In short: in carefully screened clinical trials, serious harms are uncommon, but they do happen, and trial participants aren’t typical of everyone. The biggest risks are psychological (difficult experiences, and rarely psychosis or mania in vulnerable people), cardiovascular (raised heart rate and blood pressure, and serious heart-rhythm risks with ibogaine) and drug interactions.

Why trial safety data has limits

Clinical trials screen people carefully and exclude many who might be at higher risk. They provide trained staff, a controlled setting and follow-up. So the safety record from trials describes what happens under those conditions. It doesn’t tell us what happens with unsupervised use, unknown doses or unscreened people.

Common short-term effects

These are frequently reported in trials and usually pass within hours:

Classic psychedelics (psilocybin, LSD, DMT and others): anxiety or fear during the session, confusion, nausea, headache (sometimes the next day), and temporary rises in heart rate and blood pressure.
Ketamine and esketamine: dissociation (feeling detached or unreal), dizziness, nausea, sleepiness and a temporary rise in blood pressure. Because of this, esketamine is only given in a clinic with monitoring afterwards.
MDMA: jaw clenching, reduced appetite, nausea, raised heart rate and blood pressure and body temperature, and low mood or fatigue in the days after.

Serious risks

Challenging experiences. Intense fear, panic or distressing thoughts during a session. In trials these are managed by trained staff, and they’re one reason preparation and support matter.
Psychosis and mania. Rarely, psychedelics may trigger psychosis or mania, especially in people with a personal or family history of psychotic disorders or bipolar disorder. This is why trials usually exclude them. A small 2026 pilot that deliberately included people with bipolar II depression reported that 3 of 14 participants experienced suicidal thoughts or hypomania, which resolved with support.
Suicidal thoughts. Some trials have reported suicidal thoughts or behaviour after treatment, including in people who received psilocybin for treatment-resistant depression.¹ Follow-up care matters.
Heart-rhythm problems with ibogaine. Ibogaine can disturb the heart’s electrical rhythm (a prolonged “QT interval”). Deaths have been reported, particularly outside medical settings and in people with heart conditions or taking other drugs.²
Bladder damage and dependence with ketamine. Heavy, frequent non-medical ketamine use is linked to serious bladder and urinary tract damage, and ketamine can be habit-forming. The long-term effects of repeated therapeutic treatment are still being studied.
Lasting perceptual changes. A small number of people report visual changes that persist long after use, known as hallucinogen persisting perception disorder (HPPD).

Drug interactions

Interactions are one of the most important and least known risks:

Ayahuasca contains MAO inhibitors. Combined with many antidepressants (such as SSRIs) or other serotonin-raising drugs, it can cause serotonin syndrome, which can be dangerous.
MDMA combined with MAO inhibitors, and some other medicines, can also cause serotonin syndrome.
Lithium combined with classic psychedelics has been linked to seizures in user reports.³
Antidepressants can blunt the effects of classic psychedelics. Many trials ask participants to taper off them first, under medical supervision.
Ibogaine interacts with many medicines that affect heart rhythm.

Who clinical trials usually exclude

Exclusion criteria vary by study, but commonly include:

A personal or close family history of psychotic disorders, or bipolar I disorder
Uncontrolled high blood pressure, heart disease or a history of stroke
Pregnancy or breastfeeding
Current use of medicines that interact (see above)
Active substance use disorder (except in addiction trials)
Significant suicide risk that can’t be safely managed in the study

The bottom line

“Natural” doesn’t mean safe, and “prescribed” doesn’t mean risk-free. The research so far suggests these substances can be given with an acceptable safety profile when people are screened, prepared, supervised and followed up. That’s very different from use without those protections.

This chapter is educational. It isn’t medical advice. Talk to a qualified health professional about your own medical history and medicines.

Sources

Goodwin GM, et al. Single-dose psilocybin for a treatment-resistant episode of major depression. New England Journal of Medicine, 2022. PubMed
Koenig X, Hilber K. The anti-addiction drug ibogaine and the heart: a delicate relation. Molecules, 2015. PubMed
Nayak SM, et al. Classic psychedelic coadministration with lithium, but not lamotrigine, is associated with seizures: an analysis of online psychedelic experience reports. Pharmacopsychiatry, 2021. PubMed

Safety, side effects and who shouldn't take part