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Harm Reduction ⭐️ Biology, Pharmacology and Drugs 101 ⭐️


Bluelight Crew
Dec 9, 2012

Biology, Pharmacology and Drugs 101

The aim of this guide is to provide a broad and simple overview of the human body and drug pharmacology. This is an ongoing project that will be updated as time permits. If you find any mistakes or want to add something, please PM me or any other OD mod.

A special thanks to my amazing friend Jekyl Anhydride - this madman fact and spell checked everything! - and also to CFC for help with formatting.

Disclaimer: The dosing information presented herein has been collated from a combination of both user experiences and various other reliable drug resources, including TripSit and PsychonautWiki among others. However, this is not a recommendation and you should always verify your doses with other sources! Also (a) always start with an allergy test when dealing with a new substance; (b) always start with the lowest effective dose; and (c) beware drug combinations, which can dramatically heighten the risk of harms, and thus necessitate the use of lower doses than might ordinarily be recommended or expected.

Now get your stimulant of choice ready as this is quite a long thread (last I checked nearly 22000 words long).

Index of Contents
2.1 ADME
2.1.1 Absorption
2.1.2 Distribution
2.1.3 Metabolism
2.1.4 Excretion​
2.2 Bioavailability
2.2.1 pH and transporter dependence​
2.3 Half life
2.4 Other lingo
2.5 Blood brain barrier
2.6 Transporters
2.7 Plasma proteins​
3.1 Synapse​
3.2 Potential
3.2.1 EPSP and IPSP​
3.3 Ligands
3.3.1 Agonist
3.3.2 Antagonist
3.3.3 Partial agonist
3.3.4 Inverse agonist​
4. Receptors
4.1 GABA receptors
4.1.1 GABA-A
4.1.2 GABA-B​
4.2 Opioid receptors
4.3 Adrenoceptors
4.4 Dopamine receptors
4.5 Serotonin receptors
4.6 NMDA receptor
4.7 hERG
4.8 TAAR1
4.9 VMAT (transporter)​
5.1 Serotonin syndrome
5.2 Depressants
5.3 Vasodilatants
5.4 Stimulants
5.5 Enzyme induction/inhibition​
6. Drugs
6.1 Stimulants
6.1.1 Caffeine
6.1.2 Amphetamine
6.1.3 Methamphetamine
6.1.4 Cocaine
6.1.5 Methylphenidate
6.1.6 MDMA​
6.2 Depressants
6.2.1 GHB/GBL
6.2.2 Pregabalin
6.2.3 Gabapentin
6.2.4 Phenibut
6.2.5 Benzodiazepines
6.2.6 Opioids
6.3 Psychedelics
6.3.1 LSD
6.3.2 2C-x
6.3.3 Mescaline
6.3.4 Psilocin
6.3.5 DMT
6.3.6 Ibogaine​
6.4 Dissociatives
6.4.1 PCP
6.4.2 Ketamine
6.4.3 DXM
6.4.4 Nitrous oxide​
6.5 Deliriants
7.1 Nociception​
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1. Human cell

To start we first have to take a look at the human cell.

The difference between us (eukaryotes) and prokaryotes (bacteria and archaea) is a cell nucleus with the nucleolus and other membrane bound organelles, for example the mitochondria ("the powerhouse of the cell" you might remember).

The outer layer of the cell (animal cell that is) consists of a phospholipid-bilayer, meaning that the membrane is made of two layers of molecules consisting of fatty acids (hydrophobic meaning they repel water) and a phosphate group (hydrophilic meaning it's attracted to water ) linked together via a glycerol molecule. Due to the fatty acid and phosphate group part the bilayer is amphiphilic (meaning it's both hydrophilic and lipophilic). There are of course other molecules like cholesterole in the membrane, but they aren't important for now.

The primary role of the phospholipid-bilayer is to seperate the cell content from its environment as it's only permeable for certain molecules (water for example or small lipophilic molecules), but not for others (hydrophilic molecules, ionized molecules etc.). To get those non permeable molecules across the membrane we have pumps, channels and transporters.

Transporters play a key role for example in the bioavailability of loperamide, but we'll go into detail later on.

So for now we've learned that the animal and thus human cell membrane consists of a phospholipid-bilayer making it permeable for some molecules and not permeable for others.
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2. Pharmacokinetics

Pharmacokinetics is all about invasion and elimination of a drug in the body. It's the entirety of processes (known as ADME) a drug is subjected to after taking it.

2.1 ADME

Now let's take a look at ADME: absorption, distribution, metabolism and excretion

2.1.1 Absorption

How we consume drugs plays a crucial role in the bioavailability, onset of action etc.. There's a variety of different routes of administration (RoA) including intravenous (i.v.), intramuscular (i.m.), subcutaneous (s.c.), oral (p.o.), sublingual, intranasal, intrarectal, transdermal and via the lungs. Each RoA comes with its pros and cons so let's analyze the most common RoAs:

a) I.V.

If you inject your drug of choice into your vein 100% of it will go into systemic circulation. The drug goes through the vein (depending on your vein of choice most likely venae cephalica) directly to the heart, get's pumped through the pulmonary circulation (so through the lungs, where hydrophobic molecules can be retained and the lung has some enzymes, like ACE, but that's not important for now) back to the heart into systemic circulation. The onset of action is extremely fast and we avoid the first-pass metabolism (more on it later on). In this case the drug concentration starts to decrease exponentially immediately.

But this RoA comes with the cost of many risks like infection (your body has no chance killing bacteria or other microorganisms before they get into your bloodstream), abscess, amputation, lung problems (particularly with injecting pills as the insoluble particles may accumulate in the capillaries) etc. While those risks can be decreased by using micron filters, new syringes each time and a sterile injection technique it's always better to use the oral route if possible.

b) I.M.

Injecting your doc into a muscle will lead to a slower onset as i.v. as the drug has to be absorbed into the bloodstream, so it's dependent on the solubility and size of the drug and perfusion of the muscle.

A list of usable muscles includes musculus gluteus medius/minimus (don't inject more than 10ml at once and watch out for the nervus ischiadicus), musculus vastus lateralis (don't exceed 5 ml) and the musculus deltoideus (not more than 2 ml). It's important to get the right needle size as too long of a needle can cause you to get down to your bone, while a short needle might lead to a s.c. injection instead of i.m.. And don't forget to check if you draw blood before injecting (i.e. aspirate before injecting so you don't accidentally inject into a blood vessel). The risks are similar to the ones with i.v. but the risk of an abscess might be increased.

c) P.O.

Taking your doc oral will lead to the absorption mostly in the small gut (if the drug is a weak acid absorption in earlier parts and if it's a weak base absorption in the later parts of the small intestine). the small intestine has a surface of about 200 m^2 so quite a lot of room to absorb the drug. From the gut the drug makes its way to the liver via the portal vein. The hepatocytes (liver-cells) have a lot of enzymes that can metabolize the ingested drug (we'll talk about metabolism later on), that's what's called first-pass metabolism. After leaving the liver the drug either gets excreted back into the gut via the bile (unusual, called enterohepatic circulation) or goes into systemic circulation via the heart, lungs, heart.

d) Sublingual

Taking a drug sublingual or buccal means that you keep it in your mouth so it gets absorbed through the multilayered squamous epithelium. From there it takes the same route as i.v., most likely via the vena labialis, i.e. heart -> lungs -> heart -> systemic circulation

e) Intranasal

Snorting a drug (don't snort too hard or a part will get into your lungs, which can lead to lung disease like pneumoconiosis) will bypass the first-pass effect and leads to a fast onset of action as there's only a single epithelial cell layer the drug has to cross to get into systemic blood circulation. Part of the snorted drug will most likely drip down your throat and can thus be absorbed in the stomach/gut leading to a second, right-shifted onset. The most likely route is nose -> venae nasalis externa -> heart -> lungs -> heart -> systemic circulation

f) Intrarectal (Plugging)

With intrarectal administration you can bypass first-pass metabolism depending on the depth of penetration.

The blood vessels around the last part of the rectum lead directly to the venae cavae, while the blood vessels higher up lead to the portal vein, where first part metabolism takes place.

Another thing to consider is that stool can absorb your drug, so make sure you're cleared out before plugging. And don't forget to use some lube ;)

g) Lungs

With this RoA you skip the right part of the heart and the drug goes directly into systemic circulation after passing the left part of the heart. This way you bypass first-pass metabolism and have a rapid onset of action.

h) Intra-arterial

Normally only done for x-ray diagnostic or neoplasm therapy and shouldn't be done as it can lead to thrombosis, heavy bleeding (hard to stop), quite some pain and in the worst case amputation (for example due to particles you inject clogging capillaries, stopping the blood flow downstream, leading to ischemia).

2.1.2 Distribution

Distribution describes the transfer of a drug from one location to another in the body.

After a drug is absorbed into the bloodstream (systemic circulation) it can either stay in the bloodstream (macromolecules) or can be transported into interstitial and intracellular fluids. This way it can be distributed to different tissues/organs. Highly perfused organs would be the brain, liver, heart and kidney, while less perfused tissues would be fat, muscle and other organs. Some of the factors that dictate distribution are regional blood flow, vascular permeability, lipid solubility of the drug, pH (this concept will be looked at later on in Bioavailability) and the drugs affinity to plasma proteins (this has its own caper, 2.6).

Now, why is this important you might ask? For this we'll look at two examples, one is the benzodiazepine diazepam and the other the anesthetic agent etomidate.

Etomidate is a short-acting anesthetic agent used for the induction of general anesthesia. It's not something you will come in contact with other than during an operation, but it's a good example for distribution. I know we haven't talked about half life in depth yet so bear with me. The elimination half life (the time it takes for half the ingested drug to be metabolised) of etomidate is around 75 minutes. one might think that therefore the duration of the induced narcosis would be at least 75 minutes or even longer. But surprise surprise, you'll most likely wake up 5-10 min after the injection. So why's that? Because of distribution. After injection due to high perfusion there'll be a high concentration of etomidate in the brain. Now the concentration in the brain drops rather fast as the drug is redistributed to other tissue in the periphery. This will lead to you waking up even though the drug hasn't been metabolised yet, because the concentration in your brain dropped under the effective concentration that is needed for narcosis.

This fast redistribution without metabolism/excretion is the reason why etomidate shouldn't be redosed after the first injection as this can lead to an overdose (the periphery is already saturated and another dose will lead to a high concentration in the brain that can't be redistributed).

For diazepam it's similar. Diazepam has a pretty long elimination half life (and active metabolites, but that's not the point here), but for some people the duration of action can be quite short as it's redistributed into adipose tissue and muscle where it can build up. The duration of action of an i.v. bolus of diazepam can be as short as 10-20 minutes.

Acid trapping:

Lipophilic drugs that act as weak bases tend to accumulate in acidic intracellular compartments like lysosomes. The plasma and lysosome-membrane are permeable for neutral, lipophilic drugs, but once inside the slightly acidic lysosome the drug is protonated and thus can't get out of it anymore. This leads to accumulation of the drug inside the lysosome reaching drug concentrations of 100 to even 1000 times more than outside. This leads to higher tissue concentrations and half life than plasma in plasma.
Many recreational and medical drugs are weak bases and thus accumulate in lysosomes. This can lead to the inhibition of lysosomal enzymes like sphingomyelin phosphodiesterase, drugs that inhibit SMase to a meaningful degree are called FIASMA (functional inhibitors of acid sphingomyelinase). Drugs that belong to this class are among others amitriptyline, sertraline and fluoxetine.

2.1.3 Metabolism

Now try to put yourself into your bodies place. What would you wanna do when there's a new molecule you don't recognize?
Right you want to get rid of it as you don't know if it'll harm you or get you high. This means either excreting it directly (hydrophilic substance) via your kidneys into your urine or, if the substance isn't really hydrophilic, you want to metabolize it into a more hydrophilic substance so you can excrete it. That's were our liver comes into play (drugs aren't only metabolized in the liver, for example our gut has CYP3A4 enzymes, but for now we'll concentrate only on the liver as that's the most important organ for the drug metabolism).
So when a drug enters the hepatocyte two phases can take place, phase I and phase II:

- Phase I aka functionalization -> in this step we add a functional group to the molecule (through oxidation, reduction, hydrolysis) or expose a functional group that was already there but couldn't be used due to steric hindrance; this phase can be skipped

- Phase II aka conjugation -> now that we have a functional group in the molecule we want to excrete we add a polar molecule (mostly glucuronic acid or sulfuric acid) to make the resulting molecule more hydrophilic

For phase I the enzymes our body relies on are mostly enzymes belonging to the CYP-450 family including CYP2D6 and CYP3A4, aminooxidases, alcohol dehydrogenase (the enzyme responsible for metabolizing ethanol into acetaldehyde), aldehyde dehydrogenase and the list goes on.
For phase II it's [/SIZE]glucuronosyltransferase (UGT), glutathione s-transferase, n-acetyltransferase etc.

The most important enzymes are the isoenzymes belonging to the CYP-450 family. Those are heme-proteins anchored in the ER-membrane. For drug metabolism we have 12 isoforms belonging to 7 subfamilies of 3 gene-families (CYP1, 2 and 3). The liver has the highest CYP-enzyme concentration (around 90-95% ) with
CYP3A4 being the most important for drug metabolism (some CYP3A4_ligands). Some CYP-enzymes show large phenotypical variability meaning that there are different variant of the gene coding for the enzymes (genes are sequences in our DNA that can be translated into proteins).

I'm going a little bit into genetics here, if you don't care here's the TL,DR: some people can metabolize drugs faster than others and some can't metabolize them at all.

Now for the genetics part: Each person has two alleles of one gene (remember, we have 46 chromosomes, 23 from our mother (maternal) and 23 from our father (paternal), which are homologous meaning they have the same genes at the same loci (fixed position on a chromosome)). Now those alleles can have the same sequence of base pairs or can differ, for example by a point mutation etc.. This leads to something called a polymorphism (several gene variants in a population). Now let's try to understand what this means for us using an example. Say we have a gene coding for the CYP-2D6 enzyme with 2 copies on each allele. This means we have a total of 4 copies. Now if 3 or four of those don't function (for example due to a mutation causing the final protein to fold in a wrong way) we have someone called poor metabolizer, meaning there's little to no CYP2D6 function. If only 1-2 copies aren't functioning we have someone called intermediate metabolizer. If all copies function normally we have an extensive or normal metabolizer and if the person has more than 4 copies or the enzyme works more efficient due to a mutation we have someone called an ultra rapid metabolizer, meaning this person metabolized drugs faster than a normal person.

If you're interested in more info about the CYP isozymes, up/down regulation and the implication of CYP3A4 in Vitamin D metabolism check out those links:


With all the knowledge we should now easily understand the first pass metabolism occurring after consuming a drug p.o.. Remember, when you take a drug via the oral route it's going through the stomach into your gut, from there it's absorbed into your bloodstream (portal vein) going to the liver. And as we learned the liver has quite a lot of enzymes metabolizing drugs. Now first pass metabolism/effect simply means the part of the drug that is metabolized in the liver before getting into the systemic circulation

For a better understanding of why that's important, a few examples:

Buprenorphine underlies quite a heavy first pass metabolism, the bioavailability is only around 10% if taken orally versus around 30-50% if taken sublingually and thus skipping the first pass metabolism.

Codeine for example has only minor analgesic effects on its own making it a prodrug (drug that only becomes active after metabolism). During the first pass metabolism it's metabolized into morphine, norcodeine and codeine-6-glucuronide (C6G).

The metabolism into morphine is catalyzed via CYP2D6, so if you remember the polymorphism I was talking about earlier, there are people who don't metabolize codeine into morphine, reducing analgesia and there are the ultrarapid metabolizers that get quite a lot of morphine making it even dangerous as even normal doses of codeine can cause respiratory depression, so start with a small testing dose when taking codeine for the first time. Norcodeine isn't really active while C6G is a major active metabolite and may even be responsible for more than half the analgesic effects of codeine in normal metabolizers.

With that in mind you should now understand why it's stupid to inject codeine directly into the bloodstream: it's a prodrug and thus we want the first pass metabolism. And it can lead to an anaphylactoid reaction due to mast cell degranulation.

While paracetamol (apap) isn't a substance we abuse it's still an interesting topic as drug combinations sometimes contain it (Tylenol for example). Usually our body metabolizes apap via a phase II reaction which isn't harmful and we can just piss out the metabolite. But if we take a high dose of it (anything over 3-4 g per 24 hours can be liver toxic so check out Cold-Water-Extraction) the enzyme gets saturated and another reaction takes place. In this case some of the apap is metabolized via a CYP-450 family enzyme (mostly via CYP2E1) leading to a metabolite called NAPQI (N-acetyl-p-benzoquinone imine). This metabolite can react with proteins of the
hepatocytes leading to liver necrosis and in the worst case liver failure. Now normally our body can handle some of this toxic metabolite (even at normal apap doses some of it will be produced) as a reaction with glutathione (GSH) can intercept it. But we don't have unlimited amounts of GSH so if the apap dosage is too high (above 4 g, 10 g can lead to liver failure and death) all GSH is consumed and the NAPQI (N-acetyl-p-benzoquinone imine) causes liver death.

Now in the case of apap overdose time is key as up to 10 hours after ingestion N-acetyl cysteine can be given in the hospital to save your liver.

Enterohepatic circulation:

The enterohepatic circulation describes the circulation of drugs between the gut, liver and gallbladder.

Orally ingested drugs are absorbed in the gut and transported via the portal vein into the liver. After Phase-2 metabolism (conjugation with polar molecules like glucuronic acid or sulfuric acid) the drug is transported from the hepatocytes into the bile via different transport mechanisms. The bile is now secreted into the gut again. The now hydrophile conjugate can't be absorbed back into the blood, but bacteria residing in the gut is able to cleave the O-glucuronide bond setting the drug free. Now the drug can be absorbed into the blood again.

But this circulation doesn't take place for infinity. Some of the drug-conjugate in the liver is absorbed straight into the blood and excreted via the kidney and urine.

2.1.4 Excretion

The most important way of drug excretion/elimination is via the kidneys and urine after phase-II metabolism. A small part can be excreted via the feces (the drug is absorbed, goes to the liver, is secreted via the bile into the gut and then excreted). Other ways include lungs and skin, but those don't usually play a big role.

2.2 Bioavailability

Bioavailability is "the fraction of an administered dose of unchanged drug that reaches the systematic circulation".
Now let's dissect that definition:
Fraction of an administered dose of unchanged drug -> this means that the drug hasn't been metabolized (i.e. due to first pass metabolism)
drug that reaches systematic circulation -> this means that the drug made it to the left atrium of the heart and is being pumped to the different organs (the brain being the most important one for CNS drugs).

2.2.1 pH and transporter dependence

The pH of your stomach, gut and urine play a huge role in the bioavailability of drugs.

If the drug is a weak base, as a rule of thumb this can be indicated by a N-group for example, it's not protonated in a basic environment (the drug will start getting protonated more if the pH drops below the pKa) thus can be absorbed better (if you remember charged molecules can't normally be absorbed). If the drug is a weak acid, as rule of thumb this can be indicated by a COOH-group, the drug is protonated in an acidic environment (the drug will start getting deprotonated more when the pH exceeds the pKa) thus can be absorbed better. As most drugs are excreted via the urine it's important to know that acidic urine will increase the excretion of basic drugs while urine with high pH will increase the excretion of acidic drugs.

To understand this better let us take a look at an example:

Amphetamine is a weak base (notice the NH2? This can be protonated to a NH3+) so taking an antacid before taking it orally will increase absorption in the gut.

Some drugs, like gabapentin, have to be transported from the gut into the blood via active transport. For gabapentin LAT1 is the responsible transporter. But LAT1 doesn't only transport gabapentin but other molecules like amino acids. Because of that taking it with a meal rich in proteins will reduce absorption as LAT1 has to transport gabapentin and amino acids. Additionally the transporter is easily saturable, meaning that once a certain dosage is reached all transporters are being active and no additional gabapentin can be transported. Because of this staggering your dose and possibly slowing down your gut motility will increase bioavailability.

2.3 Half life

Let's start this one with a quote:
" A drug's half-life of elimination from plasma or serum has long been considered a familiar and important pharmacologic property. In fact, elimination half-life has limitations, and its value has been overestimated. Elimination half-life is a dependent variable, related directly to volume of distribution and inversely to clearance. Changes in drug distribution as well as in rate of clearance can alter elimination half-life. Half-life also has limitations as a predictor of a drug's duration of pharmacologic action after single doses, which is related more to distribution than to elimination or clearance. During multiple dosage, elimination half-life does have value in predicting the rate and relative extent of drug accumulation, as well as the rate of washout after termination of treatment. Clinicians should consider volume of distribution and clearance, in addition to elimination half-life, when evaluating the pharmacokinetic properties of drugs." (https://www.ncbi.nlm.nih.gov/pubmed/3994325)
But this didn't really explain what half life is.

The elimination half life of a drug is a parameter that is defined as the time it takes for the concentration of a certain drug to be reduced by half (of course it's not as simple as that in the body but it's a good approximation).

For example:

Drug X has an elimination half life of 1 hours. At T=0 we take 100 mg.
After 1 hours 50 mg of X remain in the body
After 2 hours 25 mg
After 3 hours 12.5 mg.
After 4 hours 6.25 mg.
And finally after 5 hours we're left with only 3.125 mg of X.

As a rule of thumb the drug is mostly excreted and normally has negligible therapeutic effects after 5 elimination half lifes.
The distribution half life is the time it takes for half of the drug present in the plasma to be distributed outside the bloodstream.
To make matters worse some substances have different half lifes in different parts of the body, but that's not important for us.
What you should remember is that elimination half life doesn't equal duration of action. Some drugs can have a long half life but a short duration of action (i.e. Diazepam) or the other way around (i.e. irreversible MAOIs, aspirin).

2.4 Other lingo
Additional important terms:
Dosing interval -> time between drug dose administration
cmax-> the peak plasma concentration of a drug after administration
tmax -> the time it takes to reach cmax
AUC -> Area under the curve (the total drug exposure after administration until full excretion), the integral of the concentration-time curve
Clearance -> the volume of plasma cleared of the drug per unit time
ED50 -> ED 50 stands for effective dose 50 or median effective dose, it's the dose that produces an effect in 50% of lab animals/study participants
LD50 -> LD 50 stands for lethal dose 50, so it's the dose were 50% of the lab animals are killed
Therapeutic Index -> TI = LD50/ED50, it's the range of dosage between no effect and toxicity

2.5 Blood brain barrier

The blood brain barrier is the most important blood-tissue barrier for us (others include heart, liver, pancreas and placenta/testicle). The endothelium of the CNS (central nervous system) offers no pores for the drugs to pass through and is highly selective. Water and lipid soluble small molecule drugs are mostly able to diffuse through and transporter proteins can selectively transport molecules across the membrane, but even if a drug is able to make it across the membrane into the endothelia cell doesn't mean it's out of the woods. There are proteins, like P-glycoprotein, created to transport xenobiotics right out of the cell again. A great example being loperamide, an opioid that is only peripherally active as it's a substrate of P-Gp so after getting into the endothelia it's pumped right back out into the bloodstream.

2.6 Transporters

P-glycoprotein (PGP) sits in the cell membrane and pumps molecules out of the cell. It's not very substrate specific meaning it pumps a lot of different substances out of the cell. This is important for drugs like loperamide. Loperamide is a substrate of PGP sitting mostly in the blood brain barrier (=BBB; as the name suggests it's a barrier between blood vessels and the brain) so after loperamide enters the BBB it gets pumped right back out of the cells. This means that normally loperamide only acts peripherally (mostly in the gut) and not centrally (the brain), meaning that you won't get high but constipated.
There are inducers (lead to more PGP) and inhibitors (less PGP/compete as a substrate). So if you want to get high off of loperamide (a really bad idea as it's cardiotoxic in high doses, meaning that it'll mess up your heart and could lead to serious side effects and in the worst case death) you want to inhibit PGP (bad idea as those inhibitors come with a wide range of side effects and we have PGP for a reason).
The large neutral amino acid transporter (LAT1) is a transporter relevant for gabapentin. After taking gabapentin orally it'll be absorbed from the intestines via an active transport mediated via the LAT1. This is important as LAT1 not only transports gabapentin, but amino acids, preferentially valine, leucine, isoleucin, tryptophan and tyrosine, as well. Because of this you shouldn't combine gabapentin with your protein shake or a meal rich in protein. Another drawback with this transporter is, that it can be saturated. This means that if you take a high dose of gabapentin your transporters will eventually all be active (saturated) and can't transport more than a certain dose. Because of that the absorption and therefore bioavailability drops with higher doses. For example " The absolute bioavailability of gabapentin drops from 60% to 33% as the dosage increases from 900 to 3600 mg/day" https://www.ncbi.nlm.nih.gov/pubmed/20818832. To increase the bioavailability it's useful to stagger doses instead of taking one high dose. Another way to increase absorption would be to slow down gut motility.

2.7 Plasma proteins

Plasma proteins, or sometimes referred to as blood proteins are an umbrella term for commonly occurring proteins in the blood plasma. Plasma proteins serve quite a few different functions, like maintenance of the oncotic pressure, transport of lipids (HDL for example), importance for the immune system and last but not least binding of drugs.
Plasma proteins can be categorized into different families, the most important one for drug binding being albumins. Serum albumin usually has a concentration of 4.6 g/100 ml blood and accounts for around 55% of all blood proteins.
So why are those proteins important for drug users? Because as I said, plasma proteins are able to bind drugs and plasma protein bound drugs aren't pharmacologically active (they aren't metabolized either as they can't diffuse through cell membranes).
If you check the Wikipedia entry of a drug, say clonazepam for example, you'll find the 'Protein binding' on the right side. For clonazepam the protein binding is around 85%. This means that if you have a total concentration of 100 ng/ml clonazepam the effective concentration is only 15 ng/ml the other 85% being bound to preferably albumin (and to a lesser extend 1-acid glycoprotein).
Normally drugs have a much higher affinity to their target receptors than plasma proteins and the binding is reversible, so the plasma protein binding is dependent on the effective concentration and usually proportional to the drug concentration.
So plasma proteins act kind of like a depot as they bind drug molecules when the drug concentration is high and supply drug molecules as the concentration is decreasing. They decrease intensity but increase the duration of action.
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3. Brain/Neuron

This chapter is to prepare you for the next one about different important receptors.

Now most of the effects of psychoactive drugs take place in this squishy pinkish/grey organ called brain. The brain takes about 2% of the body-weight and consumes quite a lot of glucose for its weight. The brain is divided into two hemispheres, the left and right one, connected via commissural nerve tracts, with the corpus callosum being the largest.

The brain consists of various different cells, the primary ones being neurons, glia cells and blood vessels.

For us the neuron is the most important one as that's where the fun takes place. The neuron is a cell that can be electrically excited and receives, processes and transmits information using electrical and chemical signals. Its structure consists of a cell body, also called soma, with dentrites and an axon (usually wrapped in myelin sheat) with axon terminals. Usually a signal is received via the dendrites leading to the soma, the fate of the signal (either transmission or no transmission) is chosen at the axon hillock. From there the signal travels to the axon terminals. This is where the synapse is located.

3.1 Synapse



The synapse is a structure found between neurons that permits those neurons to communicate via chemical signals. It consists of the pre-synapse (= axon terminal), the synaptic cleft and the post-synapse (= dendrite). Now besides this classical axodentritic synapse there are other arrangements like axosecretory (the axon terminal secretes substances directly into the bloodstream) and axoaxonic (the axon terminal secretes into another axon) for example.

3.2 Potential

Now that we understand the structure let's try to understand the processes involved in signaling. As you might remember we learned that the neuron can be electrically excited. I'll now explain how this works.

A cell, like the neuron, is sealed from the outside by the cell membrane. Now there's a difference in voltage due to different ions, the most important ones being sodium, potassium, chloride and calcium, and other stuff, like proteins (usually slightly negatively charged) between the inside of the cell and the outside. This is the reason for the (resting) membrane potential. A typical voltage across a membrane is around -75 mV (resting potential), meaning that the inside of the cell has a negative voltage relative to the outside as long as nothing perturbs the cell.

But as we learned the membrane is packed with different transporters and channels that are able to transport ions and other molecules.

This leads us to the action potential:

The action potential is a temporary shift in the membrane potential from negative to positive due to influx and efflux of different ions.
In the resting phase the two types of voltage gated ion channels, potassium and sodium, are closed. If a stimulus now leads to an increase in voltage and once a certain threshold is reached the voltage gated sodium channels are opened. This leads to a flow of positively charged sodium ions inside the neuron, thus resulting in a positive inside. This phase is called depolarization. Once a voltage of around +40 mV is reached the voltage gated sodium channels will be shut down and inactivated. At the same time voltage gated potassium channels are opened. Positively charged potassium rushes out of the neuron making the inside more negative again. This phase is called repolarization. As the voltage gated potassium channels need some time to close again the potential overshoots to around -90 mV (after hyperpolarization). To get back to the resting potential (-75 mV) the neuron uses Na+/K+ ATPase pumps moving 3 Na+ out and 2K+ ions inside the cell.

Remember the structure of the neuron? Many signals from other neurons arrive at the dendrites, those signals can either.

3.2.1 EPSP and IPSP

So now that we understand the structure of a synapse and how the resting and action potential work we can put it together to understand EPSP (excitatory postsynaptic potential) and IPSP (inhibitory post synaptic potential).

If you remember the structure of a synapse it starts with dendrites. Here's where the EPSPs and IPSPs happen.

An action potential in the pre-synapse leads to the release of neurotransmitters into the synaptic cleft. Those neurotransmitters bind to receptors on the post-synaptic membrane and lead to either an EPSP or IPSP.

Action potentials are all or nothing signals that usually start at the axon hillock. Both excitatory and inhibitory signals from the dendrites are added up and if the excitatory signals exceed the inhibitory an action potential arises at the axon hillock making it's was to the axon terminal where it triggers the release of vesicles with neurotransmitters into the synaptic cleft to trigger an EPSP or IPSP in the downstream neuron.

Glutamate is the most common neurotransmitter associated with EPSP and GABA with IPSP.

3.3 Ligands

3.3.1 Agonist

An (full) agonist is a substance that has an affinity to a certain receptor, binds to this receptor and activates (intrinsic activity) the receptor producing a biological response.

3.3.2 Antagonist

An antagonist is a substance that has an affinity to a certain receptor, binds to this receptor but produces no effects (no intrinsic activity). Another word for antagonist would be blocker, as it block the receptor without activating it. The activity can be reversible (binds to a receptor or enzyme only for a certain period of time) or irreversible (certain MAOIs bind irreversible to the monoaminooxidase rendering the enzyme worthless, so your body has to produce new, functioning enzymes). Antagonists can be competitive (bind to the same binding site as the endogenous ligand/agonist thus competing for the binding site) or non-competitive (doesn't compete for binding either by binding to the receptor irreversibly/nearly irreversible or by binding to another site, this would be called an allosteric antagonist).

3.3.3 Partial agonist

A partial agonist is a substance that has an affinity to a certain receptor, binds to this receptor and activates (intrinsic activity) the receptor, but only partially, producing a biological response lesser than a full agonist. To visualize it think of it this way: We have 100 receptors, a full agonist has a 100% chance of activating the receptor, so by taking a full agonist we activate all 100 receptors. Now a partial agonist has only for example a 50% chance of activating the receptor, so by taking a full agonist we activate on average only 50 receptors.

This can be a problem with certain drugs, like buprenorphine. If you're physically dependent on a full agonist, like morphine, but want to switch to bupe there's something called precipitated withdrawal due to the fact that bupe is only a partial agonist with a high affinity for the mu-opioid receptor. If you take the bupe too soon after taking morphine the bupe will bind to the opioid receptors due to the high affinity but only activate them to a partial extend, leaving you in withdrawal as you're used to the full activation. This can be bypassed by waiting a certain time (check out the COWS score) before buprenorphine induction.

3.3.4 Inverse agonist

An inverse agonist is a substance that has an affinity to a certain receptor, binds to this receptor but induces a response opposite to that of an agonist. This one takes some time to understand, so bear with me. A precondition for a inverse agonist is that the receptor it binds to has something called basal activity, this simply means that there's a certain chance that the receptor spontaneously, without the binding of an agonist, activates itself. Now with that in mind it's easier to understand. The inverse agonist binds to the receptor but instead of activating it, it decreases the activity below the basal level, by decreasing the chance of the receptor activating itself.
If you haven't fully understand this yet let me explain it by using an example. Let's take receptor X with a basal activity of 10 activations a minute. By adding an inverse agonist we decrease the activity from 10 activations a minute to say 2 activations a minute. So the inverse agonist has a negative intrinsic activity.
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4. Receptors

Receptors are categorized by their structure and different mechanisms of action. Classification can differ depending on the book you look it up so here's the one I like the most:

1. Ionotropic receptors are kind of the simplest ones in that there's no second messenger or DNA transcription involved. They're trans-membrane receptors and can be thought of as a channel going through the cell membrane. When a agonist (i.e. drug) binds to it, the receptor will change conformation allowing ions to flow through inside or outside the cell, depending on the ion. That's why they're called IONotropic. The GABA-A or glycine receptor would be examples.

2. Metabotropic receptors are cell-membrane receptors too, but the difference to ionotropic receptors is that they lead to a signal-cascade on the intracellular side of the cell. They can be divided further into GCPRs as the most important ones and other types like tyrosine kinase receptors and others, but those aren't that important for understanding drugs of abuse.

2.1 G protein coupled receptors (GPCR). GPCRs don't have a channel for ions, but as the name suggests, these are receptors that are coupled to another protein, called G-protein, consisting of the alpha, beta and gamma subunit. When a ligand binds to the receptor the receptor in turn activates the G-protein. The G-protein now dissociates into the alpha subunit and the beta-gamma subunit. The alpha unit now activates/deactivates (depending on which type it is) another protein downstream. There are a few alpha units i.e. Gs, Gi, Gq/11 and G12/13. Examples for GPCRs are the adrenoceptors, muscarinic acetylcholine receptor, opioid receptors and dopamine receptors.

For the sake of completeness there are protein synthesis regulating receptors and toll like receptors too, but those aren't important for understanding the mechanism of most drugs of abuse. Additionally there's something called biased agonism or functional selectivity, meaning that a drug can selectively activate/deactivate a certain signal pathway (for example 2C-N binds to 5-HT2B but only leads to the activation of the second messenger PLA2 without activating PLC, this leads to the release of arachidonic acid without the production of IP3) but afaik this is still not fully understood and would be too much for this thread.

4.1 GABA receptors

4.1.1 GABA-A


The GABA-A receptor belongs to the ligand gated ion channels and selectively conducts chloride-ions, leading to an inhibitory postsynaptic potential, meaning that the postsynaptic neuron is less likely to generate an action potential, overall leading to inhibitory effects.

The receptor is a pentamer, meaning that it consists of five subunits. The subunits can be split into various isoforms that are important for properties like agonist affinity etc. The alpha unit can be divided into alpha 1-6, with alpha1 being important for the sedative effects of benzodiazepines, alpha2 for the anxiolytic effects and alpha3 for the muscle-relaxant properties. Then there are three different beta units as well as three gamma units. And finally each one delta, epsilon and theta unit. Most commonly a GABA-A receptor consists of two alpha, two beta and one gamma unit.

There are various endogenous and exogenous ligands with different binding sites. There's the orthosteric binding site (that's where the endogenous ligand GABA binds to) and different allosteric sites (a binding site where the endogenous ligand doesn't bind to).
To activate the receptor two GABA molecules have to bind to the GABA binding site located between the alpha and beta unit. The activation usually leads to an influx of chloride-ions.

Benzodiazepines bind to a allosteric binding site located between an alpha and gamma subunit. For the binding to happen the alpha unit has to contain a histidine residue.

Other binding sites include the loreclezol binding site (valerenic acid most likely binds to this site) and possibly a binding site for ethanol and different volatile anesthetics.

4.1.2 GABA-B

GABA-B is, like GABA-A, a mostly inhibitory receptor, but unlike GABA-A it belongs to the GPCR-family. GABA-B is Gi-coupled and leads to postsynaptic activation of potassium channels and presynaptic inhibition of calcium channels (mostly N-type or P/Q-type). Those effects cause an IPSP and thus decrease the excitability of the downstream neuron.

This receptor is distributed throughout the central and peripheral nervous system, with the highest density in the cerebral cortex, thalamus, cerebellum and amygdala.

Drugs that bind to GABA-B include ethanol, Baclofen, GHB in high doses and Phenibut.

4.2 Opioid receptors

The opioid receptors include the mu-, delta- and kappa-receptor, all of which modulate pain perception. All three are GCPR located in the brain, spinal cord as well as in the gut and bladder. They act pre- as well as post-synaptic. Presynaptic the Gi protein decreases cAMP via a second messenger and causes calcium channels to close, effectively inhibiting the release of substance P and glutamate. Postsynaptic activation of opioid receptors leads to the opening of potassium channels resulting in the hyperpolarization of the postsynapse reducing neurotransmission.

The mu-receptor can be subdivided into mu-1 and mu-2, both of which are the target of most pain meds on the market. Mu-1 is implicated in analgesia, sedation, euphoria, miosis, cough suppression and physical dependence. Mu-2 additionally leads to respiratory depression and constipation.

The delta receptor is implicated in analgesia, antidepressant effects but also in physical dependence and convulsant effects.
The kappa receptor is implicated in analgesia, miosis, sedation, neuroprotection and anticonvulsant effects, but side effects are depression, diuresis and hallucinations (Salvinorin A is a selective kappa-receptor agonist).

4.3 Adrenoceptors

The adrenoceptors are a class of GCPR that are subdivided into alpha- and beta-adrenoceptors. They are targets of many catecholamines like epinephrine and norepinephrine as well as many drugs.

Activation generally leads to stimulation of the sympathetic nervous system and thus is responsible for the fight-flight-or-freeze response leading to an increase in heart rate, increase of blood flow into skeletal muscle and dilated pupils.

Alpha-1 is Gq/11-coupled and activation causes mostly smooth muscle contraction via PLC induced cleavage of PIP2 into DAG and IP3 which in turn increases intracellular calcium. This leads to vasoconstrictions of blood vessels of the skin, GI-tract, kidneys and brain as well as contraction of the urinary bladder. In the brain alpha-1 stimulation produces anorexia and partially mediates the appetite suppressant effects of amphetamine.

Norepinephrine has higher affinity for alpha-1 than epinephrine.

Alpha-2 couples with Gi and is mostly located on vascular prejunctional terminals, inhibiting the release of norepinephrine in a form of negative feedback. In addition alpha-2 receptors are located on vascular smooth muscle cells of certain blood vessels, like skin arterioles and veins. Activation causes Gi to dissociate from the complex and inactivate adenylyl cyclase decreasing cAMP levels. Agonists are have sedative, muscle relaxant and analgesic effects.

Norepinephrine has slightly higher affinity for alpha-1 than epinephrine.

Beta-1 is Gs-coupled and is expressed predominantly in cardiac tissue. Activation leads to a cascade of effects that increase the availability of calcium in cardiac myocytes. Stimulation results in positive chronotropic, dromotropic and inotropic as well as positive lusitropic effects.

Affinities: Isoprenaline > Epinephrine > Norepinephrine

Beta-2 is directly associated with L-type calcium channels and coupled to Gs (and can couple with Gi as well). Agonism leads to adenylyl cyclase activation which in turn increases cAMP concentration triggering PLA which in turn phosphorylates MLC-K causing smooth muscle relaxation. This in turn leads to a decreased motility of the gut, bronchodilatation, increased blood flow to skeletal muscle and as beta-2 activation has stronger effects than alpha-1 on the detrusor urinae muscle urinary retention.

Affinities: Isoprenaline > Epinephrine > Norepinephrine

Beta-3 receptors are Gs-coupled and mainly located in adipose tissue and agonism leads to increased lipolysis.
Affinities: Isoprenaline > Epinephrine > Norepinephrine

4.4 Dopamine receptors

The dopamine receptors consist of 5 different receptors,D1-5, categorized in D1-like (D1 and D5) and D2-like (D2, D3 and D4), all of which are GPCR, but the coupled G-protein varies.

D1-like are Gs coupled (D1 additionally coupled with Golf), thus activation stimulates adenylyl cyclase leading to the rise of cAMP increasing PKA activity.

D2-like are Gi coupled, thus inhibiting adenylyl cyclase, decreaseing cAMP concentration ultimately decreasing PKA activity. Additionally activation leads to opening of potassium channels.

Evidence suggests that G-proteins isn't the only mechanism involved in signaling.

D1 receptors are located on smooth muscle cells of the kidney and mesentery vessels (activation leads to vasodilatation thus better perfusion of kidney and gut) as well as high levels in the basal ganglia (dorsal striatum and ventral striatum, important for motor function as well as learing, cognition and emotion).

D2 receptors are located in the nucleus accumbens, corpus striatum, area postrema (nausea) and anterior pituitary (inhibits release of prolactin). Alternative splicing results in D2Sh (short, presynaptic autoreceptor) and D2Lh (long, postsynaptic).

D2 receptors seem to be down regulated after addictive stimuli like cocaine, heroin or alcohol.

Hyperstimulation of D2 receptors in the mesolimbic system lead to positive symptoms of schizophrenia, while hypostimulation of D2 receptors in the mesocortical system lead to negative symptoms.

D3 receptors are located, among others, in the cerebellum, ventral striatum and nucleus accumbens.

D4 receptors are located in the hippocampus, amygdala and frontal lobe. Mutations/polymorphisms of the gene coding for the D4 receptor have been associated with various behavioral phenotypes, including novelty seeking, ADHD and schizophrenia.

D5 receptors are located in the kidney (regulating sodium excretion), dentritic and T helper cells and in the CNS for example in the hippocampus and amygdala. D4 receptors show 10 times higher affinity for dopamine than D1 receptors.

Dopamine signaling involves many different pathways, the four most important ones are:
a) Mesolimbic (reward-related and aversion-related cognition);
b) mesocortical (executive functions);
c) nigrostriatal (motor function, with substantia nigra); and
d) tuberoinfundibular (inhibition of prolactin release) pathway and hypothalamospinal (motor function) projection.

I'll try to go into more detail in the upcoming chapter 7.

If you're really interested in the dopamine receptors you can check out this book:
'The physiology, signaling and pharmacology of dopamine receptors' http://pharmrev.aspetjournals.org/content/63/1/182

4.5 Serotonin receptors

Serotonin receptors (5-HT receptors) are located, among others, in the CNS, gastrointestinal tract (here's most of the serotonin), cardiovascular system and platelets. With the exception of 5-HT3 (ligand gated ion channel) are all GPCRs.

5-HT1 has 5 characterized subtypes: A,B,D,E,F (after 5-HT1C was cloned and characterized it seemed to have more in common with 5-HT2 than 5-HT1 so it was redesignated as 5-HT2C)
5-HT1 is Gi coupled so activation leads to inhibition of adenyly cyclase thus reducting cAMP levels
5-HT1A is located in blood vessels and the CNS and is implicated in, among others, anxiety (people suffering from anxiety and depression seem to have reduced density of this receptor in certain parts of the brain) and memory as well as regulation of temperature and blood pressure
5-HT1B and 5-HT1D are Gi coupled as well and are located in the CNS and blood vessels. They play an important role in migraines, as they are located in meningeal blood vessels. Activation of postsynaptic 5-HT1B leads to vasoconstriction while activation of presynaptic 5-HT1D leads to inhibition of neuropeptide secretion.
5-HT1E is located in both the CNS and blood vessels
5-HT1F is found in the CNS and seems to be important for suppression of neuronal inflammation.

Migraine hypothesis: Activation of 5-HT2B leads to NO release which in turn causes vasodilatation in meningeal blood vessels and stimulation of the trigeminal nerve. This leads to the secretion of neuropeptides which reinforce the vasodilatation leading to edema and triggers action potentials that cause nausea and pain

5-HT2 has 3 characterized subtypes: A, B and C that are Gq coupled .
5-HT2A is pretty much ubiquitous as it's located in blood vessels, CNS, PNS, GI tract, smooth muscles and platelets. The receptor plays important role in hemostasis in platelets and due to vasoconstriction. In the CNS the receptor seems to mediate the effects of classic psychedelics like LSD and psilocin. 5-HT neurons in the brainstem project to glutamergic pyramidal cells in deep cortical layers V and VI and cortical pyramidal neurons. Activation of 5-HT2A receptors located on the glutamergic pyramidal cells leads to the release of glutamate into the synaptic cleft stimulating NMDA and AMPA receptors on cortical pyramidal neurons. In addition 5-HT2A receptors are located on cortical pyramidal neurons as well. Both lead to the increased expression of BDNF (brain-derived neurotrophic factor).
Drugs that target 5-HT2A are used as platelet aggregation inhibitors and to treat high blood pressure. 5-HT2A is also targeted by atypical antipsychotics like clozapine and antidepressants seem to down regulate postsynaptic 5-HT2A receptors leading to the anxiolytic effects.
5-HT2B is implicated in high blood pressure and chronic activation might cause damage of heart valves as it plays a role in the regulation of cardiac structure and function leading to proliferation of cardiac valves fibroblasts
5-HT2C is implicated in sexual behavior as well as food intake (activation leads to the activation of the proopiomelanocortin-system in the hypothalamus as well as decreasing the release of neuropeptide Y and agouti-related peptide, suppressing appetite).

5-HT3 is the only ligand gated ion channel (selective for sodium and potassium) located in CNS, PNS and GI tract with an important role in the Area postrema and afferent vagus neurons. Stimulation leads to nausea.

5-HT4 is Gs coupled and located in the GI tracts, CNS and PNS. This receptor plays an important role in regulating gut motility and heart rhythm.

'Higher' 5-HT-receptors include 5-HT5A (possible regulation of circadian rhythm) and B (pseudogene), 5-HT6 (possibly implicated in learning) and 5-HT7 (regulation of circadian rhythm and blood pressure as well as thermoregulation).

4.6 NMDA receptor

NMDA stands for N-methyl-D-aspartate-receptor, named after N-methyl-D-aspartate, a selective agonist of this receptor. The NMDA receptor is an ionotropic glutamate receptor, both ligand gated (activated with co-binding of glutamate and glycine/D-serin) and voltage-dependent due to a magnesium/zinc block that only dislodges after AMPA receptor activation depolarizes the cell enough. Activation leads to an influx of mainly calcium as well as sodium influx and potassium efflux. Compared with AMPA receptors NMDA's postsynaptic current last for a few hundred microseconds, which is rather long. Overactivation with a high level of calcium influx is thought to be excitotoxic.
The NMDA receptor is a heterotetramer complex consisting of two obligatory GluN1 subunits and two variable subunits (GluN2 A-D or GluN3 A-B).
NMDA receptors are implicated in learning and memory formation as well as synaptic plasticity.

If you're really interested in the NMDA receptor you can check out this book:
'Biology of the NMDA Receptor' https://www.ncbi.nlm.nih.gov/books/NBK5283/

4.7 hERG

hERG stands for human Ether-a-go-go Related Gene, a gene coding for the alpha subunit of a cardiac voltage gated potassium channel (called Ikr) responsible for the electrical activity coordinating the heartbeat. Now as you might imagine drugs interacting with this channel are able to cause arrhythmia and in the worst case can kill you. To go a little more into detail, this channel is partially responsible for the repolarization due to potassium efflux. Now if you change the timing of repolarization you get either a too fast (short QT syndrome) or not fast enough (long QT syndrome) repolarization. Both of those syndromes can lead to abnormal heart rhythms and can lead to sudden cardiac death. The long QT syndrome is the more common one and there are quite a few drugs that can cause it, including antihistamines like diphenhydramine, methadone, various antidepressants, cocaine, Dextromethorphan and loperamide. Normally the long qt syndrome only persists as long as you take the drug, but some people are genetically predisposed and the prolongation won't resolve itself after cessation of the drug.
Symptoms of QT prolongation include palpitations, chest pain, fainting (= syncope) and fatigue. This syndrome can be lethal as it can lead to an abnormal heart rhythm called 'Torsade de pointes' which in turn can lead to sudden cardiac arrest. Because of that high doses of drugs that are known to cause QT prolongation and combinations of those drugs can be dangerous and shouldn't be done.

4.8 TAAR1

TAAR1 stands for trace amine-associated receptor 1. TAAR1 is a GPCR coupled with Gs and Gq-proteins and is located in the CNS (presynaptic plasma membrane of monoamine neurons) and peripheral cells/organs (stomach, gut, white blood cells, kidney, lungs). TAAR1 is one of six trace amine-associated receptors and plays an important role in regulating monoamine neurotransmission.
As the name suggests TAAR1's endogenous ligands are trace amines with the following potencies:
tyramine (related to dopamine) > beta-phenethylamine (related to dopamine) > dopamine () = octopamine (related to norepinephrine).
TAAR1 is an intracellular receptor, thus ligands have to diffuse across the presynaptic membrane (methamphetamine) or through membrane transporters ((meth-)amphetamine) to bind to it.
There's some selectivity as for example a drug that is only able to enter the presynapse via SERT will mostly bind to TAAR1 receptors found in serotonin neurons.
With TAAR1 coupled with Gs activation leads to activation of adenylyl cyclase increasing cAMP in the presynapse which in turn can up-regulate the expression of trace amines. Another mechanism is DAT phosphorylation by either PKA (leads to DAT internalization) or PKC (reveres transporter function).

4.9 VMAT (transporter)

VMAT stands for vesicular monoamine transporter. VMAT2 is a protein located in the membrane of cytoplasmic vesicles and is only found in vertebrata. Besides the CNS VMAT2 is located in pancreatic islets (regulates insulin response to glucose) and uterus. Mouse studies suggest a difference of neuronal VMAT2 activity in genders.
In the CNS it's responsible for the transport of the monoamines dopamine, serotonin, histamine and norepinephrine (and sometimes GABA) from the cell cytosol into synaptic vesicles. As antiport VMAT2 swaps intravesicular H+ for monoamines from the cell cytosol.
VMAT2 possesses at least two binding sites characterized by tetrabenazine (for the treatment of hyperkinetic movement disorders, for example seen in Huntington's disease, mechanism not fully understood but most likely reversible depletion of monoamines due to VMAT2 antagonism) and reserpine (has been used to treat high blood pressure and psychotic symptoms, works by depleting monoamines). Amphetamines work similarly by inhibiting VMAT2, but, unlike reseprine and tetrabenazine, reverse the direction of monoamine transporters so the cytosolic monoamines can be transported to the synaptic cleft.
Fun fact: in the book 'The God Gene: How faith is hardwired into our genes' by molecular biologist Dean Hamer it's suggested that VMAT2 is responsible for spirituality/'is the gene where God may reside' but the study the claims are based on hasn't been published in a peer review journal and is highly controversial.
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5. Interactions

5.1 Serotonin syndrome

What is serotonin syndrome (SS)?
SS or better serotonin toxicity is a consequence of the buildup of serotonin in the synaptic cleft leading to an overstimulation of both peripheral and central postsynaptic serotonin receptors, 5HT-2A receptors being the most important ones. This results in a number of different and possibly life threatening symptoms. So if you think you or a friend suffers from SS call an ambulance now!

What causes SS?
Serotonin syndrome can occur via the therapeutic use of serotonergic drugs alone, an overdose of serotonergic drugs, or classically, as a result of a complex drug interaction between two serotonergic drugs that work by different mechanisms. A multitude of drug combinations can result in serotonin syndrome.

What are the symptoms?
The symptoms of serotonin syndrome usually present within 6 to 8 hours and most likely within 24 of overdosing or combining serotonergic drugs and can be barely noticeable to fatal.

Autonomic effects include:
Nausea, Diarrhea, Headache, Sweating, Shivering, Tachycardia, Rise in blood pressure, Rapid breathing, High pulse, Mydriasis

Somatic effects include:
Muscle twitching, Tremor, Hyperreflexia, Akathisia, Ocular clonus (slow continuous lateral eye movement), Increased muscle tone (lower limb>upper limb)

Cognitive effects include:
Confusion, Hallucination, Agitation, Restlessness, Anxiety, Delirium, Coma

Drugs that can cause SS:

Increased serotonin synthesis
- Tryptophan
- 5-Hydroxytryptophan

Increased serotonin release
- Amphetamines
- Hallucinogenic amphetamines

Inhibition of serotonin uptake
- Tricyclic antidepressants
- Cocaine
- St john’s Wort
- Dextromethorphan (DXM)
- Tramadol

Decreased serotonin metabolism
- Monoamine oxidase-Inhibitors
- Syrian rue

Activation of serotonergic receptors
- Buspirone, Triptans

Increasing the effects of serotonin
- Lithium

Other drugs
- Panax ginseng, Nutmeg, Yohimbe, valproate chlorpheniramine, risperidone, olanzapine, ondansetron, granisetron, metoclopramide, ritonavir and linezolid, Fentanyl, methadone, (tapentadol)?

Another mechanism involves the inhibition of certain cytochrome P450 (CYP450) enzymes with white grapefruit juice, cimetidine, methadone etc.

SS is potentially lethal as hyperthermia, rhabdomyolysis, seizures, kidney failure, aspiration and other symptoms can occur.
Stop taking the drugs/medication and call an ambulance!

5.2 Depressants

Combining CNS depressants (ethanol, benzodiazepines and opioids for example) will lead to synergism in most cases. While this synergism is mostly sought-after it increases side effects and potentially lethal effects exponentially.
Let's look at an example taken from the Wikipedia entry about barbiturates: " Barbiturates in overdose with other CNS (central nervous system) depressants (e.g. alcohol, opiates, benzodiazepines) are even more dangerous due to additive CNS and respiratory depressant effects. In the case of benzodiazepines, not only do they have additive effects, barbiturates also increase the binding affinity of the benzodiazepine binding site, leading to exaggerated benzodiazepine effects. (ex. If a benzodiazepine increases the frequency of channel opening by 300%, and a barbiturate increases the duration of their opening by 300%, then the combined effects of the drugs increase the channels overall function by 900%, not 600% )."
Now this synergism is what makes CNS depressant combos so dangerous, as it's not as simple as 1+1=2. Most of the time the effects increase exponentially and are hard/impossible to control.
The some of the most dangerous effects are a drop in blood pressure, in some cases increase in nausea (take ethanol + ketamine for example), decreased inhibition (while this may sound like fun it increases the risk of getting into a fight, accidents etc.) and black outs, ischemia due to a bad position while sleeping and last but not least respiratory depression.
Take benzodiazepines for example. Usually you can munch on a whole bottle without risking your life (don't do it though), but if you add another CNS depressant like ethanol or an opioid your risk of respiratory depression increases exponentially (I know I've used this word three times in the last few sentences, but I can't stress enough how dangerous those combos are).
Many great people have died due to such combos, it's not worth it!

5.3 Vasodilatants

Combining poppers (alkyl nitrites) and PDE-5 inhibitors like sildenafil (viagra) is a really bad idea as both lead to vasodilatation thus working synergistically. This can lead to fainting and a potentially lethal drop in blood pressure.

5.4 Stimulants

Combining certain stimulants with a MAOI can cause serotonin toxicity and hypertensive crisis.
Combining stimulants may cause exra strain to your heart.
This is not a combination per se but if you suffer from hypertension (high blood pressure) taking stimulants is a bad idea as they usually increase BP and can do so to dangerously high levels which can result in a hypertensive crisis and in the worst case hypertensive emergency.
There has been a dogma to not give beta-blockers in stimulant overdose due to unopposed alpha-stimulation, but
stimulants cause excessive catecholamines. Beta-blockers are the only class of medication that directly antagonizes this effect. Based on the results of our systematic reviews we determined alpha-blockers (phentolamine), nitric-oxide mediated vasodilators (nitroglycerin, nitroprusside), and calcium channel blockers treat hypertension, not heart rate. A beta-blocker like labetalol will do both effectively and safely.
Either way if your heart rate and blood pressure are through the roof go to the ER!

Stimulants like (meth-)amphetamine and MDMA might be neurotoxic, meaning that they damage neurons. It seems that brain hyperthermia (high temperature of the brain) reinforces the toxicity so try to stay cool and stay hydrated as well.

5.5 Enzyme induction/inhibition
Here's a list of the most common CYP isozymes with substrates, inhibitors and inducers http://www.resourcepharm.com/pre-re...-and-inducers-of-the-major-CYP450-enzyme.html
6. Drugs

6.1 Stimulants

Stimulant is an umbrella term for drugs that have sympathomimetic effects and thus increase the activity of the CNS, i.e. increase of alertness, arousal and motor activity. Those drugs include prescription drugs like methylphenidate and lisdexamphetamine, as well as more recreational drugs like cocaine.

Most interact with monoamine (dopamine, norepinephrine and serotonin) neurotransmission. They often work by inhibiting the re-uptake of monoamines from the synaptic cleft into the pre-synapse as well as by reversing the monoamine transporter (VMAT).
Stimulants can be divided into different subgroups depending on their chemical backbone. The most important groups are amphetamines, cathiones and phenidates.

Subjective effects include wakefulness, stimulation, euphoria, appetite suppression and increased focus. Side effects include teeth grinding (chewing gum helps with this), anxiety (especially if you're predisposed), problems sleeping and vasoconstriction leading to increased heart rate and blood pressure.

6.1.1 Caffeine


While most people don't see Caffeine as a drug it is indeed a psychoactive substance and can quite addictive. But it's legal and enjoys great popularity. It doesn't really offer the recreational effects of other stimulants, but provides stimulation and wakefulnass.

Caffeine is an alkaloid belonging to the xanthine-class with around 60 plant species producing it. The most common sources are the coffee plants "Coffea arabica" and "Coffea canephora" and tea. Other sources include the kola nut, yerba mate and guarana.

Funnily enough plants use caffeine as pesticide to inhibit insect feeding most likely by inhibition of PDE and cAMP increase, killing insects that haven't adapted to it yet.

Effects include CNS activation, increased heart rate and contraction (positive chronotropic and inotropic), bronchodilatation, weakly diuretic and increased peristalsis.

Caffeine main mechanism of action is acting as an antagonist at all four adenosin receptor subtypes with decreasing affinity A2A>A1>A2B>A3. Caffeine also acts as phosphodiesterase inhibitor leading to increased intracellular cAMP and acetylcholinesterase inhibitor. Additionally it has effects on many important neurotransmitters, including dopamine, serotonin and in high doses even GABA and norepinephrine.

While awake the brain concentration of adenosine is steadily increasing and exceeding a certain threshold triggers fatigue. As caffeine is structurally quite similar to adenosine it binds to said adenosine-receptors and blocks adenosine from binding to them, without activating them, making it a competitive inhibitor.

Oral dosages go from 20 mg as a threshold to 400-500 mg as a strong dose.

The duration of action is around 3-5 hours for oral and less for insufflation (dosage has to be decreased accordingly for intranasal application).

Caffeine's half life is around 3-7 hours and has active metabolites including paraxanthine (increases lipolysis, so the breakdown of lipids [fats]) and theobromine (vasodilatation).

6.1.2 Amphetamine


Amphetamine or alpha-methylphenetylamine is, as the name suggests, a methyl homolog of phenethylamine as it has an additional methyl-group on the alpha-carbon after the amino-group. This makes amphetamine chemically related to trace amines like phenethylamine.

Amphetamine was used under the brand name Benzedrine for a wide range of ailments and it's still used today to treat ADHD, narcolepsy and in some rare cases obesity.

Normal amphetamine is a racematic mixture of 1:1 levo- and dextroamphetamine.

The amphetamine base is a colorless liquid with a quite strong amine smell. Given that the base is rather volatile and caustic amphetamine is usually sold in its salt form (the amino-group is usually protonated, giving it a positive charge, while the sulfate is negatively charged, making amphetamine-sulfate neutral) with amphetamine sulfate being the most prevalent one.

The mechanism of action of amphetamine is complex as it has quite a few biological targets, but it primarily acts by increasing dopamine and norepinephrine concentration in the brain.

Amphetamine enters the presynaptic neuron either through DAT, thereby inhibiting the reuptake of dopamine, or by simply diffusing across the neuronal membrane.

Amphetamine is a potent full agonist of TAAR1, a Gs- and Gq-coupled GPCR. Activation of TAAR1 in turn activates adenylyl cyclase increasing cAMP concentration in the cell. Additionally activation leads to DAT phosphorylation through PKA and PKC signaling. This inhibits monoamine transporter function. Dextroamphetamine is a roughly 3-4 times more potent agonist at this site as levoamphetamine.

In addition amphetamine also inhibits both vesicular monoamine transporter 1 and 2. Both acidic glycoproteins are used to transport the neurotransmitters dopamine, serotonin, histamine, norepinephrine and epinephrine into transport vesicles ready to fuse with the presynaptic membrane, releasing the neurotransmitters into the synaptic cleft. By inhibiting VMATs cytosolic catecholamine levels are increased and this can result in an efflux through the plasma membrane.

Other targets of amphetamine include SLC1A1, SLC22A3, SLC22A5 and CART.

Amphetamine can be used oral, intranasal, can be plugged and can be injected.

The oral bioavailability depends on the gastrointestinal pH and increases when pH increases. The oral bioavailability is normally over 75%.

Oral and insufflated dosages range from 5 mg to 70 mg, with 20-30 mg being a common dose, while injected dosages are smaller.
Amphetamines half life depends on the enatiomer form (levo has a longer half life than dextro) and urinary pH.

Orally taken, amphetamine usually lasts for around 3-8 hours, while intranasal and injected amphetamine usually doesn't last as long.
Amphetamine is metabolized via CYP2D6, DBH, FMO3, XM-ligase and GLYAT with active sympathomimetic metabolites.

6.1.3 Methamphetamine



N-methylamphetamine is amphetamine substituted with a methyl group at the amine making it more lipophilic. It was synthesized in 1893, but only became popular around the 1930s. It has been used medically and recreationally due to its productive stimulation and euphoric effects. Methamphetamine is still sometimes used to treat ADHD and rarely used to treat obesity under the trade name Desoxyn.

Even though most of its harms have been exaggerated neurotoxicity and psychosis at heavier doses and prolonged usage, especially combined with sleep deprivation are a major concern.

Like amphetamine methamphetamine is a full agonist of TAAR1 and acts on VMAT-1 and -2, as well as SLC1A1, SLC22A3, SLC22A5 thus increasing the concentrations of norepinephrine > dopamine > serotonin in the synaptic cleft. It is also known to increase intracellular calcium concentrations which increases DAT phosphorylation. Additionally, methamphetamine is an agonist of alpha-2 and sigma receptors and inhibits MAO-A and -B in high doses. And like amphetamine, the dextro-enantiomer has higher CNS stimulation effects while the Levo-enantiomer leads to more peripheral stimulation and has a longer half-life.

Methamphetamine can be taken orally, intranasally, plugged, smoked and injected.

Orally effects last around 6-12 hours, intranasal/inhaled/i.v. around 1-6 hours with a more rapid onset. Sleep and peripheral stimulation can last even longer.

The half-life ranges from 5 hours up to 30 hours.

Oral doses usually range from 5 mg to up to 50 mg for strong effects, intranasal and inhaled 5-40 mg and with i.v. 5-25 mg.

Methamphetamine is metabolized via CYP2D6, DBH, FMO3, XM-ligase and GLYAT with active sympathomimetic metabolites, like amphetamine.

Excretion is primarily renally through the urine

6.1.4 Cocaine



Cocaine is a tropane-alkaloid usually extracted from Erythroxylum coca (alkaloid content ranges from 0.25 . 0.77% ). It is a weakly alkaline compound and therefore can be used either as the free base (created by neutralizing the compounding salt with an alkaline solution, for crack baking soda is used) or in salt form. Cocaine has been used as an antidepressant, stimulant, local anesthetic and as coca tea for altitude sickness.

Cocaine is potentially cardiotoxic, especially when combined with ethanol (forms cocaethylene) and high doses have been implicated in sudden cardiac death.

Cocaine acts by inhibiting DAT (IC50 = 690 nmol/l), NET( IC50 = 367 nmol/l) and SERT (IC50 = 389 nmol/l) as well as by inhibition of 5-HT3, activating sigma receptors and blocking sodium channels. This leads to increased concentrations of dopamine, norepinephrine, and serotonin in the brain. Due to the sodium channel blockage, it inhibits the propagation of action potentials and therefore can lead to numbness as well as arrhythmia.

Cocaine has a short half-life of around 1 hour and is extensively metabolized via cholinesterases and CYP3A4.

The most common route of administration is intranasal with a rapid onset of usually < 1 min and a total duration of under two hours. Bioavailability is around 30-60%. Dosages range from 10 mg to 90 mg for a strong experience.

Another route is via injection, which has the highest bioavailability so dosage decreases compared to insufflation. As cocaine is a strong vasoconstrictant subsequent injections during a binge are progressively harder to administer.

Cocaine free base, mostly as crack cocaine, is inhaled and exhibits the fastest onset of action, but has the shortest duration of effects of only around 5-15 min. This can lead to compulsive re-dosing and craving.

High doses of cocaine can lead to extreme nausea and some people report that puking after a particularly high dose is common. This might be due to excessive stimulation of the Area postrema.

Massive doses of cocaine, when injected or smoked, can lead to a so-called Bell-ringer, an experience that includes high pitched sounds and tunnel vision. The cause still isn't known, but an excessive rise in blood pressure in the ear and intraocular pressure are implicated. It is advised against taking such massive amounts as increased blood pressure takes a strain on the heart and especially cocaine has been implicated in causing seizures and strokes.

6.1.5 Methylphenidate



Methylphenidate is a stimulant that is commonly used in children as first-line treatment for ADHD under the brand names Ritalin and Concerta. It belongs to the substituted phenethylamine and piperidine classes. It is phenethylamine with a methyl acetate group added on the alpha carbon and four carbons connecting the beta carbon and amino group, building piperidine.

Methylphenidate is used recreationally, but usually produces less euphoria than amphetamine, therefore is mostly used for its motivational and focusing effects, making it a good tool for all-nighters.

Methylphenidate works by increasing the activity of the CNS by inhibiting the reuptake of norepinephrine and dopamine. It binds and blocks both DAT (IC50 = 34 nmol/l)and NET (IC50 = 339 nmol/l) with no significant effects on SERT (IC50 = >1000 nmol/l). It may be a sigma 1 receptor agonist leading to the phosphorylation of the NMDA receptor.

Methylphenidate can be taken orally or intranasally (advised against due to the fillers and binders used in the pills).

When used orally methylphenidate has a bioavailability of around 11-52% and a half-life of around 2-3 hours. The effects usually only last for a few hours most and sometimes come with a rebound. Dosages range from 5 mg to 60-80 mg for a strong experience.

Used intranasally the onset of action is faster, but the duration of action decreases a little. Doses range from 5 mg up to 60 mg for a strong experience.

Methylphenidate is metabolized into ritalinic acid by CES1A1 and primarily excreted renally in the urine.

6.1.6 MDMA



3,4-Methylenedioxymethamphetamine (MDMA) is a substituted amphetamine and the most popular entactogen (coined by D. E. Nichols, produces distinct effects like empathy, sociability, and interpersonal closeness). It was first synthesized by German chemist Anton Kollisch for Merck as a precursor for an anticoagulant, methyl hydrastinine. The great therapeutic and recreational potential was later discovered by Alexander Shulgin, the 'godfather' of MDMA, thanks to Marty, Merrie Kleinman, Flip, and C.B.

MDMA has been used as an adjunct in psychotherapy, but as of now, it hasn't been approved for medical use. However, there are clinical trials for MDMA-assisted psychotherapy by MAPS (https://maps.org/research/mdma).

Recreationally it is often used in the rave scene. As pills and powder are often cut, sometimes with extremely dangerous drugs like PMA, use a pill checker like https://www.bluelight.org/vb/forums/159-Pillreports-net-Testing-Q-amp-A-and-Discussion as well as reagent tests, for example, https://dancesafe.org/shop/

Here's a great source of info about MDMA's neurotoxicity https://thedrugclassroom.com/video/mdmas-neurotoxicity-research-shows-reduce-risk-detailed/

MDMA is a releasing agent of serotonin, norepinephrine, and dopamine due to TAAR1 agonism and VMAT2 inhibition activity with serotonin being the most important neurotransmitter for its action. In addition, MDMA is a competitive reuptake inhibitor of monoamines as MDMA itself is a substrate of those transporters. There seems to be weak agonism of 5-HT-1 and -2 receptors and some affinity for alpha-2. Application of MDMA leads to the rise of oxytocin (via activation of the paraventricular nucleus and supraoptic nucleus of the hypothalamus), cortisol and prolactin.

The metabolism is catalyzed by CYP450 isozymes with CYP2D6 being the most important one and HMMA as main metabolite. MDA is another minor metabolite (plasma concentrations < 5-10% of MDMA's) that is active.

The half-life is around 8 hours.

Dosage ranges from 40 mg to 150 mg orally with the rule of thumb of roughly 1.5 times body weight

The duration of action is around 4-6 hours with an onset normally after 30-45 min orally.
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6.2 Depressants

Like stimulants depressant is an umbrella term for drugs that depress the CNS, thus decreasing brain activity. Some drugs are legal, like ethanol, some prescription only, like the gabapentinoids gabapentin and pregabalin, while others are illegal.

The members of this group are chemically relatively diverse, ranging from a small molecule, like ethanol, to more complex ones, like the barbiturates and gabapentinoids.

Their mechanism of action is relatively diverse as well with increased GABA activity and glutamatergic inhibition, mostly via NMDA receptors, being the most prominent ones.

Effects include sedation, anxiety suppression/decrease of inhibitions, though deceleration, euphoria and muscle relaxation. The most serious side effects is respiratory depression, especially when two or more depressants are combined.

Depressant usage can lead to physical dependence and withdrawal can kill you, especially from high doses of benzodiazepines due to seizures and excitotoxicity.

6.2.1 GHB/GBL



GHB (gamma-hydroxybutyric acid) is structurally related to GABA (gamma-aminobutyric acid) but instead of the amino group it has a hydroxy-group and can be found in the human body as well as in small concentrations in, among other things, wine and some citrus fruits due to fermentation.

While one might think that it behaves much like GABA itself and binds and exerts it's function via the GABA-A receptors, it binds to the newly found GHB-receptor and in higher doses to the GABA-B receptor. It has been used by bodybuilders due to its positive effects on growth hormones and as an anesthetic. It's still used in people suffering from narcolepsy.

We still don't know a lot about the GHB receptor, but activation seems to cause stimulant effects, thought to be mediated through an increased Na+/K+ current as well as increased release of dopamine and glutamate.

At therapeutic doses GHB reaches high concentrations in the brain leading to the activation of GABA-B receptors. As we learned earlier GABA-B is an inhibitory GPCR, thus activation leads to the sedative effects of GHB.

Due to the activation of both GHB and in higher doses GABA-B receptors GHB has a biphasic effect of more stimulating effects with smaller doses and more pronounced sedative effects in higher doses. This also causes the 'rebound effect' as low doses of GHB stimulate dopamine release while higher doses inhibit the release. So after a high dose dopamine release is inhibited until most of the GHB is metabolized, leading to an increase in dopamine release afterwards. This also explains the sudden awakening of people after a so called 'GHB coma' due to an overdose.

GBL, the lactone of GHB, is rapidly metabolized into GHB in vivo by lactonase enzymes in the blood. Because GBL is more lipophilic than GHB the onset of action and bioavailability are increased, making GBL stronger than GHB.


Oral doses range from 0.5 g as a light dose to 2.5 - 4 g being a strong to heavy dose.

First effects are usually felt after 5-30 min with the peak after 45-90 min. The duration of action is between 1.5 - 2.5 hours but after effects can be felt for a few more hours.


Oral doses range from 0.3 ml as threshold to 1.5 - 2 ml. Anything over 2 ml can induce heavy sleeping, also referred to GHB-coma (in this case turn the person into recovery position, make sure he/she doesn't stop breathing or chokes on their vomit and call an ambulance).

6.2.2 Pregabalin



Pregabalin is a GABA analogue with an isobutyl-group added to the third carbon of the aminobutyric chain, belonging to the gabapentinoid class. It's marketed under the brand name Lyrica to treat epilepsy, fibromyalgia, neuropathic pain, GAD and RLS. Pregabalin is also used recreationally die to its euphoric, pro-social and anxiolytic effects.

Pregabalin has a similar pharmacological profile as Gabapentin, but has higher bioavailability and potency.

Pregabalin exerts its effects via voltage gated/dependent calcium channels (VDCCs) binding to the alpha-2-delta-1 and -2 site acting as an inhibitor. By inhibiting alpha-2-delta subunit-containing VDCCs it reduces the release of excitatory neurotransmitters like glutamate, substance P, acetylcholine and norepinephrine. In addition Pregabalin seems to increase the expression of the enzyme L-glutamic acid decarboxylase that catalyzes the decarboxylation of glutamate into GABA, thus increasing GABA concentration.

Pregabalin is rapidly absorbed from the gut via LAT1 and other carriers. As LAT1 isn't the only carrier responsible for absorption the pharmacokinetics aren't dose dependent, like with gabapentin and are linear without saturation of absorption. The high bioavailability of around 90% isn't significantly influenced by food, but food can delay absorption and reduce peak plasma levels.

While pregabalin isn't that lipophilic the carrier LAT1 transports it across the blood-brain-barrier leading to systemic effects.

The onset of action varies widely from 30 min to 2 hours and effects can last up to 14 hours with some after effects being still present the day after. The half life is around 6-7 hours.

Medical doses range from 150 mg to 600, while recreational doses can go as high as 600 to 900 mg for strong effects and some people even report doses over 1 gram, but as we don't know much about its safety at doses this high its best to avoid taking this much.

Pregabalin undergoes nearly no metabolism and is mainly excreted renally in the in the urin.

6.2.3 Gabapentin



Gabapentin is another GABA analogue with a cyclohexane ring added to at the 3 position of the aminobutyric chain, belonging to the gabapentinoid class. It's marketed under the brand name Neurontin to treat epilepsy, neuropathic pain and RLS. Gabapentin is also used recreationally die to its euphoric, pro-social and anxiolytic effects.

Its pharmacological profile is similar, acting as an inhibitor of alpha-2-delta VDCCs. It potentially modulates the enzymes glutamate decarboxylase and branched chain aminotransferase, both involved in GABA synthesis.

As gabapentin is only absorbed by an active transport via LAT1 the pharmacokinetics are dose dependent with bioavailability decreasing with dosage. This leads to an oral bioavailability of 80 % at 100 mg and only 27 % at 1.6 g. Decreased bioavailability can be avoided by taking gabapentin enacarbil, staggering doses, or possibly by slowing down gut transit time.

The onset of action varies from 30 min to 1.5 hours and effects can last up to 8 hours. The half life is around 5-7 hours.

Doses range from 300 mg to 900 mg - 1200 mg for strong to heavy effects.

Pregabalin undergoes nearly no metabolism and is mainly excreted renally in the in the urin.

6.2.4 Phenibut



Phenibut is yet another GABA analogue with a phenyl ring substituted in at the 3 position if the aminobutyric chain and is similar to baclofen (has a chloride-atom added at the para-position). It has been used for medical purposes as anxiolytic in Russia while it's a non-prescription, not approved drug in most other countries. It's usually sold as 'supplement', but this might be misleading, as phenibut possesses powerful effects and long term use/abuse can lead to physical and psychological dependence.

Until a few years ago phenibut was seen as a GABA-B agonist, but recent studies have shown its activity at the alpha-2-delta site of VDCCs. Phenibuts affinity for alpha-2-delta is around 60 ?M for the racemate while only around 177 ?M for GABA-B making the action as alpha-2-delta inhibitor its main mechanism of action.

The threshold dose is around 0.25 - 0.5 g and a strong to heavy dose is 2 - 3.5 g.

The onset is rather slow taking up to 3 - 4 hours after ingestion. Effects can last for around 10 to 16 hours and some after effects can be felt the next day.

Oral bioavailability seems to be around 63 %, but other routes of administration, like rectally or intravenous are advised against due to the low pH of phenibut solution.

The elimination half life is around 5 - 6 h and phenibut seems to only minimally undergo metabolism. Phenibut is excreted renally in the urine.
6.2.5 Benzodiazepines

What are benzos ?
Benzodiazepines are a class of GABAminergic psychoactive drugs whose core chemical structure is the fusion of a benzene ring and a diazepine ring. The first such drug, chlordiazepoxide (Librium), was discovered accidentally by Leo Sternbach in 1955, and made available in 1960 by Hoffmann–La Roche
They are used to treat insomnia (only short term, as tolerance to the hypnotic properties of benzos builds rapidly), anxiety, seizures (not commonly used due to tolerance), muscle spasm and alcohol withdrawal.

How do they work ?
Benzos are positive allosteric modulators of the GABA-A receptor. Unlike other positive allosteric modulators that increase ligand binding, benzodiazepine binding acts as a positive allosteric modulator by increasing the total conduction of chloride ions across the neuronal cell membrane when GABA is already bound to its receptor. So they work by increasing the efficiency of a natural brain chemical, GABA, to decrease the excitability of neurons. This reduces the communication between neurons and, therefore, has a calming effect on many of the functions of the brain.
The GABA-A receptor consist of different subtypes, the predominant subtypes in the brain being those that contain alpha1-, alpha2-, alpha3-, and alpha5-subunits.
Studies show, that hypnotic effects seem to be mediated via alpha1 subunits sites, anxiolytic and muscle relaxant effects via alpha2/3 subunits and anticonvulsant properties via alpha5 subunits.
So different benzos have different affinities for the subtypes making every benzo unique in its effects.
Although it is relatively simple to address questions at the level of individual receptor subunit isoforms, we can only speculate how many GABA-A receptors are expressed in our brain and what their subunit composition is, not to mention subunit arrangement. Experiments have therefore been limited to the role of defined receptor subunit isoforms. Knock-out mice in which a functional gene for a certain GABA-A receptor subunit is lacking have been prepared. Elimination of a particular subunit isoform would be expected to suppress synthesis of all those GABAA receptor isoforms containing the subunit in question and cause alteration in the behavior of the mutant mice. This is expected to give information on the function of the corresponding subunit isoform. Such studies have the inherent drawback that hundreds of genes show adaptive changes as a consequence of the lack of a subunit. A more elegant approach to this question is knock-in mice carrying the point mutation alpha1-H101R (and homologous mutations in alpha2, alpha3, and alpha25), rendering the site for benzodiazepines at the alpha/gamma subunit interface insensitive to these drugs. In behavioral experiments, it was tested which benzodiazepine effects were missing in the mutant animals. Such experiments associated the alpha1 subunit with sedation, the alpha2/3 subunits with anxiety, and the alpha5 subunit with temporal and spatial memory. In attempts for simplification, it was stated that “alpha1 receptors” or “alpha1 subunit-containing receptors” confer sedation, “alpha2/3 receptors” or “alpha2/3 subunit-containing receptors” confer anxiolysis, and inhibition of “alpha5 receptors” or inhibition of “alpha5 subunit-containing receptors” confers cognitive enhancement. Both types of simplification are problematic. As many receptors contain two different alpha subunits, such statements should be avoided. For example, for alpha6-containing GABA-A receptors in the cerebellum, alpha1-alpha6-betax-gamma2 and alpha1-alpha6-betax-delta receptors dominate over alpha6-betax-gamma2 and alpha1 -betax-delta receptors, respectively. As only the alpha subunit neighboring the gamma subunit contributes to the benzodiazepine action, a receptor with mixed alpha subunits may contain an alpha1-subunit exclusively at the alpha/beta interface, which would not affect the response to classical benzodiazepines.
As a further complication, several experimental drugs exist that contradict the above assignment. For example, the experimental compound ocinaplon (DOV-273547), which stimulates alphax (x = 1, 2, 3, or 5) receptors without subunit preference, is a non-sedative anxiolytic. Another example is pyrazolopyrimidine (DOV-51892), which is specific for alpha1-containing receptors. Therefore, DOV-51892 is predicted to have sedative properties, but behavioral studies demonstrate that DOV-51892 is a non-sedative anxiolytic. At the moment, we should be careful to make any simplified statements. Behavior is a complex phenomenon, and most probably, there are several types of GABA-A receptors involved even in simple behavioral traits.

Dangerous combinations
Benzodiazepines are CNS depressants and thus can increase the action of other CNS depressants and can increase sedation, provoke a black out, impaired motor coordination, suppressed breathing and other adverse effects that can be lethal.
If you don’t have a extremely high tolerance to both CNS depressants don’t combine ‘em, it’s not worth the risk.
Even a normal dose of a benzo and a few beer can result in a black out.
If you insist on doing it, have someone around to have an eye on you!

Benzodiazepine withdrawal is no joke and can be lethal in the worth case, as GABA is the most important inhibiting neurotransmitter and going of cold turkey can result in seizures and has the potential to kill you. A taper is advised, look up the Ashton manual, it’s the golden standard for a benzo taper.

Approximately Equivalent Oral dosage means equivalent to 10mg diazepam

Onset of action: Peak concentrations in the plasma occur in 1 to 2 hours following administration
Onset: 15-30 min with peak concentrations in the plasma after 1-2 hours after administration
Half life: Mean 11.2 hours
Duration of action: For IR 4-6 hours
Bioavailability of different ROAs: 80-100 % orally
Approximately Equivalent Oral dosage: 0.5 – 1mg
Water solubility: 0.04 mg/ml
Good to know: Metabolism by CYP3A4

Onset of action: Peak concentrations in the plasma occur in 0.5 - 4 hours following administration
Half life: 10-20 hours with a mean of 17-20 hours
Duration of action: ?
Bioavailability of different ROAs: 60-84% orally
Approximately Equivalent Oral dosage: 3-6mg
Water solubility: 0.1 % in water at 25?C
Good to know:Most likely metabolized by an enzyme belonging to the CYP family, could be CYP1A2

Onset of action: 15-30min
Half life: 5-30 hours; active metabolites around 36-200 hours
Duration of action: ?
Bioavailability of different ROAs: up to 100% for oral, for i.m. only around 86%
Approximately Equivalent Oral dosage: 25mg
Water solubility: 2 mg/mL
Good to know:

Onset of action: 0.5 – 1 hours with peak plasma concentrations being reached in 1-4 hours
Half life: 18-50 hours
Duration of action: 6-12 hours
Bioavailability of different ROAs: Around 90% orally
Approximately Equivalent Oral dosage: 0.5 mg
Water solubility: < 0.1 mg/mL
Good to know: Metabolized by CYP3A4

Onset of action: 1-5 min i.v.; 15-30 min i.m.; 15-90 min oral
Half life: 20-100 hours and up to 200 hours for the main metabolite desmethyldiazepam
Duration of action: Due to fast redistribution from the brain into the rest of the body, especially muscle and adipose tissue the DoA can be relatively short (1-6 hours) but some people report some effects the day after
Bioavailability of different ROAs: 64-97% orally; 90% rectal
Approximately Equivalent Oral dosage: 10mg
Water solubility: 0.05 mg/mL
Good to know:Metabolized by various CYPs including CYP2B6, CYP2C19 and CYP3A4

Onset of action: 15-30 min
Half life: 18-26 h
Duration of action: 4-8 h
Bioavailability of different ROAs: 64–80% oral, 50% suppository
Approximately Equivalent Oral dosage: 1 mg
Water solubility: insoluble in water; 0.00858 mg/ml, 166 mg/L, 0.0086 g/L
Good to know: Metabolized by CYP3A4

Onset of action: 15-90 min
Half life: 10-20 h
Duration of action: 6-24 h
Bioavailability of different ROAs: 85-99% orally; up to 94% sublingually
Approximately Equivalent Oral dosage: 1mg
Water solubility:0.08 mg/mL
Good to know: poor lipid solubility, metabolized by CYP450 isozyme

Onset of action: 10-30 min with peak plasma concentrations after 1-2 hours
Half life: 1.5 – 4 h
Duration of action: 1-6 h
Bioavailability of different ROAs: 31-72% orally, > 90% i.m.
Approximately Equivalent Oral dosage: 2-6mg
Water solubility:0.024 mg/mL
Good to know: Metabolized by CYP3A4

Onset of action: peak plasma concentration in around 2-3 h
Half life: 15-57 h with a mean of 30 h
Duration of action:
Bioavailability of different ROAs: 53-94% oral
Approximately Equivalent Oral dosage: 5 mg
Water solubility: 0.0299 mg/mL, 0.03 g/L
Good to know: 10 mg seems to be a high dose, reported to significantly decrease stage 1,3 and 4 sleep to increase stage 2, no clinically active metabolites

Onset of action: 30-120 min
Half life: 4-21 h with a mean of 8.2 hours
Duration of action: ?
Bioavailability of different ROAs: 95-96% orally
Approximately Equivalent Oral dosage: 20-30mg
Water solubility: 0.179 mg/ml
Good to know: Can suppress cortisol levels [https://www.ncbi.nlm.nih.gov/pubmed/1349754], metabolized by glucuronidation into inactive metabolite

Onset of action: 30-60min
Half life: 8-22 h
Duration of action:
Bioavailability of different ROAs: 96% orally
Approximately Equivalent Oral dosage: 15-20mg
Water solubility:0.164 mg/mL
Good to know: No active metabolites, it has some cardiovascular depressant effects at high doses

Onset of action: 15-30 min
Half life: 1-6 h
Duration of action: 1-2 hours
Bioavailability of different ROAs: 44% orally; 53% sublingually
Approximately Equivalent Oral dosage: 0.5mg
Water solubility: 0.00453 mg/mL
Good to know:

Z-Drugs (group of nonbenzodiazepine drugs with effects similar to benzodiazepines)

Onset of action: 15 min
Half life: 2-3 h
Duration of action: 3 h
Bioavailability: 70% oral
Dosage: 5-30 mg
MoA/Affinities: Zolpidem has about 10-fold lower affinity for the alpha2- and alpha3- subunits than for alpha1, and no appreciable affinity for alpha5 subunit-containing receptors.
Good to know: belongs to the imidazopyridine class, may cause sleepwalking, can cause hallucinations in high doses
Interesting to watch: The Ambien Effect

Onset of action: peak plasma concentration in 1-2 h
Half life: 3-7 h
Duration of action: 3-9 h
Dosage: 2-7.5 mg
Bioavailability: 75-80% oral
MoA/Affinities: it is regarded as being unselective in its binding to alpha1, alpha2, alpha3, and alpha5
Good to know: belongs to the cyclopyrrolone class, In the United States, zopiclone is not commercially available, although its active stereoisomer, eszopiclone, is sold under the name Lunesta

Onset of action: full concentration in around 1h
Half life: 1-1.5 h
Duration of action: 1h
Dosage: 5-20 mg
Bioavailability: 30% oral
MoA/Affinities: selectively binds with high efficacy to the benzodiazepine site (omega1) on the aplha1-containing GABA-A receptors
Good to know: belongs to the pyrazolopyrimidine class, zaleplon appears to induce sleep without disrupting the natural sleep architecture, may cause hallucinations in high doses


Flumazenil competitively inhibits the activity at the benzodiazepine recognition site on the GABA receptor. Because the body does not produce endogenous benzodiazepines, flumazenil only creates behavioral effects when administered concurrently with a benzodiazepine receptor agonist or inverse agonist. It can lower the seizure threshold and can cause agitation and anxiety thus should only be administered by a trained medical professional in a clinical setting.
6.2.6 Opioids

What are opioids ?

Opioids are a wide range of substances that act on opioid receptors (mu, delta, kappa, nociceptin). They can be categorized into opiates (natural alkaloids found in the resin of Papaver somniferum), semisynthetic (compounds of the poppy plant are used to synthesize new substances)and synthetic opioids (fully synthetically produced). So all opiates are opioids, but not all opioids are opiates. Papaver somniferum has been used for hundreds, if not thousands of years, while moprhine was first isolated in the 19th century and synthetic opioids were invented in the 20th century. Medical uses include pain, diarrhea and cough.

How do they work ?

Opioids mimic the actions of endogenous opioid peptides by interacting with mu, delta or kappa opioid receptors. The opioid receptors are coupled to G1 proteins and the actions of the opioids are mainly inhibitory. They close N-type voltage-operated calcium channels and open calcium-dependent inwardly-rectifying potassium channels. This results in hyperpolarization and a reduction in neuronal excitability. They also decrease intracellular cAMP which modulates the release of nociceptive neurotransmitters (e.g. substance P).

Good to know

Hormone imbalance

Opioid-induced hypogonadism seems to be a common complication of therapeutic or illicit opioid use.

For further reading:


Constipation megathread

Sorted by potency from low to high


You can check out the megathread here:

Morphine equivalency

Full/partial agonist:
full µ-opioid-receptor agonist, low affinity and intrinsic activity

Onset of action:
orally IR 30-60min; injected 20-45min; orally XR 60-90min

Half life:
around 6h, metabolites around 9-10 hours

Duration of action:
IR 6-10h; injected 6-9h

Bioavailability of different ROAs:
oral IR 70–75%; rectal 77%; i.m./i.v. 100%

Mode of action:
low affinity for µ-opioid receptor, SRI&SRA
metabolite O-Desmethyltramadol has a higher affinity for the µ-opioid receptor and NRI

a common dosage would be around 25-100mg IR oral

Dangerous dosage:
anything above 300mg can lead to seizures, risk of respiratory depression is rather low

Good to know:
acts as SRI (primary metabolite is a NRI) so combining it with SSRIs, MAOIs etc. can result in serotonin toxicity;
lowers the seizure threshold, so don’t go over 300mg;
Main metabolite O-Desmethyltramadol has higher affinity for the µ-opioid receptor and adds a lot to the effects, so people with a CYP2D6 mutation making them poor metabolizers won't feel as much
those with decreased CYP2D6 activity require a dose increase of 30% in order to achieve the same degree of pain relief as those with a normal level of CYP2D6 activity. (Wikipedia)


You can check out the megathread here:

Morphine equivalency:

Full/partial agonist:
barely active on its own

Onset of action:

Half life:

Duration of action:

Bioavailability of different ROAs:
oral around 50-90%; no other ROAs as it's a prodrug and thus needs to be metabolized
i.v. can kill you as codeine can cause non-immune mast-cell degranulation which can lead to anaphylactoid reactions

Mode of action:
barely active on its own
main active metabolites are morphine and codeine-6-phosphate

for someone with no CYP2D6 polymorphism a single oral dose of around 100 mg is metabolized to around 10 mg morphine, so 100 mg is a common starting dosage

Dangerous dosage:
for fast metabolizers normal dosages can be too much as they metabolize more codeine into morphine

Good to know:
Prodrug -> needs to be metabolized into morphine; thus people people with a CYP2D6 mutation making them poor metabolizers won't feel as much/anything;
Injecting Codeine can result in pulmonary edema (fluid in lungs), facial swelling and other life threatening complications as it provokes a strong histamine reaction, don't do it!;
If you have a codeine-apap/ibuprofen/something else combo do a CWE


Morphine equivalency:

Full/partial agonist:
full agonist, but low potency

Onset of action:

Half life:
3-5h; metabolites 3,5-5h

Duration of action:
IR 4-6h; XR up to 11-13h

Bioavailability of different ROAs:
oral around 6-7%, i.v. 100%

Mode of action:
only a really weak opioid on its own
the active metabolites are mostly responsibly for the effects (tilidine-> nortilidine-> bisnortilidine. Dextilidine seems to responsible for the analgesic activity)

a common dosage would be around 25-50 mg oral

Good to know:
needs to be metabilized via the enzymes CYP3A4 and CYP2C19, thus people people with a CYP2D6 mutation making them poor metabolizers won't feel as much/anything

Pethidine aka Meperidine

Morphine equivalency:

Full/partial agonist:
full MOR agonist, possibly kappa-agonist

Onset of action:
10-20 min

Half life:
2.5-4 h

Duration of action:
2-5 h

Bioavailability of different ROAs:
50–60 % oral

Mode of action:
MOR agonist, NET and DAT inhibition, interaction with sodium ion channels, muscarinic acetylcholine receptor antagonist, possibly kappa-opioid agonism, possibly interaction with serotonin neurons as it has been associated with serotonin toxicity

it's hard to find a good common dosage as some sources state a single dose of around 30-50 mg oral while others suggest much higher doses

Dangerous dosage:
regular dosing can lead to seizures due to the buildup of the metabolite norpethidine

Good to know:
don't combine with MAOIs and antidepressants as it may interact with serotonergic neurons;
toxic metabolite, norpethidine, with an half life of 8-12 (regular administration can lead to accumulation), has convulsant and hallucinogenic effects (probaply due to anticholinergic activity) and SRI effects;
higher rate of urinary retention, most likely due to additional mACh-antagonism;
structural similarities to tropane alkaloids like atropine


Morphine equivalency:

Full/partial agonist:
full MOR agonist

Onset of action:
0.3-1 h

Half life:
3-4 h

Duration of action:
3-5 h

Bioavailability of different ROAs:
10-40 % oral

Mode of action:
MOR agonist

a common dosage would be around 50-150 mg oral

Good to know:
I.V. can lead to anaphylaxis and pulmonary edema;
metabolites dihydromorphine (via CYP2D6) and dihydromorphine-6-glucuronide have higher affinities for MOR, but most likely only produced in small amounts


Morphine equivalency:
0.6-1 (in rhesus monkeys higher than morphine)

Full/partial agonist:
full MOR agonist

Onset of action:
10-20 min

Half life:
3-5 h

Duration of action:
4-8 h

Bioavailability of different ROAs:
25-70 % oral, 75 % rectal

Mode of action:
MOR agonist, six times less affinity for DOR

a common dosage would be around 5-20 mg oral

Good to know:
Metabolized to norhydrocodone (CYP3A4, but poor BBB-penetration) and hydromorphone (CYP2D6), around 40 % are metabolized via non-cytochrome-catalyzed reactions


Morphine equivalency: 0.3

Full/partial agonist:
most likely KOR agonist and MOR antagonist

Onset of action:
15-30 min

Half life:
2-5 h

Duration of action:
3-5 h

Bioavailability of different ROAs:
high first pass metabolism, so only 20 % oral

Mode of action:
most likely KOR agonist and MOR antagonist

a common dosage would be around 20-50 mg oral

Good to know: I.V. of pentazocine lactate may lead to necrosis and sepsis;
can be plugged (decrease dosage, as BA is higher);
can increase BP and HR
can cause hallucinations and delusions due to KOR agonism;
woman seem to be less sensitive to the side effects


Morphine equivalency: 0.3 -0.6

Full/partial agonist:
full MOR agonist

Onset of action:
15-45 min

Half life:
4-6 h

Duration of action:
4-6 h

Bioavailability of different ROAs:
around 30% oral

Mode of action:
MOR agonist and NRI

a common dosage would be around 30-50 mg

Dangerous dosage:
may lower the seizure threshold and may raise intracranial pressure

Good to know:
don't combine with MAOIs and antidepressants;
may lower seizure threshold;
may cause hypotension


Morphine equivalency:

Full/partial agonist:
full MOR agonist

Onset of action:
i.v. 10 s - 5 min, i.m.15 min , 20 min oral

Half life:
2-3 h

Duration of action:
3-7 h

Bioavailability of different ROAs:
20-40 % oral, 36-71 % rectal, 100 % i.v./i.m.

Mode of action:
MOR agonist

a common dosage would be 10-15 mg oral or 2.5-5 mg i.v.

Good to know:
high histamine release;
may influence the production of neutrophiles and cytokines;
endogenous opioid
metabolites are M3G (60 % ) and M6G (6-10 % )


Morphine equivalency:
oral 1.5-2, i.v. 1

Full/partial agonist:
full MOR agonist

Onset of action:
10-30 min IR, 60 min CR

Half life:
2-3 h IR, 4-5 h CR

Duration of action:
3-6 h IR, 8-12 h CR

Bioavailability of different ROAs:
oral 60-87 %, intranasal 45-77 %, i.v. 100 %

Mode of action:
MOR agonist, talk of KOR agonism is likely unfounded

a common dosage would be around 10-15 mg

Good to know:
metabolized primarily by CYP3A4 to noroxycodone and CYP2D6 to oxymorphone but sespite both metabolites being active, analgesia is produced mainly by oxycodone itself due to poor CNS penetration of noroxycodone and only 10 % converted to oxymorphone. Studies with poor 2D6 metabolizers have shown little difference in pain relief compared to normal metabolizers insinuating oxycodone and not oxymorpone produces the analgesic effect;
available in many dosage forms with or without acetaminophen (paracetamol) or NSAIDs. Most common would be Percocet (oxycodone + APAP, IR) 2.5, 5, 7.5, and 10mg/ 325 oxy/apap, IR oxycodone (various forms Roxicodone, Oxynorm) 5 to 30mg, and oxycodone ER/CR (Oxycontin 10 to 80mg)

Methadone (racemate)

Morphine equivalency:

Full/partial agonist:
full MOR agonist

Onset of action:
0.5-4 h oral, 0.3-3 h rectal

Half life:
10-60 h

Duration of action:
4-12 h

Bioavailability of different ROAs:
40-99 % oral

Mode of action:
MOR agonist, weak NMDA antagonist, weak SRI, nicotinic acetylcholine receptor antagonist

a common dosage would be around 3-10 mg oral

Good to know:
Levo-methadone is twice as potent;
binds to and blocks hERG (alpha subunit of potassium ion channel in the heart) thus can lead to Long-QT-syndrome;
metabolism via CYP3A4 -> CYP3A4 can be inhibited by WGJ;
don't combine with MAOIs and antidepressants

Diacetylmorphine (Heroin)

Morphine equivalency:

Full/partial agonist:
full MOR agonist

Onset of action:
usually within minutes

Half life:
2-3 min, morphine around 3h, 6-MAM around 20 min

Duration of action:
4-5 h

Bioavailability of different ROAs:
< 35 % oral (first pass metabolism into morphine), 44–61 % smoked, 100 % i.v.

Mode of action:
Heroin itself only has relatively low affinity for the µ-opioid-receptor;
depending on ROA its either a prodrug for systemic morphine when taken orally or when injected or smoked it rapidly crosses the BBB as the acetyl groups make it more lipophilic and is then deacetylated into the active 6-MAM and morphine

a common dosage would be around 5-15 mg smoked or 7.5-20 mg intranasal

Good to know:
Comes in the forms of "Black Tar" (diacetylmorphine acetate with varying chemical contents like 6-MAM and other morphine derivatives due to crude acetylation; higher risk of infection from injecting) and "White powder" which can further be sub-divided into #3 (base form so not readily soluble in water, most often smoked; to make it soluble in water add something like citric acid or ascorbic acid) and #4 (HCl form so readily soluble in water, most often snorted or injected)


Morphine equivalency:

Full/partial agonist:
full MOR agonist

Onset of action:
20-60 min oral, 20 s - 10 min i.v.

Half life:
2-3 h

Duration of action:
3-5 h

Bioavailability of different ROAs:
30-50 % oral, 50-60 % intranasal

Mode of action:
MOR agonist, may be weak kappa-agonist

a common dosage would be around 2-4 mg oral


Morphine equivalency:

Full/partial agonist:
full MOR agonist

Onset of action:
10 s -10 min i.v.

Half life:
7-9 h

Duration of action:
3-6 h

Bioavailability of different ROAs:
10 % oral, 40 % intranasal

Mode of action:
MOR agonist, may be DOR agonist

around 1 mg i.v. is equipotent to 10 mg morphine i.v.
due to high first-pass metabolism oral dosages need to be adjusted


Morphine equivalency:

Full/partial agonist:
partial MOR agonsit

Onset of action:
usually 30 min

Half life:
20-70 h

Duration of action:
up to 24 hours

Bioavailability of different ROAs:
30 % sublingual, 50 % intranasal

Mode of action:
partial MOR agonist, DOR and KOR antagonist

0.2-0.8 mg

Good to know:
high first-pass metabolism;
potential ceiling
high affinity for but low intrinsic activity
can block other opioids from binding
is metabolized into norbuprenorphine which seems to have high affinity for P-GP and thus has little antinociceptive potency, but can depress respiration


Caution, fentanyl is extremely potent (active in the µg-range) and even a few milligram can kill you, handle carefully and never eyeball. When dealing with pure powder use gloves while dealing with it, clean everything afterwards and only use volumetric dosing!

Morphine equivalency:

Full/partial agonist:
full MOR agonist

Onset of action:
10 s - 5 min

Half life:
depends on ROA, around 3-12 h (longer with transdermal application, shorter with i.v.)

Duration of action:
depends on ROA, around 30-60 min i.v.

Bioavailability of different ROAs:
92 % transdermal, 89 % intranasal, 50 % buccal, 33 % oral

Mode of action:
MOR agonist

12-40 µg

Good to know:
metabolized by CYP3A4;
little histamine release;
half life may increase with repeated administration due to accumulation in muscle and fat-tissue due to high lipophilicity
may cause serotonin toxicity



It's not a substitute for professional medical care, always call an abulance when someone overdoses!

Bioavailability: 2% oral due to high first-pass metabolism

Onset of action: 2-5 min

Half life: 1-1.5 h

Duration of action: 30-60 min

Mechanism of action: Non-selective and competetive opioid receptor antagonist, affinities mu(Ki 0.56 nM)>delta(4.9 nM)>kappa (36.5 nM), (-)naloxone is active, (+)naloxone is pretty much inactive

Dosage: for i.v./i.m. 0.4-2 mg, intranasal 1-4 mg, maximum dosage 10 mg (if no response occurs at this time, alternative diagnosis and treatment should be pursued)

Good to know: In the United States, naloxone is classified as a prescription medication, though it is not a controlled substance. While it is legal to prescribe naloxone in every state, dispensing the drug by medical professionals (including physicians or other licensed prescribers) at the point of service is subject to rules that vary by jurisdiction. In the following states, you can purchase naloxone from a pharmacist directly without getting a prescription from a doctor: Alabama, Alaska, Arizona, Arkansas, California, Colorado, Connecticut, Florida, Georgia, Idaho, Illinois, Indiana, Iowa, Kentucky, Maine, Maryland, Massachusetts, Minnesota, Nevada, New Hampshire, New Jersey, New Mexico, New York, North Carolina, Ohio, Oregon, Pennsylvania, Rhode Island, South Carolina, Tennessee, Texas, Utah, Vermont, Washington, West Virginia and Wisconsin.




Primarily used to manage alcohol/opioid dependence. For opioid dependence should only be taken after detoxification as it can cause precipitated withdrawal. Can be taken orally or i.m.. Competetive antagonist at the mu-opioid receptor (Ki 0.0825 nM) > kappa (Ki 0.509 nM) > delta(Ki 8.02 nM). Half life of 4 h, active metabolite, 6ß-naltrexol, half life of around 13 hours, depot injections/SC implants have considerably longer duration of action.
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6.3 Psychedelics

Psychedelics are a class of drugs that produce alterations in, among other things, perception and mood by mainly activating serotonin receptors, with 5-HT-2A playing the biggest role. Psychedelics can mostly be categorized into the classes substituted tryptamines (for examples you can read TIHKAL) and phenethylamines (check out PIHKAL for those).

The term psychedelic is derived from the Greek 'psyche' and 'delein' which together mean something like 'soul-manifesting'.

Most psychedelics are considered to be safe both physiologically and non-addictive, but they can cause 'bad trips' that can take a toll on the psyche.

Psychedelics, especially psilocin and DMT as well as mescaline, have a long history of traditional use in both religion and medicine.
Subjective effects include color enhancement, distortions like 'breathing' objects, tracers, analysis enhancement, increased creativity, thought acceleration and both open and closed eye visuals.

Negative effects include a rise in blood pressure, delusions, dehydration, muscle contractions and cramps, nausea and psychosis.

Sources for future improvements:
2) https://www.cell.com/cell-reports/f...m/retrieve/pii/S2211124719302906?showall=true

6.3.1 LSD



LSD-25 or 'Lysergsaeurediethylamid (lysergic acid diethylamide )' was first synthesized by Albert Hofmann from lysergic acid (extracted from the fungus ergot; making LSD a semisynthetic drug) in 1938 at the Sandoz Lab in Basel in the search of a new analeptic. The psychedelic effects however weren't discovered until a few years later when A. Hofmann accidentally ingested an unknown quantity of LSD, riding his bike home while having his first trip. Days later he intentionally ingested 250 mcg of LSD as he extrapolated from other ergot alkaloids that this was a threshold dose. This pretty high dose lead to strong mind-altering effects that would be later used by the medical community to induce model-psychosis in healthy people under the trade name Delysid. The psychedelic research flourished during those years and generated over 1000 scientific papers. Later on LSD was used predominantly by the youth driven counterculture in the 1960s and made illegal in 1968.

LSD binds to various serotonin receptors, including 5-HT1A (Ki = 1.1 nM), 5-HT2A (Ki = 2.9 nM), 5-HT2B (Ki = 4.9 nM) and 5-HT2C (Ki = 23 nM) with 5-HT2A being the most relevant for the psychedelic effects. LSD is quite unique as it binds to dopamine receptors as well as activates DARP-32-related pathways (dopamine- and cAMP-regulated neuronal phosphoprotein, a potent protein phosphatase-1 (PPP1CA) inhibitor in its phosphorylated form). LSD shows functional selectivity at 5-HT2A and 5-HT2C as it activates PLA2 instead of PLC.

The possible mechanism of its psychedelic effects may be an increase of glutamate in the cerebral cortex layers IV (internal granular layer) and V (internal pyramidal layer).

LSD is metabolized by CYP450 isozymes and is eliminated with first-order kinetics with a terminal half life of 3.6 hours for up to 12 h and a terminal half life of around 9 hours afterwards. It shows kinetic selectivity as well:

LSD dissociates exceptionally slow from both 5-HT-2B and 5-HT-2A - a major target for its psychoactivity. Molecular dynamics simulations suggest that LSD's slow binding kinetics may be due to a "lid" formed by extracellular loop 2 at the entrance to the binding pocket.

LSD is consumed sublingual in the form as blotter, sugar cube or LSD-solution with doses ranging from 15 mcg as threshold to 150-300 mcg for a strong to heavy experience.

LSD usually sets in after 15-45 min with a duration of action of around 8-12 hours.

6.3.2 2C-x



The 2C-x compounds are a class of drugs derived from phenethylamine, most of which were first synthesized by Alexander Shulgin and published in his book 'PIHKAL - Penethylamines I have known and loved'.

The general backbone is phenethylamine with methoxy groups on the 2 and 5 position of the benzene ring and a substitute at the 4 position.

2C-B, bromide
2C-C, chloride
2C-D, methyl
2C-E, ethyl
2C-I, iodide
2C-P, propyl
2C-T series, thioether

6.3.3 Mescaline



Mescaline belongs to the phenethylamine class of drugs and is a psychedelic alkaloid found in a variety of cacti belonging to the Cactaceae family, especially Echinopsis pachanoi and Lophophora williamsii and is biosynthesized from tyrosine. Chemically mescaline is phenethylamine with three methoxy (OCH3) groups added at the 3, 4 and 5 position.

Mescaline has been used religiously for nearly 6000 years and is traditionally consumed as cacti button with a distinct bitter taste than can cause extreme nausea (puking is viewed as toxic cleansing however, so it can be a good thing). It has been studied as treatment for depression and alcoholism as well, but due to illegalization few studies have been conducted in recent years.

Mescaline is a classic psychedelic with the main mechanism of action being the activation of serotonin receptors, especially 5-HT2A (Ki = 6.3 microM) and 5-HT1A (Ki = 4.6 microM). Additionally mescaline shows affinity for alpha2A (Ki = 1.4 microM) and probably TAAR1 (rat, Ki = 3.3 microM).

Compared with LSD mescaline has lower receptor affinities and activation potency, thus higher oral doses are needed and are in the range of 50-100 mg as threshold to 400-800 mg as a strong to heavy dose.

It usually takes 45-90 min for the onset and the total duration of action is around 8-14 hours with after effects reaching into the next day.

Mescaline seems to be partly metabolized by MAO and partly is excreted unchanged. The plasma half life is around 6 hours.

6.3.4 Psilocin



Psilocin and psilocybin (phosphorylated psilocin) are substituted tryptamine alkaloids that can be found in psilocybin mushrooms constituted of more than 200 species of mushrooms with the genus Psilocybe being the most important one. Psilocin is the 4-hydroxy analogue of DMT (dimethyltryptamine) and has been first isolated and named by Swiss chemist A. Hofmann in 1958.

Due to prehistoric murals and rock painting it is though that psilocybin mushrooms have been used for longer than recorded history and Terence McKenna introduced the 'Stoned Ape' hypothesis in 1992 claiming that psilocin catalyzed human evolution.

There have been various studies with psilocin/psilocybin containing mushrooms with the 'Concord Prison Experiment' and 'Marsh Chapel Experiment also called Good Friday Experiment' being the most popular ones.

Psilocin's main mechanism is as a serotonin receptor (partial-)agonist with affinities for, amongst others, 5-HT2A (Ki = nM), 5-HT2C (Ki = nM) and 5-HT1A (Ki = nM).

Psilocin is around 100 times less potent than LSD (w/w) with oral dosages ranging from 5 mg to 25-40 mg for a strong experience, which translates to around 1-5 g of dried or 10-50 g of fresh mushrooms depending on alkaloid content.

Psilocybin is a prodrug that undergoes first-pass metabolism to be dephosphorylized into psilocin, which is psychoactive. Psilocin is then metabolized by MAO or glucuronidated with a half life of around 2.6 hours. The duration of action is around 4-6 hours with an onset after around 10-45 min.

6.3.5 DMT



N,N-Dimethyltryptamine (DMT) is a powerful psychedelic that can, with the right dosage, produce a 'breakthrough' experience (https://www.bluelight.org/vb/thread...-DMT-experience-where-is-quot-hyperspace-quot).

It belongs to the tryptamine class of psychedelic drugs and may be found endogenously in the human body. For recreational purposes it is mostly found as freebase or as DMT fumarate as other acid salts are extremely hygroscopic.

DMT has been traditionally used as Ayahuasca (DMT combined with MAOI) and in the form of snuff for centuries. It was first synthesized in 1931 by R. Manske and isolated from Anadenanthera peregrina in 1955. In 1956 a Hungarian biochemist, S. Szara, first injected pure DMT and reported hallucinogenic effects. The drug was later popularized by Terence McKenna who frequently talked about his experiences and even used in trials at the University of New Mexico Hospital Clinical Research Center by Rick Strassman. Strassman condensed his findings in the book 'DMT: The spirit molecule'.

DMT is a 5-HT agonist with affinity for, among others, 5-HT2A (Ki = 237 nM) and 5-HT1A (Ki = 75 nM), as well as some affinity for sigma-1 and TAAR1 (Ki = 3.3 microM). Additionally DMT seems to bind to to SERT (IC50 = 3.1) and NET (IC50 = 3.9).

DMT is usually smoked with dosages ranging from 10-60 mg and shows a rapid onset and total duration of only 10-15 min.

Oral doses from 30-60 mg are combined with a MAOI (for example beta-carboline around 160 mg) to prevent early break down by MAO-A with an onset after around 30-45 min and a total duration of action of around 3-4 hours.

It's advised against injecting if the DMT extracted from plant material due to possible allergic reactions and microorganism contamination.

DMT is metabolized via MAO-A.

6.3.6 Ibogaine



Ibogaine is a naturally occuring psychedelic and dissociative drug found in plants belonging to the Apocynaceae family like Tabernanthe iboga . It is an indole alkaloid derived from tryptamine.

The root bark has been used for centuries, tracking back to the Pygmy tribe of Central Africa, who used is as stimulant to treat fatigue, hunger and thirst. It was brought to Europe by French explorers and used as a neuromuscular stimulant starting in the 1900s. In the 1960s the use as anti-addiction medication, especially for opioid addiction, was discovered but it still isn't approved in the US.

Ibogaine seems to generate adverse effects on the cardiovascular system and is associated with more than a few death, so if you decide to try it an EKG would be advised.

Besides lowering the heart rate, therapeutic concentrations of the alkaloid interact with cardiac ion channels, and these effects most likely determine ibogaine’s potentially life-threatening cardiotoxicity. Based on the findings of the above described studies, we propose the following sequence of deleterious events to explain the cardiotoxicity associated with the application of ibogaine as anti-addiction drug: (1) blockade of repolarizing hERG potassium channels; (2) retardation of the repolarization phase of the ventricular AP; and (3) concomitant prolongation of the QT interval in the ECG, ultimately paving the way for life-threatening TdP arrhythmias. Due to the longevity of noribogaine—ibogaine’s active metabolite—in human plasma, cardiac adverse events may also occur several days, in some cases weeks after intake of a single dose of ibogaine. Noribogaine, on the other hand, may also convey long-lasting anti-addictive efficacy after ibogaine application.

Ibogaine and its metabolite noribogaine (by CYP2D6) binds to a variety of different receptors and the pharmacology still is poorly understood.

Both substances are potent serotonin reuptake inhibitors (Ki = 500 nM and 40 nM respectively), ibogaine has high affinity for nicotinic acetylcholine receptors (Ki = 20 nM) and sigma-2 (Ki = 90-400 nM) and both are thought to be kappa (Ki = 2-4 microM and 0.6-1 microM) and weak mu-receptor (Ki = 2-100 microM and 0.7-3 microM) agonists.

The dosage varies depending on if you want to use it as a stimulant (8 mg - <50 mg total), psychedelic (8-12 mg/kg) or for opioid dependence (15-25 mg/kg).

The total duration can be up to 36 hours.

Here's an amazing trip report about ibogaine used to combat long-term opioid addiction: https://www.bluelight.org/vb/threads/723353-Ibogaine-(flood-dose)-First-Time-Into-The-Flood
6.4 Dissociatives

Dissociatives are a group of drugs that mostly act as NMDA receptor antagonists. With glutamate being a receptor agonist NMDA receptors are implicated in excitatory effects and thus inhibiting the effects leads to a reduction/blocking if signals. Even though other drugs are capable of reducing cell signals dissociatives are able to do so and produce powerful hallucinogenic effects. Some drugs, especially ketamine, are able to cause a K-hole. The K-hole is hard to describe, so here's a link to a thread where people try to put into words what they experienced: https://www.bluelight.org/vb/threads/444003-Your-k-hole-experience

Effects of dissociatives include dissociative effects, like depersonalization and derealization, pain relief, euphoria, tactile suppression and perception of bodily lightness.

Side effects include dizziness, amnesia (especially in high doses), motor control loss and nausea.

6.4.1 PCP



PCP, or more chemically Phencyclidine, is a drug that was initially used as dissociative anesthetic during the 1950s and early 1960s under the brand name Sernyl, but was discontinued in 1965 due to high rates of side effects, especially psychosis and the discovery of ketamine. It belongs to the arylcyclohexylamine class of drugs and is a potent NMDA antagonist. When compared to other dissociatives, PCP is more likely to produce psychosis and mania and high doses have been associated with dangerous psychosis sometimes leading to aggression and violence. It may be neurotoxic so better stay away from frequent high doses.

PCP acts as potent NMDA receptor antagonist (Ki = 44-59 nM), sigma-2 agonist (Ki = 136 nM in rats), SERT inhibitor (Ki = 2,234 nM) and D2-high receptor partial agonist (Ki = 2.7-4.3 nM). In addition PCP seems to inhibit dopamine reuptake, but has no significant affinity for DAT (Ki > 10,000 nM). It is proposed that the DRI is mediated by interactions with allosteric sites of the monoamine transporters.

PCP can be taken orally, insufflated, smoked and can be injected.

Smoked the duration of effects 4-6 hours with an onset between 2-20 min. The dosages range from 1-10 mg. Exceeding those dosages can result in a psychotic state, so it's advised against.

Oral the effects last for around 4-8 hours with an onset between 30-90 min. Dosages are between 1-12 mg. After effects can last up to two days.

PCP undergoes oxidative hydration in the liver by CYP450 isozymes and has a half life of 7 up to 46 hours.

6.4.2 Ketamine



Ketamine is a medication mainly used as anesthetic (it's used in veterinary medicine as well and some people try to downgrade ketamine by calling it horse narcotic), but esketamine has recently approved by the FDA for treatment of depression.

It was discovered in 1962, approved in 1970 and extensively used during the Vietnam war due to its safety as breathing and airway reflexes generally remain functional during narcosis. But due to ketamines interaction with catecholamines changes in heart rate and blood pressure are common.

In emergency medicine ketamine is used as dissociative anesthetic as an i.v. bolus induces a short narcosis with a subsequent trance like state accompanied by analgesia and amnesia. Ketamine belongs to the arylcyclohexylamine class like PCP.

Ketamine is used recreationally in smaller doses in the rave/club scene as well as in higher doses.

The mechanism of action of ketamine is complex, but its main MoA is non-competitive antagonism of NMDA receptors (Ki = 250-660 nM) binding to the dizocilpine site and possibly through an allosteric mechanism.

S(+) ketamine has higher affinity for NMDA than R(-) ketamine.

Ketamine has a slow off-rate (also called high-trapping antagonist) from the NMDA receptor, meaning that it causes continuous blockage even after glutamate dissociates from the receptor. This might lead to higher side effects, but anesthetic effects in contrast to a low-trapping antagonist like memantine.

Other targets of ketamine include L-type voltage-dependent calcium-channels implicated in its bronchio-relaxing effect, blockage of monoamine transporting systems (Kis for DAT, NET and SERT are in the double digit micromolar range) possibly via allosteric modulation, HCN1 blockage potentially leading to arrhythmia and hypnotic effects, BK channels and voltage-gated sodium channels.

One of its metabolites, (2S,6S;2R,6R)-hydroxynorketamine, has been implicated in the antidepressant effects via AMPA receptor activation. Other mechanisms implicated in its antidepressant effects are acetylcholine receptors, reducing cholinergic neurotransmission, increased BDNF mRNA expression and histone deacetylase modulation. NMDA receptor 1 dephosphorylation might be the cause of its effects of chronic pain.

Ketamine is metabolized predominantly by CYP3A4, minor routes include metabolism by CYP2B6 and CYP2C9. Some metabolites are active on their own, like norketamine that's 1/3-1/5 as potent as anesthetic as ketamine.

Ketamine can be taken orally (BA = 17-29% ) but is readily broken down by bile acids and undergoes high first pass metabolism leading to plasma levels of norketamine three times higher than ketamine, sublingual (BA = 11-30% ), insufflated (BA = 8-50% ) and injected with i.m. (BA = 93% ) being more common than i.v. in a recreational setting.

Peak plasma concentration are achieved after 5-15 min i.m.; 10-20 min after intranasal and 30 min oral application. The duration of action ranges from only 30 min up to 6 hours depending on the route of administration.

Oral doses range from 50 mg to 450 mg, insufflated 5 mg to 150 mg and i.m. 10 mg to 100 mg with high doses leading to the K-hole.

6.4.3 Dextromethorphan (DXM)



Dextromethorphan is a dissociative from the morphinan class of drugs, but has the opposing chirality to that seen in the structure of morphinan class opioids. The levorotatory isomer, levomethorphan, however does exhibit activity at opioid receptors.

DXM is the primary active ingredient in OTC cold and cough medicines (always check that DXM is the only active ingredient as you need to overdose to feel the dissociative effects and added active ingredients like acetaminophen (paracetamol) can kill you in high doses!) and has been used recreationally soon after being approved in 1958 as an OTC antitussive. DXM in combination with quinidine (to inhibit CYP2D6 metabolism) is approved for treatment of pseudobulbar affect.

As DXM is able to trigger a histamine release people who are susceptible to allergic reactions should stay away from abusing it. Due to DXMs inhibition of SERT it shouldn't be combined with MAOIs, SSRIs etc. due to the possibility of serotonin toxicity. There is at least one case report indicating that DXM might cause QTc prolongation and DXM can cause a significant increase in heart rate and blood pressure.

The mechanism of action of DXM and its active ingredient dextrorphan (DXO) is complex and hasn't been completely understood yet. DXM and DXO interact with a variety of receptors, the most important ones being NMDA (Ki = 2120 nm for DXM and 892 for DXO), SERT (Ki = 40 nm for DXM and 484 for DXO) and sigma1 (Ki = 150 nm for DXM and 118 for DXO). Additionally DXM has some affinity for alpha1-D receptors (Ki =830 nM) while DXO shows significant competition for muscarinic acetylcholine receptors and H1 receptors at 1 microM that may play a role in high doses as well as affinity for the mu-opioid receptor (Ki = 420 nM in rats but >1000 nM in humans). The dissociative effects most likely stem from the NMDA receptor inhibition, similar to ketamine and PCP.

Sigma1 agonism could contribute to side effects like muscle tension, tachycardia, mydiasis and maybe to the movement effects called robo walking (Because of those movement effects taking DXM is sometimes referred to as 'robo tripping').

The pharmacokinetics of DXM are important to its pharmacology as CYP2D6 catalyzes the demethylation into DXO, a more powerful NMDA antagonist. Because of the high prevalence of different phenotypes of CYP2D6 some people are able to metabolize DXM rapidly into DXO possibly receiving greater dissociative effects, while others are poor metabolizers, possibly leading to an increase in side effects. Some minor metabolism routes are catalyzed by CYP3A4 and CYP3A5.

The oral duration of high doses DXM is around 6-12 hours with possible after effects ranging into the nextday. Dosages range from 75 mg as threshold to 400-700 mg as strong experience.

6.4.4 Nitrous oxide



Nitrous oxide, or laughing gas, has been used for a very long time as inhalational anesthetic. It was first identified in 1772 by English chemist and natural philosopher Joseph Priestley. While the sedating and analgesic properties have been discovered early on it took some time until it was first used for anesthesia, though it was used as recreational drug primarily by the British upper class from 1799 on.

Nitrous oxide usually doesn't lead to full narcosis, but sedation. In medicine it's still used to this day, most commonly at the dentist. Medicinally it's combined with oxygen to a maximum of 80% N2O and 20% O2. N2O can also be found in the automobile industry as engine booster (don't use due to contaminants!) and in whipped cream canisters.

Laughing gas has low toxicity, but improper use can lead to oxygen deprivation. Chronic use can lead to Vitamin B12 depletion as nitrous oxide is able to inactivate the cobalamin form of Vitamin B12 by oxidation. As laughing gas leads to sedation and muscle relaxation it's advised to only use it whilst sitting or laying down.

The mechanism of action is still not fully understood, but N2O seems to be a NMDA antagonist, a positive modulator of GABA-A receptors, especially at the a1b2y2a subunit, a weak inhibitor of low-voltage activated calcium channels, agonist of the TREK-1 potassium channel, partial inhibitor of nicotinic acetylcholine receptors and it may raise opioid peptides.

Laughing gas is usually used by filling up a balloon (turn the balloon inside out as sometimes the inside is coated with talcum) with the contents of one or more whipped cream canisters either by using a whipped cream dispenser or a NOS cracker.

After sitting or laying down you start to breath in some air and then inhale the contents of the balloon. Exhale the contents back into the balloon and inhale again. Repeat this until the desired effects set in, but don't forget to breath in some fresh air once every cycle or two to not deprive yourself of oxygen!
6.5 Deliriants

Deliriants are a class of hallucinogenic drugs that can induce powerful hallucinations which display themselves seamlessly into waking consciousness, making it impossible to differentiate between real life and hallucination. The term 'deliriant' was coined by D. F. Duncan and R. S. Gold to distinguish them from psychedelics and dissociatives as they primarily produce a delirium in contrast to more lucid states by other hallucinogens like LSD.

Most deliriants are anticholinergic drugs, meaning that they antagonize the muscarinic acetylcholine receptor. This inhibition leads to decreased levels of acetylcholine, causing sedation, delirium, realistic hallucinations and due to mACh-receptors (M2) being present in the heart tachycardia.

Most deliriant plants belong to the nightshades family (Solanaceae) and include Atropa belladonna, Brugmansia suaveolens, Datura stramonium and Hyoscyamus niger with the main active ingredients being Atropine (racemate of S- and R-hyoscyamine) and Scopolamine.

Other drugs that cause delirium are antihistamines like diphenhydramine or doxylamine and nutmeg.

Even though most drugs are perfectly legal it's advised to not consume them due to the potent toxic effects. With deliriants you basically poison yourself and especially nightshades are dangerous in even small doses due to tachycardia and hyperthermia.

Additionally with plant matter it's extremely hard to get the right dosage, as concentrations of active ingredients can vary widely. And even with pharmaceutical drugs like DPH you still have to take a massive overdose to feel the effects and DPH might cause QT-prolongation due to interaction with hERG. This can lead to fatal heart arrhythmia.

The experience itself can be extremely frightening due to the realistic hallucinations that can cause potentially dangerous mental effects. As you can't distinguish between hallucination and reality it's possible to get yourself into an accident without even knowing it.

Additionally, deliriants produce nasty side effects like dehydration and urine retention. Plus high doses can lead to amnesia.

Some of the most popular hallucinations include smoking non-existent cigarettes that vanish once you drop them, seeing people that aren't real and especially with high doses DPH seeing arachnids. Another common experience is people talking with objects or taking their clothes off, most likely due to hyperthermia.

Should you insist on trying a deliriant always extrapolate from the highest alkaloid concentration, make a homogenous solution, start extremely low and always have a sober trip sitter you trust around. And try to take them away from civilization (not too far so you're still able to get to a hospital) as the delirium can cause quite odd situation that some sober people might find frightening/crazy thus calling an ambulance.

Atropin: (racemate of (S)- and (R)-Hyoscyamine)





7. Brain circuits/pathways

Under construction

7.1 The brain - an introduction

7.? The dopamine system

7.? Nociception


7.? Excursions

7.?.1 Basal ganglia & Parkinson's disease

When we talk about locomotion and when we want to understand the circuit that is most affected in Parkinson’s disease (and other neurodegenerative diseases, like Huntington’s), we have to talk about the basal ganglia:
The basal ganglia are a group of nuclei (= cluster of neurons in the CNS) located at the subcortical level (= under the cortex of the cerebrum) that consist of the putamen and caudate nucleus (separated by the internal capsule in humans; together called striatum), the globus pallidus (interna and externa) the subthalamic nucleus (the only mainly excitatory structure in the basal ganglia) and the substantia nigra (pars compacta and pars reticularis; pars compacta being the part where a major part of the brains dopamine is produced). Thalamic nuclei can also be considered part of the large-scale basal ganglia circuit, although they have a distinct structure and different functions.
The basal ganglia play, as already implied, a major role in motor behavior, but also in cognitive behavior and emotional states, depending on which part of the striatum receives input from which part of the cortex. I will only go into detail about the motor circuit for now, but for the sake of completeness: the motor circuit is based on projections from the motor cortex (e.g. SMA, PMC and M1) to the putamen, while the oculomotor, limbic and prefrontal circuits are based on projections from different parts of the cortex to the caudate nucleus.
As the basal ganglia receive most of the input (at least 80%) from the cortex (input is always excitatory) and mainly project back to the cortex (70-80% in humans, less in other animals) they can be thought of more like loops rather than linear circuits: the basic organization of the basal ganglia circuits involve a cortical input, mostly located in the frontal lobe, projecting to the putamen/caudate nucleus, which project to other structures, that in the end project to specific thalamic nuclei, which in turn project back to the cortical locations of origin. The motor circuit is organized in a somatotopical fashion, oversimplified this means that there is a circuit for right arm movement, one for left leg movement and so on (of course it’s much more detailed than whole limbs).
But now on to what is going on when we execute a movement:
The input from the motor cortex, meaning from the primary motor cortex (also called M1) as well as the premotor cortex (PMC) and supplementary motor area (SMA) projects to two distinct neurons, the D1-positive (D1) and D2-positive (D2) medium spiny neurons (MSN) in the putamen. But what does D1 or D2 mean in this context? Well, you might remember from one of my previous posts about receptors that we have two different kinds of dopamine receptors, D1-like and D2-like. And that is what is meant with D1- or D2-positive neurons. The D1-MSN make up the so called ‘direct pathway’ and are activated by dopamine, while the D2-MSN make up the ‘indirect pathway and are inhibited by dopamine’. While this might sound like there are two distinct bundles of neurons in the putamen that project to downstream nuclei, the two different MSN are actually more or less homogeneously mixed in the putamen.
While both pathways get input from the same cortical areas, there is a quantitative difference in some cases: The direct pathway gets more input from the cingulate cortex and amygdala (this can trigger a fight-or-flight response) as well as the somatosensory pathway (sensory input drives movement); The indirect pathway, on the other hand, gets more input from M1 (this can block the execution of ongoing (wrong) movement).
The direct/D1-pathway MSN (activated via cortex-glutamate and activated via SNc-dopamine) are inhibitory (GABA and SP) and project primarily to the GPi, which is inhibitory (GABA) as well, and the GPi in turn projects to the thalamus and PPN. The indirect/D2-pathway MSN (activated via cortex-glutamate and inhibited via SNc-dopamine) are inhibitory (GABA, Enk) and project to the inhibitory (GABA) GPe, which in turn projects to the STN. The STN, which is excitatory (Glu), projects to the GPi and SNr, which are both inhibitory (GABA) and project to the thalamus and PPN. The PPN projects to downstream neurons that in the end innervate muscles. In total, dopamine from the SNc will activate the direct (by inhibiting the inhibition of the thalamus via the GPi) and inhibit the indirect pathway, leading to a net increased chance of movement.
Lastly, there is also a third pathway, the so-called ‘hyperdirect pathway’ that is a direct connection between the motor cortex and STN. This connection provides a fast route for the prefrontal cortex to terminate any ongoing movement, whereas the D2 pathway appears to be slower and more related in terminating movement as part of an orchestrated pattern.
Now, this will most likely sound rather confusing, and I was quite confused as well when I heard about this, so here is a picture to visualize this complex circuit:

In normal conditions, cortical excitation of the putamen and dopaminergic (via SNc) activation of excitatory D1-receptors leads to the activation of the direct pathway, which inhibits the GPi and SNr. This inhibition in turn reduces the net inhibition of the thalamus and PPN via the GPi and SNr, facilitating movement. Cortical excitation of the indirect pathway will inhibit the GPe, which in turn decreases the inhibition of the STN. The now activated STN excites the GPi and SNr, leading to a net inhibition of the thalamus and PPN and thus a repression of motor behavior. To summarize this: Dopamine release from the SNc activates the D1-pathway, but inactivates the D2-pathway, which increases the chances of movement.
With that knowledge, we can now understand the pathophysiology of Parkinson’s disease a bit better: PD is the second most prominent neurodegenerative disorder that mainly affects the motor system (resting tremor, bradykinesia and rigidity as cardinal features), but psychological symptoms (e.g. depression and anxiety) are also common. The average age of onset of the motoric phase, which starts when around 70% of dopaminergic neurons in the SNc are dead, is 55 years with a male to female ratio of 3:2 (also true for some animal models of PD). The cause of PD is still unknown but involves both genetic and environmental factors, with age being the most important risk factor (e.g. ROS). The main pathological characteristics of PD are the aggregation of alpha-synuclein proteins to different, toxic, oligomer species and neuronal cell death in the SNc. This cell death leads to a dopamine deficiency in the basal ganglia circuit, causing a stronger net activation of the indirect pathway, thereby leading to a decreased likelihood of movement.

Interestingly, a guy messing up the synthesis of MPPP, an opioid similar to pethidine, somewhat kickstarted the modern Parkinson’s disease research and lead to a widely used animal model of Parkinson’s disease.
During one of his syntheses, the temperature of the reaction got too high, leading to the production of MPTP. MPTP itself is not toxic, but being lipid-soluble, is able to readily cross the BBB. In the brain, MPTP is oxidized into MPP+ via MAO-B. MPP+ is taken up primarily into dopaminergic neurons (i.e. neurons of the substantia nigra), possibly via a catecholamine transporter, where it causes mitochondrial dysfunction and subsequent apoptosis of the neurons. Mimicking the pathophysiology of PD, taking the tainted drug caused six people to ‘freeze’. Here’s the full story: https://arstechnica.com/science/201...g-people-but-kickstarted-parkinsons-research/
The current therapy of PD includes Levodopa (passes the BBB better than Dopamine itself, less PNS side effects than Dopamine; has to be combined with an AADC-inhibitor like carbidopa or benserazide and a COMT-inhibitor like entacapone to inhibit peripheral levodopa metabolism), dopamine agonists (lysergic acid analogues like cabergoline or non-lysergic acid analogues like pramipexol), MAO-B inhibitors (selegilin), NMDA antagonists (memantine) and deep brain stimulation, but the efficacy of the medication will decrease over time and can lead to dyskinesia as well as hallucinations.

7.?.3 Addiction

7.?.4 Non-invasive imaging techniques in neuroscience

Medical imaging is the technique, process and art of creating visual representations of the interior of a body for clinical analysis and medical intervention. It seeks to reveal internal structures hidden by the skin and bones, as well as to diagnose and treat disease. Medical imaging also establishes a database of normal anatomy and physiology to make it possible to identify abnormalities. Although imaging of removed organs and tissues can be performed for medical reasons, such procedures are usually considered part of pathology instead of medical imaging.
Imaging can be used in clinic as well as research (e.g. drug development, screening, biomarker development).

Computer tomography (CT)
Computer tomography is a medical imaging technique that uses high frequency electromagnetic waves (X-rays) for radiographs, taken from different angles, to produce a computer-processed 3-dimensional tomographic image of a body. X-rays emitted from an X-ray tube that is able to move around a slice plane, pass through the body and are scattered in different directions. Those X-rays are then detected by a detector array/stationary detector ring. The series of radiographs is then reconstructed into a tomographic image with the pixels displayed according to the relative radiodensity. This results in good contrast between bones and soft structures, but low contrast between soft structures like the brain. While the contrast can be enhanced, the use is limited in neuroscience because of the low contrast and the radiation exposure.

Positron emission tomography (PET)
Positron emission tomography uses radiotracers to visualize and measure changes in physiological activities, like blood flow (Oxygen-15) and tissue glucose metabolism (18-fluorodeoxyglucose). The high frequency electromagnetic waves (positrons) emitted via positron emission decay (positive ß-decay) by the radioisotope travel a short distance in the tissue until they interact with an electron. This interaction leads to the annihilation of the positron and electron, leading to the production of a pair of annihilation gamma-photons that move in opposite directions. These gamma-photons are detected by a scintillator, where they create luminescence, that in turn is detected. The raw data is then processed and translated into a 2- or 3-dimensional tomographic image.
Typical applications include oncology, as well as cardiology and neuroscience (for example Alzheimer’s research via hypometabolism due to plaque load or PiB-tracer), but patients are still exposed to ionizing radiation.

Single photon emission computer tomography (SPECT)
The principle of SPECT is similar to that of PET, a radiolabeled chemical tracer (for example Iodine-123) directly emits gamma-rays that are detected and translated into a 3-dimensional tomographic image.

Magnetic resonance imaging (MRI)
MRI is a medical imaging technique that uses nuclear magnetic resonance to create a 3-dimensional tomographic image. This technique uses radio waves (low frequency electromagnetic wave spectrum).
One can think of a proton as a sphere composed of positive current loops that create a magnetic dipole moment that can be spin up or spin down orientation with the same energy in the case of hydrogen.
When a proton is placed into an external static magnetic field, it will feel a torque that will tend to orient the magnetic dipole moment along the same axis as the magnetic field lines, leading to a spin-up and a spin-down orientation of the proton with different energy levels (spin-up loses energy, spin-down gains energy). The angular momentum of the proton keeps it from aligning exactly though, leading to the magnetic dipole moment precessing (the axis of rotation of a body itself rotates about a second axis) about an axis. The frequency of the precession is known as Larmor frequency.
If an electromagnetic wave pulse with the right frequency is directed at the proton, the precession will flatten out since it will tend to align with the magnetic field lines of the EM-wave and the spin-up protons will gain enough energy to transition to the spin-down state. When the magnetic fields are turned-off, the nuclei will return back to the ground state, releasing energy. This energy varies in intensity (the higher the hydrogen intensity the brighter) and can be used to construct an image.
As the human body consists of mostly water and as hydrogen nuclei have the strongest nuclear magnetic resonance, this can be used for MRI. The MRI machine contains a strong static magnet that creates a homogenous magnetic field that forces the spins of the hydrogen protons into quantum-mechanical states as well as a sender coil that emits an electromagnetic pulse (radiofrequency pulse = RF pulse), forcing spin-up protons into the spin-down orientation (the RF-frequency has to fit with the Larmor-frequency of the spin system!), and a receiver coil that detects magnetization in the x/y plane as well as a gradient coil that creates spatial encoding of spins (-> lets us know the location in the body of the released photons).
In a rotating frame that rotates around the z-axis in the xy-plane of the laboratory frame, the magnetization appears stationary and can be resolved using the Bloch’s equation. The relaxation time of the z-axis is T1 (spin-lattice relaxation), while the relaxation time of the xy-axis is T2 (spin-spin relaxation). The image can be T1 or T2 weighted, leading to a different contrast and brightness. A tissue with a long T1 and T2 like water is dark in T1 and bright in T2, while a tissue with a short T1 and long T2 like fat is bright in T1 and gray in T2.

7.?.? Oxidative stress and glutamate dysregulation in neurological diseases ?




Taschenatlas Pharmakologie
The Organic Chemistry of Drug Design and Drug Action
Campbell Biologie
Neuroscience: Exploring the brain
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I know that bumping your own thread is against the rules, but this is an exception. I'll bump the thread every once in a while for the next week or two so more people see it, before I'll make it a sticky.
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This is a really brilliant comprehensive piece of work KK, you should be proud. It's perfect for anyone deep into a stim binge and fancying a bit of reading :D
Wow! This is incredible, great work couldnt understand everything but most of the stuff I got after a few times re-reading. Thanks for taking your time to write this.
Wow! This is incredible, great work couldnt understand everything but most of the stuff I got after a few times re-reading. Thanks for taking your time to write this.
What parts did you struggle with? I might be able to explain them better :)