Nootropics conjure to mind increased productivity and mental clarity.
But what about psychedelics? When people mention psychedelics like psilocybin and LSD what comes to mind?
Personally, I think of psychedelics as intoxicants. Mind-expanding? Certainly. Helpful for transcending self/other dualities and dissolving the ego? Absolutely.
But I wouldn't drop acid before taking the bar examination. It seems like LSD could interfere with rational, sober thinking.
A growing number of self-experimenters disagree with this assessment.
I'm writing about LSD because it has received a lot of attention as a potential nootropic.
In this post, I will put my own biases aside and took a closer look at the nootropic value of LSD.
If you've used LSD for nootropic purposes, please leave a comment about your experience!
What's A Microdose of LSD?
First synthesized in 1938, LSD is the quintessential psychedelic.
My own biases about LSD originate from its link to counterculture movements and long history of recreational use.
But drugs have very different effects at different doses. People who use LSD to improve technical ability and mood use microdoses of LSD (~10ug). These are not recreational doses of LSD. 10ug of LSD will not result in profound hallucinations or psychotomimetic effects.
Microdoses of LSD fall below the threshold dose of 20-30 ug. The threshold dose is the dose at which LSD elicits noticeable effects.
LSD is extraordinarily potent. To put things in perspective, the typical, prescribed dose of modafinil is 10,000 times greater than the threshold dose of LSD.
If you take a microdose of LSD, what can you expect to feel? The feeling will be subtle or you won't feel anything at all. Escalating the dose of LSD until you feel its effects is a good way to transition into recreational, psychotomimetic doses of LSD.
Before you start imbibing acid-laced water, lets look at the evidence that low-dose LSD actually improves cognitive ability.
Can LSD Enhance Cognition?
LSD microdosing has received a lot of attention for its potential nootropic effects. Vapefker recently posted the following on Reddit:
Nothing has came close to microdosing LSD. Microdosing LSD is very awakening, but doesn't feel overstimulating like amphetamine. It greatly increases motivation and productivity. Today alone I finished all my classwork for the week and worked on a side project.
The effects I have noticed include:
Very awakening and energizing, not unlike Modafinil. It is not too stimulating like amphetamine. Very clean and uplifting.
Greatly increased motivation. I want to get stuff done. I have the drive to accomplish tasks.
Increased productivity and focus. Focusing on work is much easier, perhaps just as effective as adderall for ADHD.
Greatly reduced anxiety. In fact, I have never felt anxious while microdosing LSD.
No crash or day-after effects
No issues with tolerance. You can take a few days off to completely reset your tolerance.
Enhanced music, colors, and overall sense of wellbeing.
Stacked with CBD, microdosing LSD makes life much more pleasant, and accomplishing work has never been so rewarding.
I cannot recommend microdosing LSD enough. It will restore your love for life and make any day a perfect day.
Vapefker's LSD experience report is typical among nootropic users.
But when did this idea of microdosing LSD start?
At a technical conference in 2011, James Fadiman presented results from survey data he collected from self-experimenters. His results suggested that LSD microdosing could be beneficial.
The Rolling Stone commented in 2015:
The reports come from all over the world, but Fadiman says there's a steady, consistent stream originating in the San Francisco area. The typical profile there is an "übersmart twentysomething" curious to see whether microdosing [LSD] will help him or her work through technical problems and become more innovative. "It's an extremely healthy alternative to Adderall," says Fadiman, referring to a drug popular with programmers.
There are lots of anecdotal reports that LSD has nootropic effects. But anecdote is notoriously unreliable. So where’s the evidence?
Is Mood Enhancement Cognitive Enhancement?
Opinions differ about whether improving mood constitutes cognitive enhancement.
My bias is that it does. I function better when my mood is better and you probably do too. There's no question that depression and chronic stress impair cognitive function.
If your default state is slightly depressed and dysthymic there's solid evidence that improving your mood will also improve your cognitive ability 7. But if you're fairly upbeat without pharmacological aid it's less clear that mood enhancement is cognitive enhancement.
Source: Getty Images
Apart from bad trips, the evidence that LSD brightens mood is solid. Researchers have explored the potential of LSD as a treatment for depression. Though LSD will never be prescribed for depression for political reasons, there's reason to surmise that it would be effective.
LSD and Ketamine
The timeline of LSD's antidepressant effect is similar to ketamine. Ketamine is a dissociative anesthetic that blocks glutamate receptors (of the NMDA variety). Conversely, LSD potently activates serotonin receptors.
Ketamine has received a lot of attention as an antidepressant with long-lasting effects. A single dose can banish depression for 1-4 weeks. Nearly all other antidepressants only “work” if blood levels are maintained within certain bounds.
Like Ketamine, LSD also elevates mood in a sustained manner. Mood improvement persists well after LSD is excreted from your system. It remains mysterious how these persistent effects work.
Research on LSD was interrupted in the 1960s due to its association with counterculture movements. But the limited research that has been conducted suggest that LSD has antidepressant, anxiolytic and anti-addictive effects. For example,
The few modern studies on LSD have reported a number of both positive and negative effects:
- Improved mood and subjective wellbeing that persists for weeks
- Psychosis-like symptoms (without delusional thinking)
- Mood lability
- Changes in brain blood flow and electrical activity
Some researchers3 have suggested that LSD's prosocial effects could make it a useful aid in psychotherapy:
LSD produced feelings of happiness, trust, closeness to others, enhanced explicit and implicit emotional empathy on the MET, and impaired the recognition of sad and fearful faces on the FERT. LSD enhanced the participants' desire to be with other people and increased their prosocial behavior on the SVO test. These effects of LSD on emotion processing and sociality may be useful for LSD-assisted psychotherapy.
What Makes LSD So Potent?
LSD binds very tightly to a subset of serotonin receptors. To be fair, LSD actually hits many neuronal targets including dopamine and histamine receptors.
But it’s affinity for these other receptors is relatively low such that LSD’s effects are solely attributed to its activity at serotonin receptors.
Specifically, LSD binds the following serotonin receptors:
- 5-HT1A (Ki=1.1nM)
- 5-HT2A (Ki=2.9nM)
- 5-HT2B (Ki=4.9nM)
- 5-HT2C (Ki=23nM)
- 5-HT5A (Ki=9nM)
- 5-HT6 receptors (Ki=2.3nM)
Example: if brain tissue slices are submerged in a solution of 1.1 nM LSD, 50% of serotonin receptor subtypes 5-HT1A will be occupied.
LSD binds tightly to 5-HT1A receptors. But these receptors play a lesser role in LSD's subjective effects.
Activation of frontocortical glutamate receptors is likely the key mechanism. LSD’s effect on glutamate is secondary to 5-HT2A receptor binding; LSD does not bind glutamate receptors directly.
How Does The 5-HT2A/Glutamate Receptor Link Work?
Serotonin 5-HT2A receptor activation is coupled with several intracellular signaling pathways. The metabotropic glutamate receptor 2 forms complexes with 5-HT2A and is required for the pharmacological effects of LSD.
These serotonin/glutamate receptor complexes are implicated in schizophrenia and psychosis. In postmortem human brain samples from schizophrenics, the serotonin receptor (5-HT2A) is up-regulated and the mGluR2 is down-regulated5, a pattern that could predispose to psychosis.
Ionotropic receptors form an ion or pore, whereas metabotropic receptors are indirectly linked with ion channels on the plasma membrane.
Show Me The Evidence
Despite having profound effects on cognition, research on LSD has been stymied for decades. It's no surprise that from 1970's until very recently, no scientist wanted to touch the stuff.
Since 2015, more authors have started publishing studies on the mechanism and effects of LSD.
John Harvey of Drexel University8
specifically investigated the effects of LSD, along with other 5-HT2A agonists, on learning and memory. Harvey used Rabbits to test his hypotheses about LSD because Rabbits are a well-documented6 animal model of classical conditioning.
Harvey found that 5-HT2A was "special." Drugs that bind other serotonin receptor subtypes (e.g., 5-HT1A) appear to either have no effect or impair learning.
Harvey reported that LSD and a few other 5-HT2A agonists enhanced associative learning in the range of doses that these drugs are known to affect human cognition. Harvey also tested agonists at other serotonin receptor subtypes (e.g., 5-HT1A) and found they had no affect on associative learning.
Drugs that block the 5-HT2A receptor (antagonists) either had neutral or negative effects on learning. MDL11,939, a highly selective 5-HT2A antagonist, as well as the nonselective 5-HT2A/2C antagonists ritanserin and mianserin produced a dose-dependent reduction.
5-HTP2A Activation Upregulates BDNF
BDNF is a protein that provides trophic support for neurons. It promotes the survival of existing neurons while encouraging the growth of new neurons. BDNF plays a role in depression and resilience to stress. The mechanism of most antidepressant drugs seem to converge on BDNF, irrespective of class.
Meller et. al. reported that 5-HT2A receptor activation leads to increased BDNF mRNA expression2. LSD is a potent 5-HT2A agonist.
It's no great leap in thought to propose that LSD might also boost BDNF. For example, Catlow4 reported that low-dose psilocybin produced a trend toward increased neurogenesis in an animal model.
If LSD increases BDNF expression, it might explain its anti-addictive properties. Alcohol self-administration is inversely related to BDNF or GDNF in animal models 1.
Effects of LSD on Functional Connectivity
Functional connectivity is:
The temporal correlation between spatially remote neurophysiological events
Functional connectivity represents the network behavior underlying high level cognitive function because functional connectivity often changes on the order of seconds.
Tagliazucchi et. al. studied the effects of LSD on global functional connectivity using fMRI.
The authors reported that thalamic and cortical regions showed increased global connectivity. The areas of enhanced global connectivity overlapped with a map of 5-HT2A receptor densities. This is reassuring because LSD tightly binds this serotonin receptor subtype. LSD also augmented communication between normally disparate brain networks.
Caption: "Under the influence of LSD, the brain's visual cortex has increased connectivity with other brain regions (right) than when imaged under placebo (left)." source.
The author's findings were neatly consistent with subjective reports of “mind expansion” and dissolution of perceptual boundaries between self and environment.
The Long and Short Of It
- Some brave souls are self-experimenting with microdosing LSD for mood and cognitive enhancement.
- A microdose of LSD is 10ug - below the dose at which LSD has hallucinogenic effects.
- LSD "loosens" the strictures on the brain in a way that can elevate mood for weeks.
- LSD enhances functional connectivity between brain regions that are normally disparate.
- LSD is a potent 5-HT2A agonist that indirectly affects glutamate and actylcholine.
- LSD-induced activation of 5-HT2A may enhance cognitive ability. This serotonin receptor is unique in this regard.
Increased Global Functional Connectivity Correlates with LSD-Induced Ego Dissolution
The paradoxical psychological effects of lysergic acid diethylamide (LSD)
Bogenschutz MP, Pommy JM. Therapeutic mechanisms of classic hallucinogens in the treatment of addictions: from indirect evidence to testable hypotheses. Drug Test Anal. 2012;4(7-8):543-55. ↩
Meller R, Babity JM, Grahame-smith DG. 5-HT2A receptor activation leads to increased BDNF mRNA expression in C6 glioma cells. Neuromolecular Med. 2002;1(3):197-205. ↩
Dolder PC, Schmid Y, Müller F, Borgwardt S, Liechti ME. LSD Acutely Impairs Fear Recognition and Enhances Emotional Empathy and Sociality. Neuropsychopharmacology. 2016;41(11):2638-46. ↩
Catlow BJ, Song S, Paredes DA, Kirstein CL, Sanchez-ramos J. Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning. Exp Brain Res. 2013;228(4):481-91. ↩
González-maeso J, Ang RL, Yuen T, et al. Identification of a serotonin/glutamate receptor complex implicated in psychosis. Nature. 2008;452(7183):93-7. ↩
Gormezano, I., Kehoe, E.J., and Marshall, B. 1983. Twenty years of classical conditioning research with the rabbit. In Progress in psychobiology andphysiological psychology (ed. J.M. Sprague and A.N. Epstein), Vol. 10, pp. 197–275. Academic Press, New York. ↩
Gualtieri CT, Johnson LG. Bupropion normalizes cognitive performance in patients with depression. MedGenMed. 2007;9(1):22. ↩
Harvey JA. Role of the serotonin 5-HT(2A) receptor in learning. Learn Mem. 2003;10(5):355-62. ↩