Salvia divinorum

Other names:

• Diviner’s sage
• Maria Pastora
• Sally-D
• Salvia

Basics: Salvia divinorum is a perennial herb native to regions in Oaxaca, Mexico. Over the last decade, salvia has become more popular as a recreational drug.

Salvinorin-A has been identified as the primary psychoactive chemical in Salvia divinorum. Unlike LSD and other classic hallucinogens, salvinorin-A doesn’t act on serotonin receptors. Instead, salvinorin-A interacts with kappa-opioid receptors, which play a role in pain perception.

The method of consumption can affect the duration of the experience. Users typically vaporize the dried, crushed salvia leaves through a pipe or bong, which causes a nearly immediate, intense hallucinogenic experience that lasts only fifteen to twenty minutes. Users also drop a small amount of salvia-containing tincture under the tongue. This method takes up to ten minutes to produce effects, but the entire experience can be prolonged for up to two hours.

History: The Mazatec people have used salvia leaves for centuries as a treatment for illnesses, including headaches and gastrointestinal problems, and as part of their divinatory and spiritual practices.

Traditionally, the Mazatec consumed salvia by rolling fresh leaves into a thick wad and chewing or sucking on it, absorbing it through their cheeks, which results in a milder and longer-lasting experience. The Mazatec would also grind the leaves and mix them into a drinkable infusion.

Potential Benefits: Studies on participants who smoked salvia report intense visual and auditory effects similar to those of LSD and psilocybin, though with unusual hallmarks, such as feeling like a two-dimensional shape or perceiving the world as flat, like a coat of paint. At higher doses it also caused participants to disconnect from reality and dissociate, reducing their ability to control or feel their bodies.

Potential Risks and Side Effects: More research is needed to determine Salvia divinorum’seffects on a broad population. There are case reports of users experiencing prolonged psychosis after ingesting Salvia divinorum.

Therapy: Because salvinorin-A works on receptors involved in perception, researchers hypothesize that derivatives of this molecule might be useful in the treatment of disorders characterized by perceptual distortions, like schizophrenia and bipolar disorder.

Researchers have also conducted a pre-clinical exploration of salvinorin-A and other chemical derivatives based on it for the treatment of cocaine abuse.

Legality: In the United States, Salvia divinorum and salvinorin-A are not federally controlled substances but are illegal in some states.

Notable Studies:

• Researchers identified which receptors are affected by salvinorin-A.
• Salvinorin-A’s affinity for opioid receptors could make it a good candidate for treating pain, mood and personality disorders, substance abuse, and gastrointestinal issues.
• Salvinorin-A shows moderate anti-inflammatory properties in mice.

MDMA

Other names:

• Adam
• E
• Ecstasy
• Molly
• X
• XTC

Basics: 3,4-Methylenedioxymethamphetamine (MDMA) is a synthetic drug. Users typically consume MDMA orally in a pill or capsule and begin to feel its effects thirty to forty-five minutes later. The entire experience lasts about three to four hours.

MDMA interacts with neuronal connections (synapses) and causes the release of serotonin, norepinephrine, and dopamine neurotransmitters, with the largest effect being on serotonin. The transient increase in the actions of these neurotransmitters in the brain impacts arousal, attention, emotion, and memory. 

History: MDMA was first made in 1912 by the German pharmaceutical company Merck. It was used as an intermediate chemical in making a drug intended to stop blood loss. At that time, MDMA itself was not tested pharmacologically.

In 1977, the chemist and psychedelics pioneer Alexander “Sasha” Shulgin introduced the drug to Leo Zeff, a psychotherapist and also an early proponent of psychedelics in therapy. Over the next twelve years, Zeff treated more than 4,000 patients with MDMA and trained 150 therapists to use it in their work. Shulgin’s wife, Ann Shulgin, also treated many patients.

During the 1980s, MDMA became a popular recreational drug at nightclubs and raves. In 1985, the Drug Enforcement Administration placed MDMA on the list of Schedule I controlled substances, effectively stalling research into its therapeutic potential.

Potential Benefits: MDMA is known as an empathogen because while it does alter mood and has some psychedelic qualities, its effect profile differs significantly from that of the classic psychedelics. Rather than mystical-type experiences, MDMA produces a mellower experience during which people feel more empathic, more open to bonding with others, and better able to process emotional or traumatic memories.

Potential Risks and Side Effects: MDMA activates the sympathetic branch of the autonomic nervous system, causing transient increases in heart rate and blood pressure.

Therapy: In 2011, researchers published the results of the first clinical trial that showed MDMA could be used alongside therapy to treat post-traumatic stress disorder. Subsequent studies suggest it’s also effective at reducing social anxiety in autistic adults and in people with life-threatening illnesses and those living with eating disorders.

In 2021, researchers in the United States, Canada, and Israel published the results of a phase III clinical trial using MDMA-assisted therapy to treat post-traumatic stress disorder. The trial studied ninety participants and found that the treatment was safe and that, for the majority of participants who received it, MDMA relieved many, and in some cases most, of their symptoms.

Legality: In the United States, MDMA is listed in Schedule I of the Controlled Substances Act. It’s illegal to use it recreationally or in therapy outside of specially approved research settings.

Notable Studies:

• A phase II clinical trial that used culturally informed care to deliver MDMA-assisted therapy to people of color.
• Anecdotal reports that MDMA-assisted therapy can help treat substance abuse disorder.
• How MDMA’s effects on certain brain regions may help people reprocess traumatic memories.
• fMRI imaging that may help explain why patients report MDMA makes thinking and talking about negative experiences easier.

Ketamine

Other names:

• K
• Special K

Basics: Ketamine is a synthetic drug not known to occur in nature. It is used widely as an anesthetic, especially for children and soldiers, and as an animal tranquilizer. It is also sometimes used to treat chronic pain. While it’s not entirely clear how ketamine works, the leading theory postulates that it acts on receptors for the neurotransmitter glutamate, which may play a role in regulating mood.

Clinically, ketamine is administered intravenously, by intramuscular injection, or as a lozenge placed under the tongue. Outside of medical settings, powdered ketamine is also snorted.

History: Ketamine was first synthesized in 1962. In 1970, the Food and Drug Administration approved the medicine, trade-named Ketalar, for use as an anesthetic.

Potential Benefits: At lower doses, ketamine can alter one’s perception and sense of time and space. At higher doses, the drug can cause a dissociative state, sometimes called a “k-hole,” during which people experience oblivion and are unable to perceive or interact with the outside world. These effects have some overlap with the general effect profile of classic psychedelics.

Potential Risks and Side Effects: Some participants in clinical trials reported side effects including headache, dizziness, nausea, blurred vision, drowsiness, and poor memory, but these resolved quickly after treatment sessions. Prolonged ketamine exposure has been associated with neurodegeneration in newborn rhesus monkeys. Some people become addicted to ketamine, which can be very difficult to overcome.

Therapy: Over the last twenty years, numerous studies have suggested that ketamine can be used to treat conditions including chronic depression, suicidal ideation, obsessive compulsive disorder, and post-traumatic stress disorder.

Legality: In the United States, ketamine is a Schedule III drug, meaning that it is legal when prescribed for medical use as an anesthetic. It can also be prescribed legally for off-label use, including for the treatment of depression. In 2019, the FDA approved Spravato, delivered as a nasal spray made from esketamine, half of the mirror image of ketamine, for use in treating treatment-resistant depression, or TRD. Because it is under patent, the price of Spravato can be hundreds of times the price of generic ketamine.

Licensed providers can legally offer ketamine-assisted therapy.

Notable Studies:

• The first placebo-controlled, double-blinded trial to use ketamine to treat depression.
• A randomized, placebo-controlled, double-blinded trial that used ketamine to treat bipolar depression.
• A study that demonstrated ketamine can also treat social anxiety disorder.

An article that describes how ketamine therapy is making scientists reconsider what we know about the biology of depression.

Ibogaine

Basics: Ibogaine is a naturally occurring psychoactive compound found in the root bark of the Tabernanthe iboga, a shrub native to Central and West Africa. How ibogaine works in the brain is not well understood. It interacts with numerous neurotransmitters in the central nervous system, including components of the acetylcholine, serotonin, dopamine, glutamate, and opioid systems. Its effects are prolonged, beginning half an hour to three hours after ingestion and peaking after eighteen to thirty-six hours.

History: For centuries, members of the Bwiti religion have used iboga as a sacrament in rituals to bind themselves across time with their ancestors and descendants or with one another through a shared experience of consciousness. It is still used today by the Gabonese Fang people in religious ceremonies and as a stimulant and appetite suppressant.

Purified ibogaine hydrochloride was first introduced to European consumers in 1939 under the name Lambarène. It was sold in France until around 1970 as an antidepressant that could improve mood and physical strength, and was used by athletes and those recovering from illness. Ibogaine’s potential to interrupt drug addiction was first recognized in 1962 by Howard Lotsof, a heroin addict who experimented with ibogaine. The experience was so transformative Lotsof spent the rest of his life advocating for it as a cure for substance abuse. Chilean psychiatrist Claudio Naranjo also advocated for including ibogaine in therapy, something he describes in his 1973 book The Healing Journey.

Potential Benefits: The experience is often described as being in a “waking dream.” At first users experience visual and sensory distortions. Some describe watching a panoramic readout or “slideshow” of past memories. Afterward, they report going through a period of reflection and having residual effects including heightened awareness, mild stimulation, and disturbed sleep for up to seventy-two hours. In high doses, ibogaine can induce intense hallucinations.

Potential Risks and Side Effects: Ibogaine can be dangerous. There are numerous reports in the scientific literature of people having fatal cardiac events after taking ibogaine. Other side effects range from nausea and tremors to (less commonly) psychosis and mania to seizures and comas. Because ibogaine can affect the heartbeat, it can be particularly risky for people with preexisting cardiac problems or when mixed with other drugs.

Therapy: Ibogaine’s potential to interrupt drug addiction was first recognized in 1962 by Howard Lotsof. Since then, numerous studies have shown that ibogaine can help treat heroin, cocaine, and opioid withdrawal and addiction.

Legality: In the United States, ibogaine is listed in Schedule I of the Controlled Substances Act, making both ibogaine and ibogaine-assisted therapy illegal outside of specially approved research settings. Some ibogaine clinics operate in countries where ibogaine is not legal or is in a gray area, including Mexico and New Zealand; responsible providers administer it only with close medical supervision that includes cardiac monitoring.

Notable Studies:

• A small observational study in which ibogaine was used to treat opioid addiction showed a single ibogaine session reduced withdrawal symptoms and reduced opioid use over a twelve-month period.
• A literature review of twenty-four studies in which ibogaine was used to treat substance use disorders found that ibogaine decreases withdrawals and cravings and may help treat depression and PTSD.