Drugs and Behaviour April 3 PDF

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Drugs and Behaviour April 3...

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Hallucinogens, Phantasticants and Club Drugs Note: typo in the book on page 346, neurophysiology section ● Dexotomorphin (?) is actually an antagonist We will not talk about all hallucinogens, but different types that are examples of each class ● There are many different mechanisms in this chapter; with hallucinogens, we have a bunch of drugs that do very different looking things in terms of receptors, but they’re classified together as hallucinogens ● So classification is to do with drugs

that produce certain kinds of perceptual effects Hallucinogenic effects ● First thing that comes to mind may be hallucinations - seeing or hearing things that aren’t there, but that’s not how we define these effects ● Four categories of effects; some drugs lean towards some more than others ● Psychotomimetics ○ Effects mimic psychosis, specifically positive effects of a disorder like schizophrenia ○ Delusions - beliefs in things that are demonstrably false ● Phantasticants

○ Feelings of emotional significance ○ People may have a feeling of spiritual awakening or a form of enlightenment ○ Not necessarily seeing or hearing something that isn’t there, but have a feeling of significance ● Psychedelics ○ We aren’t creating things that aren’t there but our senses manipulate things that are there ○ Surreal sensory experiences ○ An object may start to wave, or colours are more intense than normal ○ Perception of things that are there is altered

● Entactogenic and empathogenic effects ○ Feelings of insight, but not to do with spiritual significance feelings of insider knowledge into your own state ○ People thought LSD would be useful as you go into a talk therapy situation, giving the person a better rapport with the therapist, allowing the person to get more out of the experience ○ Are people coming up with insights into their own experience, or is it an illusion in which you just feel you’ve broken through and understand yourself ● This is a large range of effects, and

they’re somewhat related - though psychotomimetics look very different from the others Mechanisms of action ● Broad array of targets and broad array of perceptual and behavioural effects ● Certain hallucinogens produce stronger effects on perceptual experiences than others ● Variety of transmitter systems; these have some common downstream effects ○ Notably, most increase cortical activity ○ Dissociative anesthetics only increase activity in some places, not others

○ Some have effects on thalamus while others don’t ■ With LSD, more things get through this filter ● Unlike some drugs we’ve seen, where mesolimbic dopamine system is the target and increase activity there (exception so far has been antipsychotics), with hallucinogens, we can’t make a general statement about effects on that system - they vary as to whether and how they affect this system ○ It’s debatable whether LSD even has an effect on this system - even caffeine may have more of an effect on the reward system

● Monoamine-like ○ Drugs that increase serotonin, dopamine, or norepinephrine transmission in varying amounts ○ LSD - primarily serotonergic and acting at two specific receptors ○ Psilocybin (looks a lot like LSD and within same general group - won’t be talked about again) ○ MDMA/ecstasy has a similar effect to serotonin but also similar properties to amphetamines ■ Like a combination of hallucinogen plus psychomotor stimulant

■ Stronger effect on reward system than LSD does ○ Mescaline ■ Primarily acts on catecholamines and less on serotonin ■ Example: peyote ● Dissociative anesthetics ○ PCP (aka angel dust) ○ Ketamine (aka special K) ○ These drugs are NMDA receptor antagonists ● Cannabis can be considered a hallucinogen and it sometimes part of this chapter in other books Note: long answer questions are posted for the exam

History of LSD ● Ergot fungus was discovered a long time ago by accident in natural environments; after consumption, people suffered from ergotism severe physical effects like convulsions, which indicate an increase in activity, so a stimulantlike effect ○ Also psychotropic effects: hallucinations and altered sensory experiences ○ Contains precursor for LSD; when you consume it, one component is synthesized into LSD ● Albert Hoffman synthesized lysergic acid compounds, coming up with LSD-25 in 1943

● People studied LSD and it was developed for therapeutic purposes (mental disorders, alcoholism, etc.), though it didn’t work for all of these purposes ● People did have feelings of insight, though it’s hard to say whether they’re real ● Studied for use in psychotic behaviour, but it’s probably the last type of drug you want to take if you’re suffering psychotic episodes LSD-like drugs ● LSD is prototypical hallucinogen as it touches on most effects ● Hallucinogenic effects ○ Verbal reports of hallucinations

○ Induction of hypnagogic states ■ Main predictor for susceptibility to hypnosis is openness to experience on the big 5 - LSD also makes people susceptible to hypnosis, allowing more sensory information to get to the brain ● Phantasticant effects ○ Used in some religious rituals ● Entactogenic and empathogenic effects ○ Maybe important in therapeutic context ● Perception ○ Slowing down of time ○ People report keener

perceptions and that sight and sound become more acute ■ This is different from whether they actually become more acute ■ It’s not the case that you can take LSD and throw your glasses away - people just have a feeling of sharpened senses LSD-like drugs: mechanism ● Primarily act on serotonin receptors ● Driving cortical activity in two layers ● One reported therapeutic use for LSD is as an antidepressant ○ Remember, BDNF was

stimulated by antidepressants to help with synaptic remodelling to allow neural growth in the cortex; we see something similar with LSD ○ Advantage of a drug like LSD is that it acts faster, whereas antidepressants take a while; disadvantage are the other effects ● Serotonin 2A - these drugs are partial agonists, so there’s an upper limit to the activity ○ This is handy because it’s hard to overdose on something like LSD - you can take 1000 times the dose, and you won’t die ● 5HT2A - same receptor we saw in

antipsychotics chapter (atypical antipsychotics tended to bind to 5HT2A more strongly than typicals; but these were antagonists whereas LSD promotes activity in these receptors) ● Act on serotonin receptors in the raphe nucleus, which filter incoming stimuli - so therefore, people experience “more” than they otherwise would (could be seen as good or bad) LSD-like drugs: other effects ● People know whether they’re on LSD; if you’re having hallucinogenic effects, it’s easy to discriminate ● Humans can discriminate LSD from

other hallucinogen classes (things like PCP, ketamine). Monoamine class vs. dissociative class. But both are hallucinogens. ● Tolerance develops rapidly; if you take LSD every day, you become accustomed quickly and it stops working ● Tolerance also dissipates quickly if you stop taking LSD for a few days, when you take it again, effects return ● Cross tolerance with other hallucinogens, but not with cannabis ● Withdrawal - normally no withdrawal symptoms; one of the first drugs we’ll see that doesn’t have obvious withdrawal effect

○ Not true of all hallucinogens ○ With LSD, no dysphoric state when people stop taking it ○ Flashbacks is the most commonly cited effect, which is interesting because it’s almost entirely anecdotal ■ Flashback is experience of a trip long after you took the drug ■ However, when people try to study flashbacks using a survey or controlled study, there’s no evidence for them ■ The book talks about flashbacks like they happen, but you shouldn’t be sure about it ○ If no withdrawal symptom,

can infer not strong effect on dopaminergic system. Looking at hedonic dysregulation, any B process, dysphoria was adaptation with that system. So no withdrawal means no activity in that system. ○ Gives weird experience, doesn’t drive incentive system (rewarding effects) LSD-Like Drugs: Self Administration - Non-humans generally not interested. Rats not interested in taking LSD. People maybe looking for surreal experience but if you’re an animal, or even if you’re yourself, and someone surprised

you with LSD, one would not be happy with this. Would likely have a panic attack - And when you think about it, this will always be the case in animal studies. No way to prepare them. If give conditionplace preference, will avoid that place where they used to get LSD Exception is monkeys with history of MDMA. Animals will take MDMA, because they produce effects like amphetamines. But, also has LSD-like effects. Is combination of both. - So if reinforcer is given along with conditioned stimulus (thing not rewarding on its own). LSD is the

hallucinogen and amphetamine is the reward. Combine both in MDMA, and you experience hallucinogenic effects with a reward - Monkeys have association with that conditioned experience, so then are inclined to take LSD Humans don’t continuously take LSD, is rapid tolerance of acute actions (but also rapid dissipation of tolerance). LSD-Like Drugs: Harmful Effects - Lots of people report positive experience, but many people don’t. - Trailing phenomena. Is a sensory experience. If someone

walks through space, get aftereffect. Get multiple images of person as they move through space. - People don’t overdose. Can take 7000-8000 micro-grams (incredibly high dose) and not die. Is a partial agonist, gives a built-in safety. - Was a study of harmful effects on drugs. LSD were absolute lowest in epidemiological study in terms of harmful effects. Lower than cannabis. - If you want to make it harmful, combine with something like MAOI. Additive effect. They prevent breakdown of monoamines, so get more serotonin, dopamine, and norepinephrine. So increasing

activity to point of potential seizure of convulsion. - Also, there is something called serotonin toxicity. Interaction between serotonin and dopamine can damage their terminals. Beyond scope of this class, but can ask professor more about it. - Might think drug should be harmful because, how would you operate a car. But people on LSD tend not to drive, exactly for this reason. People drink, tend to drive. People use LSD, lie on floor. Long-term health effects are not severe. Other Monoamine-like Drugs

- MDMA (Ecstasy) and Mescaline. Looking at effects on broader array of monoamines. Expanding to dopamine and norepinephrine. - MDMA was developed for similar reasons as LSD. Therapeutic alliance - are you on same page as therapist. If you don’t trust form of therapy being done, is not going to have good effect even if therapy is solid technically. Trust is big component. - Example of George Kelly doing therapy on farmers in Kansas. Talked to them about things they didn’t understand, yet they would feel better. So eventually just

started making stuff up (George Kelly). Then gave practical advice at end. So didn’t really matter what he was saying, he just came off as intellectual and expert, so when practical part came in at end, people took those to heart. Wrote a book called Principles of Psychology. Main thing was that people often feel they need permission. Would give permission to clients to be everything they were and were not. Complete tangent. - But, ecstasy similar. Gave people condition of intimacy with therapist.

- Mescaline is similar. At low doses, effects similar to MDMA. High doses have broader array. MDMA was reclassified in 1985 and was banned due to neurotoxic effects. Neurotoxic effects are built in to MDMA, whereas with LSD is not inherent. - Main issue with MDMA is a social problem. Were taken in large quantities at raves, STI’s became large issue (became too easy to trust someone and sleep with them). Structurally, MDMA and amphetamine are very similar. Looking at Mescaline (found in Peyote), is a bit different but still similar. Fall into similar group.

But don’t need to memorize this slide, is more chemistry related. Other Monoamine-like drugs: Mechanism - Instead of being 5HT2A agonist like LSD, increasing serotonin generally do will get increased transmission on all receptors, and will get full effect on transmitters - Get increased dopamine by blocking dopamine transporter. Gives hallucinogenic effect, psychomotor stimulant effect. More activity in that system. - Ecstasy has been promoted as antidepressant. Acts similarly. So should be able to see ways in

which MDMA is both hallucinogen and amphetamine. MDMA Toxicity - Effects can dissipate but take a while to do so. Can take about 6 months to go away after drug discontinued. Not acute effects, but ones related to damaging growth in cortex. - Increased body temperature too. Compounded by rave situated, someone moving a lot. If drinking too much water to compensate, can throw off electrolyte balance, can have epileptic like seizure. - LSD doesn’t do these things. Toxic effects are worse for MDMA than

LSD. Professor wants to mention that he is not an LSD proponent, has never taken (lol). Animals self-administer MDMA. Was large increase in emergency-room visits from this drug, then a drop off. People figured out it was harmful. Dissociative Anesthetics - Mechanisms very different than what has been seen so far. Going to be looking at drugs that are NMDA receptor antagonists. NMDA is transmitter for glutamate. Anesthetic quality in this is the dissociative experience. Seperated from experience, pain in traditional

sense of word. - Removal from pain usually to do with emotional removal from pain. How unpleasant does pain feel. Often not that they’re numb, they’re just seperated by it. Pain doesn’t matter as much. Give animals these drugs as well, seems to work for them as well. - PCP (Phencyclidine, AKA angel dust) - Had very negative side effect profile. - Ketamine - Still used in veterinary use. In animal surgery, often some combination with this and other drug. Combinations used, often

ketamine and zelyzine (more traditional anesthetic). Liquid that is colourless and tasteless (ideal April Fools joke - lol). Administered orally, good bioavailability. Can be converted into powder and snorted for more efficiency. Dissociative anesthetic: selfadministration - Do non-humans self-administer? Yes. Unlike LSD, some people do become chronic users. Not many LSD addicts, but more so of PCP and Ketamine. Tends to be popular in metropolitan areas, is cultural phenomenon, not to do with

psychological effects. Dissociative anesthetics: Neurophysiology - These drugs are NDMA receptor antagonists. Previously, NDMA receptor antagonist blocked the effects of nicotine. So why are these drugs reinforcing? - What we haven’t talked about yet (beyond scope of course) is that NDMA receptor is like GABA receptor in sense that there are subunits. Different kinds of NDMA receptors. Not just one type. Remember, Z-drugs bound to certain subunits, same for NDMA. Some drugs are picky or selective for particular receptors in the

brain. Tend to be on Gaba neurons that feed into reward system. - Multiple glutamate receptors too. So type of NDMA receptor that these drugs block feed into striatum. Glutamatergic inputs into the VTA ● If NDMA is blocked and we don’t have it in GABA, we decrease release of GABA (double negative), therefore, we increase dopamine ● On the other side, we see the opposite ○ If this NDMA receptor is blocked, we get decrease in dopamine ○ But there are multiple glutamate receptors; we’re only

blocking a subset from that input ○ Dopamine neuron has multiple excitatory receptors for glutamate; so we’ll still get a net increase of dopamine ● There are also NDMA receptors elsewhere that’ll drive dopamine release, but we don’t tend to block them as much ● So net effect of PCP or ketamine is to increase reward function ○ If you give animals these types of drugs, we get an increase in reward activity ● This is hard to remember because it’s the opposite of what we’ve been talking about so far in terms of NDMA receptor function

● These drugs still do block NDMA receptors in hippocampus, so we get memory problems - similar to alcohol Dissociative anesthetics: hallucinogenic mechanism ● Hallucinogenic effects aren’t in the same nature of LSD or monoamine like drugs ○ LSD: effects touch on most categories ○ Here, we don’t get the same level of surreal sensory experience; people don’t get the same level of hallucination and delusion ● Vague feelings of warmth and of pleasure that are hallucinogenic

but not as sensory related (not as audio and visual as with monoamine-like drugs) ● Increase in cortical activity, though mechanism is different from other drugs ● Example: ketamine binds to some GABA inter-neurons, driving glutamate into cortex ○ Also inhibits another NDMA receptor, giving us a mixed bag; we have more glutamate while also blocking NDMA receptors ○ We have increase glutamate release; the glutamate can now bind to all its receptors; AMPAR are available, giving us an increase in only this pathway so we don’t have as much

cortical effect as we would with LSD ○ So, hallucinogenic effects aren’t the same type and not as strong ○ Also we don’t have an alteration of sensory gating ■ Someone on PCP or ketamine don’t see things with more intense colours Dissociative anesthetics ● Stimulus properties ○ If an animal is trained to discriminate PCP and ketamine, they don’t generalize to other drug classes ○ Some disagree and show that animals who are trained to

respond to PCP and ketamine will also respond to LSD ■ Could be overlap in cortical activity, but this is true with lots of drugs ■ Could be activity on serotonin-2 receptors that we don’t know about; maybe there is residual activity we don’t know about ■ Otherwise, hard to figure out why there’d be generalization to LSD ● Tolerance ○ Develops when used every day ● Withdrawal ○ With LSD, we didn’t have strong withdrawal effects, but

we do here (and with MDMA) ○ Anxiety, confusion, tremors, grinding of teeth, etc. ○ Mixed bag - some are stimulant-like effects while some are depressant-like effects ■ This could make sense because we have decrease activity in some areas due to NMDA blockade, but increased activity in other areas Other hallucinogens ● There isn’t much known about these drugs; they’re included because the mechanism is different than the others ● Salvia

○ Remember opioids chapter: drugs that people want like heroin, fentanyl, etc. are mu opioid receptor agonists (?); affect potassium channels ■ Kappa was receptor no one wants; an adverse effect was hallucinogenic effects, but negative ones ■ Reason kappa was so different from mu because mu was presynaptic, resulting in increased dopamine, but kappa was postsynaptic and inhibited dopamine ● Difference wasn’t what receptors did but where they were located

■ With salvia, people are taking a kappa agonist because the aversive effect in reward system is more than cancelled out by being a dopamine D2 receptor partial agonist ■ Affects kappa receptors in cortex but avoids dysphoric problem by binding to D2 receptors ■ Hallucinogenic effects via kappa, D2 partial agonist property makes it reinforcing ● GHB ○ Binds to its own receptor and at higher doses to the GABA-B receptor ○ Normalizes sleep, so used to

treat narcolepsy ○ GHB receptors concentrated in cortex and hippocampus ■ Many effects look like hypnotics ■ Don’t get sharp, surreal experiences, but do get some mu effects - reduction in anxiety, for example ■ So GHB is like combination hallucinogen and depressant (sedative hypnotic)...