Could there potentially be novel categories of drugs that work on receptors we previously thought not to be psychoactive?

[theprinceoflife]

So far we are familiar with many different types of drugs. Here is a few example of what I mean:

GABAergics/Depressants (alcohol, benzos, barbiturates, Gabapentinoids) working on the GABA receptor (and sometimes calcium channels)

Dissociatives (Arylcyclohexylamines, Morphinans, N2O, etc.) working on the NMDA (and sometimes opioid receptors)

Opioids (oxycodone, heroin, morphine, etc.) working on the opioid receptors

Stimulants (Methamphetamine, cathinones, caffeine) working on dopamine, norepinephrine and adenosine receptors

Psychedelics (LSD, Psilocybin, etc.) working on serotonin receptors

Cannibinoids (THC) working on the endocannabinoid receptors

Deliriants (scopolamine, diphenhydramine, etc.) working on acetylcholine and histamine

KOR agonists, Hypnotics (Amanita Muscaria specifically), and inhalants as well


But for novel categories… maybe we have…
For example, orexin receptor antagonist/agonists?

What else is there?

 

[AlsoTapered]

Who knows? Nobody recognised the NOP (formally ORL1) receptor a few years ago. We keep finding that their are subtypes and the activation & inhibition of certain combinations - a5b2y2 emulates a couple of glasses of wine. a5b1y2 emulates a couple of bottles of wine,

 

[RUC4]

Well, who knows. I agree with the above commenter. This list is just the beginning and not definitive.
Drug classifications can be complex, as drugs can be categorized based on their pharmacological effects, mechanisms of action, chemical structure, or their therapeutic use. Here's a general breakdown based on their effects and uses:

1. Central Nervous System (CNS) Depressants : These slow down brain activity, leading to a feeling of relaxation. Examples include:
- Benzodiazepines (e.g., Valium, Xanax)
- Barbiturates
- Certain sleep medications

2. Central Nervous System (CNS) Stimulants : These increase brain activity, resulting in increased alertness, attention, and energy. Examples include:
- Amphetamines (e.g., Adderall)
- Cocaine
- Caffeine
- Methamphetamine

3. Hallucinogens/Psychedelics : These alter perception, mood, and a host of other cognitive functions. Examples include:
- LSD
- Psilocybin (magic mushrooms)
- PCP
- MDMA (ecstasy)

4. Dissociative Drugs : These lead to feelings of detachment from the environment and oneself. Examples include:
- Ketamine
- PCP
- Salvia

5. Narcotic Analgesics (Opioids) : These reduce the perception of pain, can induce euphoria, and are known for being highly addictive. Examples include:
- Morphine
- Codeine
- Oxycodone (e.g., OxyContin)
- Heroin

6. Cannabis Products : These are derived from the cannabis plant and can have both depressant and hallucinogenic effects.
- Marijuana
- Hashish
- CBD products

7. Over-the-Counter (OTC) Drugs : These are medicines you can buy without a prescription. Some common OTC drugs can be abused for their psychoactive effects.
- Dextromethorphan (found in some cough syrups)
- Pseudoephedrine (a nasal decongestant)

8. Inhalants : These are volatile substances that produce chemical vapors that can be inhaled to induce a psychoactive, or mind-altering effect.
- Paint thinners
- Gasoline
- Glue

9. Anabolic Steroids : Synthetic variations of the male sex hormone testosterone that athletes and others sometimes abuse.

10. Alcohol : A psychoactive substance that acts as a CNS depressant.

11. Tobacco and Nicotine Products : Containing the addictive stimulant nicotine.

 

[Rectify]

Idk but 720 mg DXM / antihistamine pills in divided doses almost every day, is like a subtly psychedelic opioid. I Had Lucid CEVs.

 

[Neuroborean]

I could imagine some sort of hypermerged human that works along nanotechnology and super evolutionary AI that builds new tissue indefinitely just to create a different experience, including new types of receptors, and at the same time agonizing/modulating/antagonizing those receptors
this is some sort of feverish transhuman druggie dream

 

[Skorpio]

The new THC like synthetic cannabinoids tend to hit a few orphan receptors, though I would be surprised if they are super psychoactive.

There are a bunch of orphan receptors in the brain, so there is a possibility of things being discovered. However, the fact that drugs of abuse tend to cluster on the mechanisms listed does make it less likely to discover a truly novel "fun" target. As nature produces drugs in a manner unbiased towards their molecular targets, I would expect for some big finding to have examples found as plant secondary metabolites or as an animal produced toxin (though there are of course mechanisms under-represented in nature such as non-competitive NMDA antagonism).

I think a big thing for future drugs is having biased agonists which activate receptors in either g protein or beta arrestin pathways selectively, and produce a tighter range of positive effects, and excluding side effects.

 

[sekio]

At the end of the day, it's all receptor binding. If there is some orphan receptor capable of causing novel psychological effects then it's only a matter of time before it is found.

 

[AlsoTapered]

I think a big thing for future drugs is having biased agonists which activate receptors in either g protein or beta arrestin pathways selectively, and produce a tighter range of positive effects, and excluding side effects.

Like those new opioids? I know brorphine was one of a series designed to be biased until they actually tested them and discovered that NO, they weren't really that biased.

Never seen a report on brorphine which suggests it's dross... and all the while bezitramide is legally controlled everywhere.... the active metabolite, norbezitramide isn't on any list of controled drugs I could find. It overlay's R-4066 very well indeed but it isn't as rigid. Still x20 M and a 1 step synthesis....

 

[Mr. Krinkle]

 

[Skorpio]

Like those new opioids? I know brorphine was one of a series designed to be biased until they actually tested them and discovered that NO, they weren't really that biased.

Never seen a report on brorphine which suggests it's dross... and all the while bezitramide is legally controlled everywhere.... the active metabolite, norbezitramide isn't on any list of controled drugs I could find. It overlay's R-4066 very well indeed but it isn't as rigid. Still x20 M and a 1 step synthesis....

I feel like a lot of the biased opioid hype deflated, I remember oliceridine being hailed as the next non-addictive mu opioid (and we have certainly heard that before), but some study showed it is just a partial agonist.

I think there is more promise with things like biased kappa ligands, or biased 5HT2A agonists.

 

[sekio]

I think the only way out is going to be social and not pharmacological, like what my local system tries to do: reducing stressors in life that drive heroin/opioid use, stabilizing them on a fixed dose of a standard opioid (XR morphine or methadone with hydromorphone as breakthrough med is used here - 'here' being Vancouver, Canada) so they are no longer reliant on/users of "street" dope of uncertain composition and purity, and a gradual taper at the speed the user feels appropriate (or continued maintenance until the point they are willing to do so).

I don't think there is going to be some sort of opioid painkiller that remains uniformly effective for severe/chronic pain that produces no/little tolerance, unfortunately.

Personally, I find NMDA antagonists to be infinitely more effective painkillers when dosed correctly. I'm not even joking when I say that 1-5mg of PCP (or equivalent long lasting NMDA antagonist) orally maybe 1-2x daily could be a very effective antidepressant/stimulant/painkiller, which is exactly what is called for in chronic pain. absent any family history of psychosis/schizophrenia/mania, and with close monitoring for the first 48-72h.

 

[TheLightBringer]

This doesnt really fit into the ”not thought to be psychoactive part” but a novel compound called Ziconotide, a selective N-type voltage gated calcium channel blocker. Inhibits the release of glutamate, CGRP and Substance P(which is released from sensory nerves and associated with pain). Its an Omega-Conotoxin 1000x stronger than morphine. Interesting molecule and might provide a non-habit forming pain killer.

 

[AlsoTapered]

I feel like a lot of the biased opioid hype deflated, I remember oliceridine being hailed as the next non-addictive mu opioid (and we have certainly heard that before), but some study showed it is just a partial agonist.

I think there is more promise with things like biased kappa ligands, or biased 5HT2A agonists.

That seems to have been the result on other 'biased' agonists. Low efficacy seems to be the commonality.

Indeed kappa activity is well known for causing dysphoria. I guess it's a good way of avoiding 'addiction' because it's deeply unpleasant to the extent that patients have to judge if the treatment is more distressing than the injury or other visceral pain.

Then we reach the moral (and indeed practical and economic issues) in that a patient prescribed an analgesic with unpleasant side-effects, that patient is going to go back to the doctor asking for an alternative.

Didn't De Quincy note that 'opium makes a good servant but a terrible master'?

For the vast majority of patients, conventional opioids represent the best treatment for chronic pain. Partly, I'm sure, because they alter the perception of pain. Chronic pain causes anxiety and depression and opioids treat those symptoms as well. I've noted (from my own experiences in emergency medicine) that loss of sleep is one of the most significant problems for those suffering chronic pain and I have witnessed people who haven't slept for days able to relax and slumber after the administration of quite modest amounts of morphine.

Indeed the BNF goes further. Diamorphine is indicated for severe pain but notes also state that it treats the anxiety and depression common in palliative care. It's admitting that it's not JUST the analgesia that is of benefit.

But then the UK has a strange rule surrounding the use of strong opioids. The rule is 'To treat unacceptable human suffering'. I find that very telling. I basically didn't leave my home for over a year until the doctor finally accepted that pain was going to kill me sooner than treatment with Oxycontin... so I get Oxycontin.

 

[blueberries]

What about SoRI-20041? Would that constitute a novel dopaminergic action?

 

[polymath]

Neuropeptide S receptor agonists seem to release dopamine in the reward circuits of the brain, improving mood and wakefulness while acting as an anxiolytic at the same time. However, there still is no small-molecule NPS receptor agonist that can cross the blood brain barrier, except a nasal spray formulation of NPS itself which gets to the CNS to some extent. A problem with the theoretical small molecule agonists of NPSr is that they could also cause obstructive changes in the airways, causing asthma, COPD, etc. unless made selective enough.

Cholinergic M4 receptor blockers improve dopamine release, as do M5 receptor agonists, but there seem to be no human trials on M4 or M5 selective cholinergics. From what I've read, I think the effect would be like a mild stimulant and potentiate the euphoria from other drugs. I would like to see someone finding a compound from herbal medicine that actually affects these receptors selectively without anyone having noticed that yet. Trialing synthetic drugs of this type isn't likely to be worth the risk.

Metabotropic glutamate receptor ligands such as the MGlur5 blocker fenobam have effects on mood and cognition and in large doses have been observed to cause "psychotomimetic side effects" (probably somewhat like those from NMDA blockers).

Systemically administered local anesthetics make people feel dizzy and weird, but that is not likely to be a completely positive feeling and they also have a small therapeutic index which makes this very dangerous. Some doctors have also tested applying many local anesthetic patches on a patient to get enough of the drug to the bloodstream to make the whole body a bit numb and reduce the opioid dose needed for some pain condition. But there again the overdose risk is even worse than with opioids itself.

It's also possible that there are drug interactions that no one knows about, yet. Suppose someone finds out that H2 receptor blockers used for acid reflux problems also potentiate some recreational drug because of the effect on H2 receptors in the CNS. Or that saturating your MT1 and MT2 receptors with melatonin reduces the needed dose of some other drug to get intoxicated. Well, actually large doses of melatonin improve the analgesia from morphine and other opioids, and also that from anti-inflammatory drugs. That's one way to get more than usual pain relief from aspirin or ibuprofen if you want to avoid opioids because of prior addiction problems or if you need to take a smaller ibuprofen dose to avoid developing an ulcer.