acts as a dissociative anesthetic.

6.16   Dicyclomine

Dicyclomine is used to treat irritable bowel syndrome.

6.17   Diphenhydramine hydrochloride

Brand names:Benadryl
Medical uses:Antihistamine, antitussive, sedative

Diphenhydramine is an antihistamine used to treat allergies, insomnia, and symptoms of the common cold. Common side effects include sleepiness.

Because of its sedative properties, diphenhydramine is widely used in sleep aids.

6.19   Fexofenadine

Brand names:Allegra

6.20   Fluticasone Propionate

Fluticasone Propionate is a drug used to treat allergies. Fluticasone propionate is a glucocorticoid_.

A glucocorticoid is a substance produced by the human body to help fight inflammation. GA glucocorticoid is a type of sertoid_.

It works in your nose to relieve your allergy symptoms. Barely any of it travels through your bod.

It is usually delivered as a nasal spray.

Fluticasone propionate acts on multiple inflammatory substances, including histamine, prostaglandins_, cytokines_, typetases_, chemokines_, and leukortienes_. Most common OTC allergy pills act on histamine alone.

Check with a doctor if you need to use it for longer than two months a year.

6.21   Flunitrazepam

Effects:amnesia, drowsiness, slurred speech

Flunitrazepam (= Rohypnol = "roofie") is a tranquilizer drug for treating severe insomnia. It is commonly known as a "date rape" drug.

6.22   Ibuprofen

Brand names:Advil

Treats pain, fever, and inflammation.

6.23   Guaifenesin

Brand names:Mucinex

Expectorant. Thins and loosens mucus in the airways, clearing congestion, and making breathing easier.

6.24   Hydrocortisone

Hydrocortisone is a white crystalline powder. It is used as a topical corticosteroid_ to treat eczema.

6.25   Ketamine

Ketamine is a anesthetic and a popular recreational drug. It may also be an antidepressant. It is also used as a horse tranquilizer. It causes dissociation.

Ketamine can be obtained legally at a ketamine clinic. It is administered through IV.

Esketamine (from "s-ketamine", the "s" being short for Latin sinister "left-handed") is an enantiomer_ of ketamine.

Ketamine can be purchased legally for about $20 per dose. Esketamine costs between $600 and $900 per dose.

The FDA demands two positive studies before they approve a drug, excluding withdrawal studies. For esketamine, the FDA counted a withdrawal study as a positive study. This may be because esketamine is an ineffective antidepressant; it performed worse (smaller MADRS score change) than SSRIs. It may also be that ketamine is more effective than esketamine. [16]

The FDA approved esketamine as a nasal spray. However, it can only be administered at clinics and patients will be disallowed from bringing it home. [16]

6.26   Loratadine

Brand names:Claritin
Medical uses:Antihistamine

Loratadine is an antihistamine. Common side effects include sleepiness, dry mouth, and headache.

6.27   Lorazepam

Lorazepam is a benzodiazepine. It is used to treat anxiety.

6.28   Levonorgestrel

Levonorgestrel is ... 1.5 mg can be used an emergency contraceptive_.

Levonorgestrel works by preventing ovulation (egg release).

6.29   Lysergic acid

Lysergic acid (= LSD = "acid") is ..

LSD was discovered by Albert Hoffman in 1943. In the 1930s, Hoffman was trying to synthesize a compound that could stimulate the circulation and respiration system. He started created combinations of lysergic acid with various substances and eventually created a substance named LSD-25. Hoffman shelved it for lack of interest, only to later revisit it and in the process accidentally absorb it through his fingertips causing severe hallucinations.

6.30   MDMA

3,4-Methylenedioxymethamphetamine (= MDMA = "ecstasy" = "E" = "molly") is a drug that increases energy, empathy, and pleasure.

MDMA is derived from amphetamine, and is chemically related. [9]

MDMA increases the activity of three brain chemicals: dopamine, norepinephrine, and serotonin. [5] If used too often, the brain may lose sensitivity to serotonin and a person will become depressed.

Effects last between 3 and 6 hours. [5]

It is usually manufactured as a color caplet. [5]

Adverse effects include teeth grinding. It sometimes leads to death due to dehydration and interference of the body's ability to regulate temperature. It may also encourage unsafe sexual behavior. Following use, people often feel depressed and tired.

It is often used for recreation at raves.

MDMA causes systematic vasoconstriction, which is hypothesized to cause `erectile dysfunction`_. This can be remedied by using Viagra_.

6.31   Modafinil

Modafinil is a wakefulness drug developed in the 1980s. In the United States, it is a Schedule IV controlled substance, but available by prescription to treat narcolepsy.

The development of Modafinil steps from adrafinil, an over-the-counter wakefulness drug developed back in the 1970s. Inside the body, adrafinil is metabolized by the liver_ into modafinil. Using adrafinil is inferior to using a straight dose of modafinil because it stress the liver, and because you need about 3 times more adrafinil to be metabolized into the same dose of modafinil. [15]

Modafinil is better, but many forms of it are patented and it is a controlled substance in the United States. [15]

According to Gwern, modafinil costs between $2-12 a day. [15]

Modafinil targets different receptors than amphetamines. [15]

Effects:

  • Cuts the need to sleep by about 2/3, or go without sleep for a day with little mental penalty. [15]
  • May enhance cognition, even if you're healthy. [15]

Modafinil is freely available over the counter in various countries (I think Spain and India) and they have yet to collapse into unspeakable wastelands of despair.

It's also worth noting that adrafinil, a prodrug of modafinil which is strictly more dangerous because it contains all the side effects of the latter plus a risk of liver damage, is totally legal without any prescription at all.

Armodafinil is an isomer of modafinil that should do about the same thing but require a lower dose.


Unrelated:

Right now America and to a lesser degree other first-world countries are caught in a trap where almost all of their economic growth is funneled to the rich and upper-middle-class, who spend it on positional goods. Since all the rich people are spending it on positional goods equally, none of their relative position changes in any interesting way and all of the positional goods are useless.

Therefore in the modern era most economic growth in first-world countries is pretty useless as a direct action. There may be useful indirect actions, like advancing technology, increasing tax revenue that can be spent on useful absolute goods, and increasing the amount that flows as charity to the Third World, but the actual direct effect of economic growth is pretty close to zero.

6.32   Ondansetron

Brand names:Zofran
Types:Antiemetic

Ondansetron can prevent nausea and vomiting.

6.33   Opium

During the American Civil War, opium and laudanum were used extensively to treat soldiers.

6.34   Prednisone

Prednisone is used to suppress the `immune system`_ and decrease inflammation_. Has some effect on cortisol.

6.35   Promethazine

Medical uses:Antihistamine, sedative

Promethazine is a antihistamine. Common side effect include sleepiness.

6.37   Pseudoephedrine hydrochloride

Brand names:Sudafed

Nasal decongestant and wakefulness agent.

6.38   Psilocybin

Psilocybin ("magic mushrooms") is ...

People consistently report in these rigorous trials—largely pioneered by Johns Hopkins University—as being more open, compassionate, and at peace following mushroom trips that are supervised by a trained psychotherapist. Investigators have yet to find any substantial health risks to consuming psilocybin either.

6.39   Sildenafil

Brand names:Viagra

Sildenafil is a medication used to treat `erectile dysfunction`_ and hypertension_.

Pfizer originally discovered the medication in 1989 while looking for a treatment for heart-related chest pain. It was approved for medical use in the United States and Europe in 1998. In 2017 it became available as a generic medication. As of 2018 in the United States the wholesale cost is less than US$1 per dose.

After the patent expired, companies such as Roman and Hims because selling generics direct to consumer.

6.40   Tretinoin

Topical skin cream for treating acne.

6.41   Triamcionolone Acetonide

Topic skin cream for treating eczema.

7   Tolerance, Dependence, Addiction

Tolerance is characterized by adaptations that result in reduced drug effects.

Dependence is defined by the development of withdrawal symptoms when the substance is discontinued.

Addiction is a set of behaviors associated with misuse of drugs and increasing drug dosages.

Some drugs with a long half-life take some time to build up in the system. For example, creatine_ or kava.

Caused by "receptor up-regulation"?

Downregulation is the process by which a cell decreases the quantity of a cellular component. The opposite is upregulation.

Tolerance develops for some drugs because the body tries to maintain homeostasis.

For years, the predominant explanation of addiction, promulgated by researchers like Nora Volkow, director of the National Institute on Drug Abuse, has revolved around the neurotransmitter dopamine. Amphetamines unleash dopamine along with norepinephrine, which rush through the brain’s synapses and increase levels of arousal, attention, vigilance and motivation. Dopamine, in fact, tends to feature in every experience that feels especially great, be it having sex or eating chocolate cake. It’s for this reason that dopamine is so heavily implicated in current models of addiction. As a person begins to overuse a substance, the brain — which craves homeostasis and fights for it — tries to compensate for all the extra dopamine by stripping out its own dopamine receptors. With the reduction of dopamine receptors, the person needs more and more of her favored substance to produce the euphoria it once offered her. The vanishing dopamine receptors also help explain the agony of withdrawal: Without that favored substance, a person is suddenly left with a brain whose capacity to experience reward is well below its natural levels. It is an open question whether every brain returns to its original settings once off the drug. [7]

7.1   Cycling

Is it possible to use a variety of drugs and avoid building up a tolerance to any of them?

8   Interaction

A drug interaction occurs when a drug affects the activity of another drug when both are administered together.

Drug interactions are grouped into four kinds:

Antagonism
One drug reduces the effect of another.
Synergism
One drug increase the effect of another.
Potentation
One drug increase the effect of another.
Interaction with metabolism
?

9   Toxicity

Some drugs are lethal in larges doses.

Some drugs interact with each other which sometimes leads to death.

LD50 is specific to species. Humans clear out toxic substances slower than rodents disproportionate to their relative weights. If no species is specified along with LD50 , it's safe to assume it refers to rats or rabbits.

10   Discovery & Development

Drug discovery is the process by which new drugs are discovered.

A lead compound is a chemical compound that has pharmacological or biological activity likely to be therapeutically useful.

When a new drug is discovered, the researcher files for a patent_.

10.1   Development

Drug development is the process of bringing a new drug to the market once a lead compounded has been identified. This includes research on animals and clinical trials.

The structure of the lead compound is usually modified many times to optimize the specificity and selectivity to the target site, its potency, safety, stability, and absorption. The structure modification of the lead compound is called structure activity relationship (SAR).

The effect of a drug must be significantly better than a placebo effect. The strength of the placebo effect is related to how promising the patient believes the drugs to be. In the early days of antidepressants when no one believed they would work, they had a very weak placebo effect, whereas after the culture was saturated with messages of antidepressant efficacy, they started having a much stronger placebo effect.

If the company can prove safety and efficacy, the FDA reward the company with a 10 year monopoly on the drug, during which time they charge whatever price they want.

The FDA usually demands two positive studies before they approve a drug. [16]

Once the FDA approves a drug, it must be manufactured under carefully monitored conditions and packed with information on the best dose, route, and schedule. The package information must also include: conditions the drug has been proven to treat, known side effects, contraindications, and unsafe interactions with other drugs.

10.1.1   Clinical studies

Clinical studies involve three steps:

  1. Phase I trials determined safety and dosing in healthy volunteers
  2. Phase II get an initial reading of efficacy in small numbers of sick patients.
  3. Phase III trials are trials with hundreds or thousands of participants to determine safety and efficacy

After Phase III, the drug is submitted for regulatory approval.

After the drug is approved and goes onto the market, manufacturers must monitor the use of the drug and report any additional undetected side effects to the FDA. The FDA may withdraw approval if new evidence indicates the drug causes severe side effects.

10.1.2   Issues

Occasionally people discover that an existing chemical treats an illness, without the chemical having been discovered and patented by a pharmaceutical company. In this case, whoever spends tens of millions of dollars proving it works to the FDA may not get a monopoly on the drug and the right to sell it for ridiculous prices. So nobody spends tens of millions of dollars proving it works to the FDA, and so it risks never getting approved. [16]

The usual solution is for some pharma company to make some tiny irrelevant change to the existing chemical, and patent this new chemical as an “exciting discovery” they just made. Everyone goes along with the ruse, the company spends tens of millions of dollars pushing it through FDA trials, it gets approved, and they charge ridiculous prices for ten years. I wouldn’t quite call this “the system works”, but again, at least we get new medicines. [16]

For example, ketamine has existed for many years. In 2000, people noticed ketamine treated depression. But since pharmaceutical companies couldn't patent it, they wouldn't fund FDA trials (which cost millions of dollars), and so it would never be approved by the FDA for depression. [16] (Perhaps an altruistic billionaire could.)

Some pharmaceutical company patented an enantiomer of ketamine and passed it through FDA trials. They charge over $500 per dose, which may not be much more than what is need to generate a return on investment on the research and development. [16]

11   Administration

static/images/injection_techniques.jpg

They also makes shorter needles for subcutaneous injections (e.g. for diabetics) so that injections are always at a 90 degree angle.

Drug delivery refers to the combination of `route of administration`_ and `dosage form`_.

A route of administration (ROA) is the path by which a drug is taken into the body. Routes can be classified by the location at which the substance is applied, e.g. oral, intravenous, nasal, dermal, rectal. (Example of dermal would be a nicotine patch or birth control.) Routes can also be classified based on where the target of action is e.g. topical (local), enteral (global, through the GI tract), or parenternal (global, but not through the GI tract).

The choice of route is determined by physical and chemical properties of the drug, the site of desired action, and the condition of the patient. The oral route is generally the most convenient and least expense.

A dosage form refers to the form of the drug along with its dosage. For example, two products may contains the same active ingredient, but one is in 500mg capsules, and another is in 250 mg chewable tablets. The same drug is often available in different forms since different medical conditions can warrant different routes of administration.

Dosage forms include pills, syrups, food (e.g. weed brownies), aerosol, inhaler, smoking, vaporizer, cream, gel, balm, lotion, or ointment, skin patch, or eye drops.

A pill is any small rounded mass that is swallowed. Some types of pills include capsules (made of gelatin_), softgels (made of gelatin_ combined with glycerin_ or sorbitol_, usually contains a liquid), tablets (most common, can pack the most material), caplets (small circular tablets that are easier to swallow), and chewables (used if people can't swallow, mixed with sugar to make it easier, usually for children).

12   Regulation

12.1   Control

Depending upon the jurisdiction, drugs may be divided into over-the-counter drugs (OTC) which may be available without special restrictions, and prescription drugs, which must be prescribed by a licensed medical practitioner in accordance with medical guidelines due to the risk of adverse effects.

12.2   Production quotas

To prevent hoarding of materials and their potential for theft and illicit use, the Drug Enforcement Agency sets quotas for the chemical precursors to drugs like Adderall. The DEA projects the need for amphetamine salts, then produces and distributes the materials to pharmaceutical companies so that they can produce their drugs. [8]

12.3   Criminalization

12.3.1   Asia

Seems to be pretty much absent in Asia, perhaps as a result of the opium trade.

13   Screening

14   Market

Drugs are sold by pharmacies.

14.1   Branding

25% of people purchase brand name product to treat headaches instead of generics. [1] More highly educated people are more likely to buy generic medications. [1]

Brand names and generic products are required by law to be "bioequivalent". [1]

  • Recommended you purchase the CostCo Kirkland Brand on Amazon, which has dramatically cheaper prices than the local pharmacy. For example:
    • 30 400mg guaifenesin tablets cost $10.50 ($0.35 each) at a Walgreens in San Francisco
    • 200 400mg guaifenesin tablets cost $8.50 ($0.04 each) on Amazon (CostCo Kirkland brand)

Stores of sell hundreds of cold-and-flu products, many of which are just combinations of the same five active ingredients.


Drug companies will list all side effects in advertisements in order to downplay the most serious.

14.2   Pricing

In many jurisdictions, drug prices are regulated. In the United States, drug prices are unregulated, and are the result of negotiations between drug companies and insurance companies.

15   History

Traditionally, drugs are were obtained through extracting from medicinal plants.

The Greek word pharmakon applied to both drugs and poisons. [19] The ancient Hebrews employed the word sam for drug and also for poison, distinguished by a prefix, giving roughly "elixir of life" and "elixir of death". The Russian word yad has the same double meaning. [19]

Many drugs are important to religion_.

Rx is the symbol for a medical prescription. According to most sources, Rx is derived from the Latin word "recipe", which is the imperative form of the verb "to receive". In other words the symbol is a command, meaning "take this".

Prior to the 1950s, the majority of prescription medications in America were compounded by pharmacists; that is, each medication was custom-made from raw ingredients to suit an individual patient's needs. After the mid-20th century, pharmacists filled most prescriptions with mass-produced products from drug companies.

15.1   Dosage forms

Pills were invented in ...?

Before the invention of pills....

15.2   Antidepressants

In the 1960s diphenhydramine was found to inhibit reuptake of the neurotransmitter serotonin. his discovery led to a search for viable antidepressants with similar structures and fewer side effects, culminating in the invention of fluoxetine (Prozac), a selective serotonin reuptake inhibitor (SSRI).

.

After the initial flush of enthusiasm for SSRIs in the 1990s, some of the concerns about drug dependency and side effects that had attached to tranquilizers in the 1970s began clustering around antidepressants. “It is now clear,” David Healy, a historian of psychopharmacology, wrote in 2003, “that the rates at which withdrawal problems have been reported” on paroxetine, the generic name for Paxil, “exceed the rates at which withdrawal problems have been reported on any other psychotropic drug ever.” [2]

15.3   Pain relievers

Willow bark was one of the earliest painkillers. Extracts or teas of willow bark have been used to treat fever and pain for more than 2,000 years. Unfortunately, the active ingredient, salicylic acid, is very hard on the stomach. In 1897, a German chemist working for the Bayer Company found a way to modify salicylic acid so it was less irritating to the stomach. The compound he created, acetylsalicyclic acid, was called Aspirin. It remained the premier over-the-counter painkiller until the development of acetaminophen in 1956 and ibuprofen in 1962. Since then, more than a dozen others have come onto the market. [22]

15.5   Modern pharmacology

Synthetic drugs became available in ...

Around 1804, German pharmacist Friedrich Sertürner isolated morphine from opium. Morphine was the first alkaloid to be isolated from any medicinal plant, the beginning of modern scientific drug discovery. Morphine was initially hailed as a wonder drug for its ability to ease pain.

The second advance, in 1851, was the refinement of the `hypodermic needle`_ by Alexander Wood and others. Development of a glass syringe with a subcutaneous needle made it possible to easily administer controlled measurable doses of a primary active compound.

Codeine was discovered in 1832 by Pierre Jean Robiquet. Robiquet was reviewing a method for morphine extraction, described by Scottish chemist William Gregory (1803-1838). Processing the residue left from Gregory's procedure, Robiquet isolated a crystalline substance from the other active components of opium.

The first scientific publication to use the term "opioid", in 1963, included a footnote stating, "In this paper, the term, 'opioid', is used in the sense originally proposed by George H. Acheson (personal communication) to refer to any chemical compound with morphine-like activities".

For most of the 19th century, drugs were ineffective.

Antibiotics were first developed in 1932 by Gerhard Domagk.

15.6   United States

15.6.1   Regulation

Until the 20th century, there were few laws regulating the sales of food or drugs. In June 1906, President Theodore Roosevelt signed into law the Pure Food and Drug Act, which tasked the USDA Bureau of Chemistry to examine food and drugs for signs of adulterated or misbranded goods. In 1927, the Bureau of Chemistry was reorganized under a new USDA body, the Food, Drug, and insecticide organization, which renamed to the Food and Drug Administration (FDA) in 1930.

In 1937, public outcry over the Elixir Sulfanilamide tragedy, in which over 100 people died after using a drug formulated with an untested solvent, led to Franklin Delano Roosevelt to sign into law the "Food, Drug, and Cosmetic Act" in 1938. The new law increased federal regulatory authority over drugs by mandating a pre-market review of the safety of all new drugs, as well as banning false therapeutic claims in drug labeling without requiring the FDA prove fraudenlent intent.

The category of "prescription-only" drugs was codified into law by the 1951 Durham-Humphrey Amendment.

In 1962, the Kefauver-Harris Amendment to the FD&C Act was passed, which required all new drug applications demonstrate "substantial evidence" of the drug's efficacy, in addition to the existing requirement of pre-marketing demonstration of safety.

15.6.2   Dietary supplements

The FDA has little power to regulate the contents of supplements until people are already getting sick from them. In the past, they tried to change this. In the late 1980s, 38 people died from l-tryptophan supplements and in response the FDA tried to expand its authority.

In 1993, the industry struck back. Consumers were urged to write to their congressman or told they may lose access to vitamins. More people wrote to Congress about the supplement bill than wrote about the Vietname War.

Senator Orrin Hatch and Senator Tom Harkin were the top two recipients of campaign funds from the supplement industry.

In 1994, the supplement industry made four billion dollars a year. In 2014, it made $32 billion a year.

  • Ephedra caused 155 deaths and 16,000 adverse events

15.6.3   War on Drugs

The War on Drugs is a campaign led by the United States federal government with the stated aim being to reduce the illegal drug trade in the United States. It began in the 1960s.

The term was popularized by the media shortly after a press conference given on June 18, 1971, by President Richard Nixon—the day after publication of a special message from President Nixon to the Congress on Drug Abuse Prevention and Control—during which he declared drug abuse "public enemy number one".

The government halted research to evaluate the medical safety and efficacy of certain recreational drugs.

The Nixon campaign in 1968, and the Nixon White House after that, had two enemies: the antiwar left and black people. You understand what I'm saying? We knew we couldn't make it illegal to be either against the war or black, but by getting the public to associate the hippies with marijuana and blacks with heroin, and then criminalizing both heavily, we could disrupt those communities. We could arrest their leaders, raid their homes, break up their meetings, and vilify them night after night on the evening news. Did we know we were lying about the drugs? Of course we did.

— John Ehrlichman, to Dan Baum for Harper's Magazine in 1994, about President Richard Nixon's war on drugs, declared in 1971.

In 1970, the United States Congress passed The Controlled Substances Act which created five schedules (classifications) of drugs depending upon the drug's acceptable medical use, the potential for abuse, and the potential for addiction. Schedule 1 drugs have the most potential for abuse, where Schedule 5 drugs have the least.

Schedule 1 No current accepted medical use and high potential for abuse. For example, heroin_, LSD, cannabis, and MDMA.
Schedule 2 High potential for abuse. For example, cocaine, methamphetamine, fentanyl_, Adderall.
Schedule 3 Moderate to low potential for abuse. For example, codeine_, ketamine, `anabolic steroids`_, testosterone.
Schedule 4 Low potential for abuse. For example, Xanax_, Valium_, Ambien_, modafinil.
Schedule 5 Low potential for abuse.

The Drug Enforcement Administration and the Food and Drug Administration determine which substances are added to or removed from the various schedules.

The Drug Enforcement Administration was established in 1973, combining the Bureau of Narcotics and Dangerous Drugs (BNDD) and Customs' drug agents.

Oregon became the first state to decriminalize cannabis in 1973. Denver followed in 1975.

The number of people behind bars for nonviolent drug law offenses increased from 50,000 in 1980 to over 400,000 by 1997.

15.6.4   Opioid crisis

The opioid crisis refers to a rapid increase in the use of opioid drugs in the United States beginning in the late 1990s.

16   Medicine cabinet

Every household should some basic products to meet a medical emergency when it arises. A medical emergy is (1) any occasion that is life threatening and requires immediate action, or (2) any occasion when it isn't convenient for the patient to obtain the products necessary to relieve uncomfortable or painful symptoms. [21]

Besides personal prescription medicines, a home medicine cabinet should contain the following: [20]

Pain or fever
Product Uses
Acetaminophen Relieve mild or moderate pain or headache; reduces fever
Ibuprofen Relieve mild or moderate pain or headache; reduces fever and inflammation
Thermometer_ Monitors fever
Wound care
Product Uses
Antibiotic ointment Prevent infection in minor wounds
Bandages Cover wounds
Disposable latex gloves Prevent contact with body fluids while cleaning wounds
Gauze and cottons balls Clean wounds
Hot and cold packs Ease sore muscles; reduce swelling
Tweezers and scissors Remove splinters
Saline solution Washes dirt from wounds
Allergic responses
Product Uses
Antihistamine_ Blocks effects of histamine
`Intranasal corticosteroid`_ Suppresses release of histamine
Hydrocortisone cream Soothes itchy skin
Rubbing alcohol Soothes and dries rashes
Cough and cold
Product Uses
Dextromethorphan Cough supressant
Guaifenesin Mucus expectorant
Phenylephrine hydrochloride Nasal decongestant
Gastrointestinal ailments
Product Uses
Antacid_ Neutralizes stomach acid
Laxative_ Relieves constipation

For homes with children, special consideration are necessary.

17   Resources

18   Further reading

19   References

[1](1, 2, 3, 4) James Hamblin. The Cold-Medicine Racket. http://www.theatlantic.com/health/archive/2014/12/dayquil-screed/383768/?single_page=true
[2](1, 2) Scott Stossel. Jan 2014. Surviving Anxiety. http://www.theatlantic.com/magazine/archive/2014/01/surviving_anxiety/355741/?single_page=true
[3]Drug Scheduling. https://www.dea.gov/drug-scheduling
[4](1, 2, 3) "GLOOM". 2015-06-09. Adderall IR vs. XR: What's The Difference? https://mentalhealthdaily.com/2015/06/09/adderall-ir-vs-xr-whats-the-difference/
[5](1, 2, 3) June 2018. What is MDMA? https://www.drugabuse.gov/publications/drugfacts/mdma-ecstasymolly
[6](1, 2, 3) Alan Schwarz. Dec 14, 2013. The Selling of Attention Deficit Disorder. https://www.nytimes.com/2013/12/15/health/the-selling-of-attention-deficit-disorder.html
[7](1, 2, 3) Casey Schwartz. Oct 12, 2016. Generation Adderall. https://www.nytimes.com/2016/10/16/magazine/generation-adderall-addiction.html
[8](1, 2) Kelly Bourdet. Feb 16, 2012. Anatomy of the Great Adderall Drought. https://www.vice.com/en_us/article/d7737v/anatomy-of-the-great-adderall-drought
[9]JC Lee. 2001. Club drugs and erectile function: Far from sexual ecstasy. https://www.pulsus.com/scholarly-articles/club-drugs-and-erectile-function-far-from-sexual-ecstasy.html
[10]2018-08-02. Is It a Cosmetic, a Drug, or Both? (Or Is It Soap?) https://www.fda.gov/cosmetics/cosmetics-laws-regulations/it-cosmetic-drug-or-both-or-it-soap
[11](1, 2, 3) Brandon Cohen; Charles V. Preuss. 2019-04-03. Opioid Analgesics. https://www.ncbi.nlm.nih.gov/books/NBK459161/
[12]Edmund J. Bourne. 1990. The Anxiety and Phobia Workbook. Chapter 2: Major Causes of Anxiety Disorders.
[13](1, 2, 3, 4, 5, 6, 7) Carl Zimmer. Sep 4 2014. How Caffeine Evolved to Help Plants Survive and Help People Wake Up. http://www.nytimes.com/2014/09/04/science/how-caffeine-evolved-to-help-plants-survive-and-help-people-wake-up.html
[14]Scott Stossel. Jan 2014. Surviving Anxiety. http://www.theatlantic.com/magazine/archive/2014/01/surviving_anxiety/355741/?single_page=true
[15](1, 2, 3, 4, 5, 6) Gwern. Feb 20 2009. Modafinil. https://www.gwern.net/Modafinil
[16](1, 2, 3, 4, 5, 6, 7) Scott Alexander. March 11, 2019. Ketamine: Now By Prescription. https://slatestarcodex.com/2019/03/11/ketamine-now-by-prescription/
[17]October 25, 1994. Dietary Supplement Health and Education Act of 1994. https://ods.od.nih.gov/About/DSHEA_Wording.aspx
[18]2015-07-15. FDA 101: Dietary Supplements. https://www.fda.gov/consumers/consumer-updates/fda-101-dietary-supplements
[19](1, 2, 3, 4, 5) David I. Macht. A Drug or Poison? The Scientific Monthly, Vol. 47, No. 1 (July 1938), pp. 34-40.
[20]

Mary K. Gurney. 2010-01-19. https://www.pharmacytimes.com/publications/issue/2010/january2010/patienteducationmedcabinet-0110

Actually I don't know if I trust this. Some questionable choices such as includying hydrogen peroxide for cleaning wounds and a nasal aspiration for adults.

[21]

Elaine D. Mackowiak. Emergency Supplies for the Home Medicine Cabinet

Couldn't find more than a preview online. Couldn't find on Library Genesis or via the SF public library.

[22](1, 2, 3, 4) 2015-01. 10 things you should know about common pain relievers. https://www.health.harvard.edu/pain/12-things-you-should-know-about-pain-relievers
[23]Jack E. James, Michael A. Keane. 2007-09-17. Caffeine, sleep and wakefulness: implication of new understanding about withdrawal reversal.