LSD microdosing for ADHD: Does it work? Not really!

Recommendable! At least the study confirmed that treatment with LSD microdosing is safe! 😊

What is microdosing anyway? If the dose is small enough it may not have an effect at all. It becomes a placebo.

"A landmark clinical trial testing the effect of microdosing LSD on symptoms of attention-deficit hyperactive disorder (ADHD) recently delivered its first data readout and the results have been surprising, to say the least, raising questions over the efficacy of this popular trend. ...

Despite this massive wealth of anecdotal evidence, robust clinical research into microdosing has been minimal. The very few placebo-controlled examinations conducted on the practice have pretty consistently struggled to find any effect at all.

The latest clinical trial to test the practice has focused on the effect of microdosing LSD for symptoms of ADHD. The trial is the first to test microdosing in a cohort of patients suffering from a specific condition. Prior trials have mostly focused on mood effects in healthy cohorts or groups with sub-clinical mental health problems. The new trial is also one of the longest and most robust investigations into the popular phenomenon ever conducted. ...

The trial recruited 53 participants, all fitting the diagnostic criteria for moderate to severe ADHD. Half were given LSD microdoses of 20 micrograms, and the other half were given a placebo. All were administered doses twice a week for six weeks.

At the end of the study period all participants showed statistically significant reductions in their ADHD symptoms, regardless of placebo or LSD. In fact, the placebo group displayed marginally greater symptomatic improvements, although that difference was considered statistically insignificant. ..."

From the key points and abstract:

"Key Points

Question

Does twice-weekly low-dose (20 μg) lysergic acid diethylamide (LSD) over 6 weeks reduce symptoms of attention-deficit/hyperactivity disorder (ADHD) in adults with moderate to severe ADHD compared with placebo?

Findings

In this multicenter, double-blind, placebo-controlled randomized clinical trial in 53 individuals, both the LSD and placebo groups exhibited a significant reduction of ADHD symptoms. However, there was no difference in symptom reduction between the 2 groups.

Meaning

LSD was not efficacious in reducing ADHD symptoms compared with placebo; these results question the anecdotal practice and highlight the importance of placebo-controlled trials in low-dose psychedelic research.

Abstract

Importance

Microdosing psychedelics, including lysergic acid diethylamide (LSD), has gained attention for its potential benefits in several psychiatric disorders, including attention-deficit/hyperactivity disorder (ADHD). However, LSD’s efficacy in reducing ADHD symptoms remains unknown.

Objective

To determine the safety and efficacy of repeated low doses of LSD in reducing ADHD symptoms compared with placebo.

Design, Setting, and Participants

This was a 6-week, multicenter, double-blind, placebo-controlled, parallel-group phase 2A randomized clinical trial conducted between December 17, 2021, and December 4, 2023. Data were analyzed from March 22, 2024, to August 19, 2024. Outpatient treatment was provided at 2 centers: University Hospital in Basel, Switzerland, and Maastricht University in the Netherlands. Adults aged 18 to 65 years with a prior ADHD diagnosis who presented with moderate to severe symptoms (Adult Investigator Symptom Rating Scale [AISRS] score ≥26 and Clinical Global Impression Severity score ≥4) were eligible for inclusion. Key exclusion criteria included selected current major psychiatric or somatic disorders and the use of potentially interacting medications.

Intervention  Participants received either LSD (20 μg) or placebo twice weekly for 6 weeks (total of 12 doses).

Main Outcome and Measures  The primary outcome was the change in ADHD symptoms from baseline to week 6, assessed by the AISRS and analyzed with a mixed-effects model for repeated measures.

Results

A total of 53 participants were randomized to LSD (n = 27) or placebo (n = 26). Mean (SD) participant age was 37 (12) years, and 22 participants (42%) were female.

The LSD group presented a mean AISRS improvement of −7.1 points (95% CI, −10.1 to −4.0).

The placebo group presented a mean AISRS improvement of −8.9 points (95% CI, −12.0 to −5.8), with no difference between groups. LSD was physically safe and psychologically well tolerated overall.

Conclusions and Relevance 

In this randomized clinical trial, repeated low-dose LSD administration was safe in an outpatient setting, but it was not more efficacious than placebo in reducing ADHD symptoms."

LSD microdosing for ADHD: new trial shows surprising results

Safety and Efficacy of Repeated Low-Dose LSD for ADHD Treatment in Adults/A Randomized Clinical Trial

Microdosing LSD for ADHD is no better than a placebo, clinical trial shows. Really!

What else was expected? How low can you go for no effects? 

A zero dose certainly has no other effect than a placebo effect if any.

"Microdosing, or low-dose treatment of psychedelics such as lysergic acid diethylamide (LSD), has gained popularity in recent years as a potential method for alleviating symptoms of attention-deficit/hyperactivity disorder (ADHD). However, the first-ever randomized clinical trial investigating the pharmacological effects of psychedelics found that microdosing LSD is as effective as a placebo in improving ADHD symptoms. ..."

Microdosing LSD for ADHD is no better than a placebo, clinical trial shows

The placebo effect unlocked: How the brain tricks itself into pain relief through a newly discovered pain pathway

Good news! Are we finally understanding the placebo effect better! What opportunities beckon to treat pain in the future?

"... Publishing in Nature, researchers ... discovered a pain control pathway that links the cingulate cortex in the front of the brain, through the pons region of the brainstem, to cerebellum in the back of the brain. ...
then showed that certain neurons and synapses along this pathway are highly activated when mice expect pain relief and experience pain relief, even when there is no medication involved. ..."

"... They found that the large, branch-like Purkinje cells in the cerebellum replicated the activity seen in the initial area of neuronal excitement, in the ACC [anterior cingulate cortex]. It confirmed that the cerebellum had a key part to play in pain messaging. ..."

From the abstract:

"Placebo effects are striking demonstrations of mind-body interactions. During pain perception, in the absence of any treatment, an expectation of pain relief can reduce the experience of pain, a phenomenon known as placebo analgesia. However, despite the strength of placebo effects and their impact on everyday human experience and failure of clinical trials for new therapeutics, the neural circuit basis of placebo effects has remained elusive. Here, we show that analgesia from the expectation of pain relief is mediated by rostral anterior cingulate cortex (rACC) neurons that project to the pontine nucleus (rACC→Pn), a pre-cerebellar nucleus with no established function in pain. We created a behavioral assay that generates placebo-like anticipatory pain relief in mice. In vivo calcium imaging of neural activity and electrophysiological recordings in brain slices showed that expectations of pain relief boost the activity of rACC→Pn neurons and potentiate neurotransmission in this pathway. Transcriptomic studies of Pn neurons revealed an abundance of opioid receptors, further suggesting a role in pain modulation. Inhibition of the rACC→Pn pathway disrupted placebo analgesia and decreased pain thresholds, whereas activation elicited analgesia in the absence of placebo conditioning. Finally, Purkinje cells exhibited activity patterns resembling those of rACC→Pn neurons during pain relief expectation, providing cellular-level evidence of a role for the cerebellum in cognitive pain modulation. These findings open the possibility of targeting this prefrontal cortico-ponto-cerebellar pathway with drugs or neurostimulation to treat pain."

The placebo effect unlocked: How the brain tricks itself into pain relief In a fascinating discovery, scientists have pinpointed what happens in our brains when we're expecting pain relief but are given a placebo, unknowingly, instead. It not only confirms 'the placebo effect,' but offers clues into how powerful the mind is in mitigating physiological functions such as pain.

Scientists Discover Brain Circuits for Placebo Effect Pain Relief (original news release) ... research published in Nature reveals a new pain control pathway from the cortex to the cerebellum crucial to placebo analgesia – when the expectation of pain relief leads to pain alleviation without a therapeutic intervention, such as with a drug.

Neural circuit basis of placebo pain relief (no public access)

Along the 'placebo pathway', the cells in yellow in the pons (left) receive input from the green cells in the cingulate cortex (rACC, right), with subdivisions Cg1 and Cg2

The power of thought - One of the greatest riddles of science

Very recommendable! Not least because one of the interviewed person's last name is Bingel (no relation)!😊 My last name is not very common!

Learn more on the latest insights into the famous placebo effect! We even can grow muscles just by thought!

If you maintain a positive attitude toward ageing you may live several years longer! A positive attitude slow down the shortening of the telomeres!

Harvard Medical School: Why are you taking a multivitamin? An unnecessary habit! Really!

The never ending debate over the benefits of taking vitamins and mineral supplements! This debate has been going on for several decades!

The latest salvo in this debate is written by no less than the Executive Editor, Harvard Heart Letter! Her article and blog post are based on a major study conducted by the United States Preventive Services Task Force.

Perhaps, the only thing we know for sure is that taken in moderation multivitamin supplements are harmless! 

Same old questions are: Do one need extra vitamins if one regularly consumes a nutritional and varied diet? What about the overdose risk? What are the actual and measurable benefits?

At least this latest, narrowly focused major meta study confirmed that multivitamins do not prevent death! (This is not a joke, see below) That is good to know! Very reassuring! 😄

Why the study by the U.S. Preventative Services Task Force was so narrowly focused on only preventing cardiovascular diseases and cancer is mysterious! Since when are multivitamins remedies for that!

"... That’s because for the average American adult, a daily multivitamin doesn’t provide any meaningful health benefit, as noted recently by the US Preventive Services Task Force (USPSTF). Their review, which analyzed 84 studies involving nearly 700,000 people, found little or no evidence that taking vitamin and mineral supplements helps prevent cancer and cardiovascular disease that can lead to heart attacks and stroke, nor do they help prevent an early death. ...

Who might need a multivitamin or individual supplements?

There are some exceptions, however. Highly restrictive diets and gastrointestinal conditions, or certain weight-loss surgeries that cause poor nutrient absorption, are examples of reasons why a multivitamin or individual vitamins might be recommended. A daily vitamin D supplement may be necessary when a person gets insufficient sun exposure. Your doctor may recommend an iron supplement if you have a low red blood cell count (anemia). ..."

"Results
Eighty-four studies (N=739 803) were included. In pooled analyses, multivitamin use was significantly associated with a lower incidence of any cancer (odds ratio [OR], 0.93 [95% CI, 0.87-0.99]; 4 RCTs [n=48 859]; absolute risk difference [ARD] range among adequately powered trials, −0.2% to −1.2%) and lung cancer (OR, 0.75 [95% CI, 0.58-0.95]; 2 RCTs [n=36 052]; ARD, 0.2%). However, the evidence for multivitamins had important limitations. Beta carotene (with or without vitamin A) was significantly associated with an increased risk of lung cancer (OR, 1.20 [95% CI, 1.01-1.42]; 4 RCTs [n=94 830]; ARD range, −0.1% to 0.6%) and cardiovascular mortality (OR, 1.10 [95% CI, 1.02-1.19]; 5 RCTs [n=94 506] ARD range, −0.8% to 0.8%). Vitamin D use was not significantly associated with all-cause mortality (OR, 0.96 [95% CI, 0.91-1.02]; 27 RCTs [n=117 082]), cardiovascular disease (eg, composite cardiovascular disease event outcome: OR, 1.00 [95% CI, 0.95-1.05]; 7 RCTs [n=74 925]), or cancer outcomes (eg, any cancer incidence: OR, 0.98 [95% CI, 0.92-1.03]; 19 RCTs [n=86 899]). Vitamin E was not significantly associated with all-cause mortality (OR, 1.02 [95% CI, 0.97-1.07]; 9 RCTs [n=107 772]), cardiovascular disease events (OR, 0.96 [95% CI, 0.90-1.04]; 4 RCTs [n=62 136]), or cancer incidence (OR, 1.02 [95% CI, 0.98-1.08]; 5 RCTs [n=76 777]). Evidence for benefit of other supplements was equivocal, minimal, or absent. Limited evidence suggested some supplements may be associated with higher risk of serious harms (hip fracture [vitamin A], hemorrhagic stroke [vitamin E], and kidney stones [vitamin C, calcium]).
Conclusions and Relevance
Vitamin and mineral supplementation was associated with little or no benefit in preventing cancer, cardiovascular disease, and death, with the exception of a small benefit for cancer incidence with multivitamin use."

Taking second look at daily multivitamins – Harvard Gazette Average healthy adult doesn't really get much benefit, Med School professor says

Why are you taking a multivitamin? For most Americans, a daily multivitamin is an unnecessary habit.

Vitamin and Mineral Supplements for the Primary Prevention of Cardiovascular Disease and Cancer Updated Evidence Report and Systematic Review for the US Preventive Services Task Force

Senility Caused By Placebo And Nocebo Effects

A Bit Of Background

I have been familiar with the Placebo effect for decades, but only recently I learnt about the Nocebo effect (in German language) from an article published online on 7/12/2012 by my favorite home town newspaper Frankfurter Allgemeine Zeitung. The following blog is not really related to the above mentioned article about the Nocebo effect.

Faith Moves Mountains

We read in Matthew 17:20 of the New Testament that faith as small as a mustard seed can make a mountain move from here to there and that nothing will be impossible. Did the Bible anticipate Placebo and Nocebo effects?

Besides faith, there is also individual will power: A will to succeed in life; a will to be healthy etc.

A Conjecture About Senility And Its Causes

I am not trying here to explain exhaustively all causes of senility. But I believe that some people as they grow older are conditioned or resigned to experience the usual frailties etc. that come with age, because this is supposed to happen with old age and we are biologically programmed to deteriorate with age.

We all know from experience that seniors have their moments. It’s considered normal by everyone.

It’s like a Placebo effect: I am old now, thus I am expected to have memory lapses, unsteady gait, etc.

It’s like a Nocebo effect, because I am old I should now be more absent minded, more napping, more prone to fall etc. With age also comes anxiety about age related frailties.

How do the trillions or so of microorganisms in our gut react when we have Placebo or Nocebo effects later in life.