Miscellaneous Most anxiolytic psychedelic drugs

[Allylbenzene]

If you want a tryptamine with a HUGE amount of seorotonin releasing activity, the 7-methyl derivative of pretty much any of them will provide it. Sadly, ring-substituted tryptamines are a total pain to produce.

There's isotryptamines also, but with a likely reduction in overt psychedelic activity.

Substituted isotryptamine - Wikipedia

wikipedia.org

The N,N-dimethyltryptamine (DMT) core structure is embedded within the tetracyclic ergoline framework of LSD. Previously, we demonstrated that transposition of the N,N-dimethylaminoethyl substituent from C3 to N1 reduced the hallucinogenic potential of tryptamines while maintaining their effects on structural neuroplasticity.

Applied to LSD:

We reasoned that an analogous modification to LSD might lower its hallucinogenic potential while preserving key contacts within the 5-HT2AR binding pocket that endow LSD with exceptional potency.

https://www.pnas.org/doi/10.1073/pnas.2416106122

 

[4DQSAR]

Well, it seems that some have been knocking about for decades but as with other related compounds in which the indole was substituted, that don't appear that exciting. Long, long ago someone asked if indazoles could substitute for indoles but it sound like the examples you give - they don't tend to cross the BBB too well and/or are substrates for the ABC transport.

At the end of the day, price is still the key metric for curent RC vendors. They are happier to sell something controlled than something that is less profitable. 7,a-DMT overlays MMA perfectly and I would be surprised if 5-MeO,7-a-DMT wasn't very similar to DOM.

 

[Allylbenzene]

If one is considering the 5HT2a receptor, it's ANTAGONISTS that seem to posess anxiolytic properties.

On that note, kratom's mitragynine alkaloid is an antagonist at HT2A.

 

[negrogesic]

Most anxiolytic psychedelic is, by a massive margin, nitrous oxide.

There really aren't even any close competitors, given its 4 pronged action at:

GABA-A: binding @ benzodiazepine binding site
NMDAR: reduced glutamatamic arousal
MOR: Endorphin release
Mesolimbic D2R: DA release

And for those who say that nitrous oxide isn't a real psychedelic: you simply haven't had enough of it. Like any drug, levels of N2O build in the blood, and it takes a sufficient blood level for the true psychedelic effects to come out. At low doses (a few cartridges) it mainly causes perceptual changes (the auditory effects being most talked about). Only after inhaling a constant stream of cartridges (best inhaled directly, not with a balloon) does the N20 headspace emerge. I'd say it takes a minimum of 10 cartridges in short succession to begin to enter the headspace of NOS. It takes a good 30+ to actually start truly tripping. Like with DXM, the nitrous oxide psychedelic experience manifests in different "plateaus".

Of course, this isn't especially safe. Nitrous oxide inhaled in that quality can cause significant depletion of blood oxygen, and of course, regular use causes B12 depletion. I used it daily at an average of 50+ cartridges a day for around a year and a half. I actually began using it to help with benzo withdrawal symptoms, since its rapid action on the GABA-A BZD binding site leads to brief but instant relief. And as an opioid addict, the endorphin release was welcomed. But the psychedelic effects, which are exclusively NMDAR mediated, were kind of a side-effect that actually exacerbate benzo withdrawal symptoms.

I've had experiences where I spoke to god, traveled the universe etc, but the big limitation is that due to GABA-A activation, it is inherently an amnestic drug, and it is very difficult to remember the totality of the psychedelic experience.

Anyway, nitrous oxide is, by wide margin, the most anxiolytic psychedelic. Second might be IV ketamine (which is odd, because IM ketamine can be anxiogenic).

As far as serotonergics, 6-APB takes the cake. But not without its own toll (the risk of 5-HT2b mediated heart damage).

I once plugged 600mg of 6-APB in the hopes of a profound experience. It wasnt what I hoped. The next day when I dragged myself into my office a colleague of mine said, "woah, you look like shit". I felt like i had been hit by a train, was completely wiped, and felt worrisomely weak (physically).

To this day, I wonder what damage that massive dose of 6-APB might have done to my heart valves. I suppose if it had it might have manifested by now. Or will I randomly have a heart attack at 45?

 

[4DQSAR]

I dunno - Xenon is used medically as is propofol. Both are abused by clinicians who one assumes has access to a large range of psychoactives.

 

[negrogesic]

I dunno - Xenon is used medically as is propofol. Both are abused by clinicians who one assumes has access to a large range of psychoactives.

I've played around with intravenous propofol (veterinary) three or four times and it has no psychedelic or psychomometic properties. I found it boring and unenjoyable. Reminded me of ethanol intoxication more than anything else. Was not barbiturate like nor disinhibiting like benzodiazepines. I am not a fan of alcohol and do not find it reinforcing, so I'm guessing the physicians and nurses that abuse it are also fans of alcohol or are perhaps alcoholic.

And xenon might be more psychedelic than nitrous oxide, but it is notably less dopaminergic than N2O (https://journals.lww.com/anesthesia...erential_effects_of_nitrous_oxide_and.26.aspx).

This is likely due to xenon's comparatively lower propensity to release opioid peptides.

So xenon might be more psychedelic, but as a recreational drug, less enjoyable/rewarding and most relevant to this thread, less anxiolytic.

Thus again I am not aware of any psychedelic that is less anxiolytic than N2O.

 

[Allylbenzene]

What about muscimol? GABA-A agonist and/or GABA-B?

The gamma-aminobutyric acid type A (GABAA) receptor agonist muscimol is widely used as a tool for reducing neuronal activities particularly in experiments in vivo. At the synapse formed by the calyx of Held in the rat brainstem slice, the GABAA receptor agonist muscimol (> 10 microM) attenuated the amplitude of excitatory post synaptic currents (EPSCs) accompanied by an increase in the coefficient of variation of EPSCs, suggesting its presynaptic inhibitory effect. This muscimol effect was not affected by bicuculline but occluded the presynaptic inhibitory effect of the GABAB receptor agonist baclofen and was abolished by the type B GABA (GABAB) receptor-specific antagonist (+)-5, 5-dimethyl-2-morpholineacetic acid (SCH 50911; 20 microM). We conclude that muscimol activates presynaptic GABAB receptors thereby attenuating synaptic transmission.

Presynaptic inhibition by muscimol through GABAB receptors - PubMed

The gamma-aminobutyric acid type A (GABAA) receptor agonist muscimol is widely used as a tool for reducing neuronal activities particularly in experiments in vivo. At the synapse formed by the calyx of Held in the rat brainstem slice, the GABAA receptor agonist muscimol (> 10 microM) attenuated t …

pubmed.ncbi.nlm.nih.gov

 

[tryptakid]

What about muscimol? GABA-A agonist and/or GABA-B?

Presynaptic inhibition by muscimol through GABAB receptors - PubMed

The gamma-aminobutyric acid type A (GABAA) receptor agonist muscimol is widely used as a tool for reducing neuronal activities particularly in experiments in vivo. At the synapse formed by the calyx of Held in the rat brainstem slice, the GABAA receptor agonist muscimol (> 10 microM) attenuated t …

pubmed.ncbi.nlm.nih.gov

Related to that - though a departure from this thread's original question (since it's asking more about 5ht-related psychedelics

Zolpidem is one of the most anxiolytic drugs I've ever used. I find the state created upon staying awake without tolerance on 5-10mg of zolpidem to be both profoundly anxiolytic, comforting, and trippy as fuck. It brings the weird out in the most mundane things - complex and subtle visual shifts, and it also has at times been cognitively enhancing. I have found it helps to find solutions to stressful problems while on it.

The downsides aren't without mention: it's amnesic, it can be disinhibiting in a way that can be troubling to others, and it reduces the "that's probably not a good idea" voice that keeps you from doing stupid things like driving to a friend's house to smoke weed (which you don't like) while on ambien (which you shouldn't drive on) at 2am because.... because... why because?

Still, the walrus (the teacher spirit associated with zolpidem) is a profoundly weird and trippy entity entirely devoid of anxiety.

I sadly quit using it a year ago and do miss it sometimes. My sleep is better for it, but I do miss that first 10mg dose of a prescription making my moments before bed moments of profound dreamy wonder.

 

[4DQSAR]

Gaboxadol (also known as OV101 or LU-2-030) was a explored as a novel hypnotic in man. Research was halted in stage 2 trials. So I'm going to BET that psychedelic side-effects was a least one issue.

 

[Allylbenzene]

21 March 2025. [Morris:] I've used high doses of gaboxadol and that is as psychedelic as anything else. It's different, of course. It's a different type of experience entirely. But that same sort of proliferation of ideas and perceptual disturbances is very much present. It is not in any way analogous to a benzodiazepine. It's something that is visionary and completely alien and strange.