Comparing Psychedelics for Therapy: Legality, Efficacy & Safety

ketamine, mdma, mescaline, lsd, psilocybin molecules

Psychedelic therapy for anxiety and depression is a hot topic these days. You may have heard about it on Michael Pollan’s recent Netflix series, How to Change Your Mind. The series devotes each episode to a different psychedelic medicine including LSD, psilocybin, MDMA and mescaline. These four drugs all have their own benefits and drawbacks, similarly to ketamine. Let’s take a look at each drug’s legal status, safety concerns and indicated uses.


lsd molecule


LSD (lysergic acid diethylamide) has been a Schedule I drug since the Controlled Substances Act was passed in 1970. Possession of LSD was made a criminal offense even earlier than that, in 1968.
Until that point, LSD was the subject of intense research, both by medical professionals and by the CIA as part of its controversial MKUltra program. Research into the therapeutic benefits of LSD dried up after its change in legal status. The last FDA-approved study was conducted in 1980.
The FDA approved clinical trials for an LSD-derived anxiety drug in early 2022. Outside of clinical trials, LSD remains illegal, but possession was decriminalized in Oregon in 2020.

What is LSD used to treat?

Recent studies in Switzerland suggest that LSD can be helpful for treating major depression and anxiety suffered by those with life-threatening illnesses. High-dose LSD also appears to be an effective treatment for alcoholism. This is backed by earlier trials conducted in the 1950s, 1960s and 1970s.
Low-dose LSD has been shown to reverse stress-induced anxiety in mice. As seen in Michael Pollan’s Netflix series, a Swiss study investigating the treatment of cluster headaches with LSD also showed promising results.

Safety & dosing

LSD is quite potent, and doses as small as 20 micrograms will have noticeable effects. Oral doses of 200 micrograms are well tolerated in controlled settings. The accidental ingestion by one subject of 550 times the normal dose did not prove fatal.
LSD was first synthesized by chemist Albert Hofmann. He spoke highly of its effects despite a harrowing experience dosing himself several times over the usual amount (100 micrograms).


lsd molecule


At a federal level, psilocybin—a naturally occurring substance found in a variety of “magic mushrooms—is a Schedule I narcotic. Possession and use of the drug has been illegal since 1970. This situation is a little more complicated at the state and local level.
In 2020, Oregon became the first state to legalize psilocybin therapy. Personal use is also decriminalized in Oregon, as well as in Denver, Colorado, Washington DC, and some other cities. This means that local police are not actively pursuing people for personal use or possession of psilocybin, although sales are technically prohibited (you are permitted to grow, gather, and gift).
Given psilocybin’s therapeutic potential, decriminalization and legalization is expected to continue around the country. Researchers from Johns Hopkins suggest that if psilocybin clears the phase III clinical trials needed for FDA approval, it might even be reclassified as a Schedule IV drug.

What is psilocybin used to treat?

Psilocybin has been demonstrated to have a rapid effect on patients with major depressive disorder. In 2016, it was also shown to decrease anxiety and depression in people with life-threatening cancer.
A 2014 study found that when used as part of a cognitive behavioral therapy program, psilocybin was very effective at helping patients quit smoking. 80% of the long-term smokers who participated in the study were still abstinent after six months. This is compared to only 35% for varenicline (Chantix), the most effective smoking cessation drug on the market. Psilocybin has also been found to curb alcohol abuse.

Safety & dosing

Psilocybin is quite safe. Serious, adverse reactions are “rare and short-lived.” Doses of 10mg and 25mg of psilocybin have been well-tolerated by clinical trial participants. The 25mg dose (equivalent to about 3g of dry mushrooms) has been shown to cause significant and long-lasting effects on patients’ depression.
Adverse effects in the short term were limited to headaches, nausea and dizziness. No symptoms reported were significant enough to cause patients to drop out of the study, nor did they appear to suffer long-term adverse effects.


mdma molecule


MDMA is illegal in the United States. It has been listed as a Schedule I narcotic since 1985. The DEA considers this drug to have a high potential for abuse and to serve no legitimate medical purpose.
This wasn’t always the case. Between 1977 and 1985, when it was still legal, MDMA was used by dozens of psychotherapists interested in its therapeutic value. Research into MDMA-assisted therapy has seen a resurgence in recent years, and the evidence of its efficacy makes a discussion about changing its legal status possible. Until then, participation in clinical trials remains the only legal avenue for patients wishing to take MDMA legally.

What is MDMA used to treat?

The FDA has given a Breakthrough Therapy Designation to MDMA for the treatment of post-traumatic stress disorder. People with severe PTSD have consistently responded better to talk therapy when they took MDMA as part of their treatment. Its breakthrough status means that MDMA will be able to move through the regulatory hurdles quicker. It has been believed that it may receive FDA approval in 2023. MDMA’s usefulness in the treatment of mood disorders remains controversial and needs further research. MDMA-assisted couples therapy has also been proposed.

Safety & dosing

Pure MDMA, the kind found in clinical trials, is relatively safe. Studies have shown doses between 75mg and 125mg to be well-tolerated in adults with PTSD. Its reputation as a dangerous drug is likely due to other illicit substances either contaminating black market MDMA, or being substituted for it completely.
Using MDMA alongside SSRIs like Lexapro and Zoloft can increase the concentrations of MDMA in the blood, however can actually reduce the effect of MDMA. Its use in non-clinical settings has also been associated with high blood pressure, seizures, and hyperthermia.


mescaline molecule


Mescaline, a psychedelic substance that exists naturally in peyote and certain other species of cacti, is a Schedule I narcotic—as is peyote itself. Its use is mostly illegal in the United States.
An exception was made, at the federal level, for members of the Native American Church allowing their use of peyote for religious purposes. In certain states, such as Arizona, the law is more lax, allowing anyone to use peyote so long as it is “in connection with the bona fide practice of [any] religious belief.”
As mentioned in How to Change Your Mind, the San Pedro cactus is another source of mescaline. Unlike peyote, it is perfectly legal to grow, although preparing and ingesting it is still illegal in most jurisdictions.
The cultivation, possession and sale of mescaline that isn’t derived from peyote has been decriminalized in Seattle. The successful Decriminalize Nature Oakland initiative decriminalized mescaline, psilocybin and other plant-based entheogens in that city.

What is mescaline used to treat?

The therapeutic benefits of mescaline have been researched somewhat less than the other drugs in Pollan’s series. His interview subjects suggested that it could help treat depression, anxiety and addiction issues. One recent survey appears to back these claims up.
Respondents variously reported that symptoms of depression, anxiety, PTSD and substance abuse disorders had all improved after mescaline use. In a separate survey, users of mescaline and other psychedelics also reported reduced suicidal thinking.

Safety & dosing

Clinical trials evaluating the effects of mescaline at different doses began in Switzerland last year. Mescaline is less potent than LSD or psilocybin, with a typical oral dose falling in the range of 200-400mg. Those using peyote as part of a religious ceremony may ingest less than 100mg of mescaline.
Nausea and vomiting are common side effects, but may be associated more with peyote than with synthetic mescaline. Other side effects include increased heart rate and agitation.


ketamine molecule


Ketamine is legal for medical purposes across the United States. It was approved by the FDA in 1970 to be used as an anesthetic. It was listed as a Schedule III non-narcotic by the DEA in 1999. Today, it can be prescribed by physicians, psychiatrists and other medical professionals for off-label uses.
“Off-label” simply means a drug is being prescribed for some condition other than those for which it has received FDA approval. This is perfectly legal—as a matter of fact, over 20% of US prescriptions are for off-label therapies. Using ketamine outside a clinical setting, however, is illegal.

What is ketamine used to treat?

Ketamine is very effective at treating depression. Esketamine nasal spray was FDA approved in 2019 for treatment-resistant depression and for major depressive disorder with suicidal ideation.
A 2020 meta-analysis of the relevant clinical trials concluded that ketamine has rapid and substantial antidepressant effects after a single-dose. Repeated doses were effective at sustaining those gains (although sustained effects are even more likely with ongoing therapy). Studies also show that ketamine could be helpful in treating patients with anxiety, anorexia, addiction and PTSD.

Safety & dosing

Patients undergoing ketamine-assisted therapy will receive a sub-anesthetic dose of ketamine. The therapeutic dose is only around 0.5-1.5 mg/kg, and is administered via IV slowly over the course of 40 minutes.
For reference, you can compare this to a dose of 1.0-4.5 mg/kg that is administered quickly for use as an anesthetic dose for surgery.
Ketamine can also be administered orally, though these methods have their disadvantages.
As seen in How to Change Your Mind, the future of psychedelic therapy is hopeful. A future with safer and wide access to ketamine, MDMA, psilocybin, LSD and mescaline may not be too far off.
As psychiatrist, Stanislav Grof once said, “Psychedelics, used responsibly and with proper caution would be for psychiatry what the microscope is for biology and medicine, or the telescope is for astronomy.”

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