Psychedelics were first discovered by indigenous cultures surveying the land for resources. Through trial, error, and knowledge sharing, they began to discover the magic hidden in the world around them. Powerful, mystical effects were uncovered about certain plants and specific combinations of plants, which altered the mind and changed perceptions of reality. In time, Western civilization caught on, and consumption expanded around the globe.
Now, psychedelic research is booming. And while most psychedelics are currently illegal in the United States and around the world, researchers are exploring their use in medicine to treat conditions such as depression, PTSD, addiction, anxiety, OCD, migraines, end of life acceptance of mortality, and eating disorders. 1
How do psychedelics work?
Most psychedelics interact with certain serotonin (5-HT) receptors in the brain, which can cause visual/auditory hallucinations, an altered sense of time and space, synesthesia (mixing up senses like hearing colors), and profound spiritual experiences. Specifically, these molecules have preference to engage with the serotonin 2A (5-HT2A) receptor. Psychedelics that work this way are often called “classical” psychedelics, and are known to produce a “trip.”
Many psychedelics are also referred to as entheogens, which are substances that expand consciousness for religious or spiritual purposes.
In addition to their effects on serotonin, psychedelics alter activity within the default mode network (DMN), a group of brain structures where we process internal thoughts, obsess or experience repetitive negative thoughts, and ruminate. 2
When our mind wanders – that’s the DMN. As activity increases in this network, we may be more self-critical and have rigid thought patterns. Psychedelics have been found to modify DMN activity, and may help us break out of these patterns. 3
Turning down activity in the DMN allows better access to new areas of the brain, which can boost creativity and improve problem solving. This is the mechanism for healing depression and learning new ways of thinking. Some scientists have noticed similarity in the DMN and Freud’s definition of ego. This decrease in DMN activity from psychedelics is sometimes referred to as “ego death,” and can be therapeutic to reset unhealthy thought patterns, almost like a brain reboot. 4
Psychedelics can also have positive effects on neurogenesis and neuroplasticity, the brain’s ability to form and reorganize synaptic connections. These properties may be responsible for many of the therapeutic effects of psychedelics, especially in response to learning or experience or an injury. In other words, psychedelics may help us adapt to challenges by promoting the growth and reorganization of our brain connections 5
The positive effects of psychedelics seem to be long-lasting in what is known as the “after-glow.” These prolonged effects on mood and energy levels linger after a psychedelic experience, well after the drug has been cleared from the body. The after-glow is essentially the opposite of a hangover.
Using integration or psychotherapy along with these medicines allows patients to incorporate the positive effects permanently. Scientists are hopeful that psychedelics might have more of a curative effect when it comes to mental health than many existing treatment options; meaning that unlike most psychiatric medications, psychedelics may be able to prompt long-term changes to our mental state with only a few doses. 6
Are psychedelics safe?
In general, psychedelics are regarded as reasonably safe, and not addictive. They do carry the risk of a “bad trip,” in which anxiety, confusion and unpredictable behavior can be potentially dangerous in the wrong environment. There’s also a risk of psychosis, and the potential for heart complications. Making sure you have the proper set (the state of your mind) and setting (your environment) is important to minimize these risks. 7
Most of the negative effects caused by psychedelics occur in the mind, but not all of them. Like any substance, there are expected effects based on the dose, along with some expected side effects. If consumed in the wrong setting – like while driving a car for example – you could cause harm to yourself and others.
Responsible consumption is key, and in the case of psychedelics – where you could potentially become detached from reality – it’s important to be in a safe space, preferably around people you’re comfortable with. If you’re new to psychedelics or are nervous about trying them, you can seek out a friend or loved one to serve as your “trip-sitter”. There are even health care professionals you can hire, for example a psychedelic therapist, who specialize in guiding psychedelic trips.
What is microdosing?
Everyone is different. A microdose is a dose that does not elicit a perceivable intoxicating or trip-like effect. At most, a mood boost should be all that is felt, and if any visual or auditory effects are noticeable then the dose is not, by definition, a microdose.
The classical psychedelics (mushrooms, LSD, ayahuasca, mescaline, DMT) all bind to the 5-HT2A receptor – a specific serotonin receptor that is densely located in the brain. This receptor is highly involved in our perception of the world, especially visual and auditory perception. This makes sense given well-known psychedelic effects such as the walls melting, patterns moving, and changes in perception of light. 8
Comparing psychedelics: dosing and consumption information
Primary SourcePrimary active ingredient/sMicrodosePsychedelic doseConsumption methodOther namesPsychedelic mushroomsFungi fruiting bodies – Psilocybe cubensis is a common varietyPsilocybin/ psilocin100-200 mg1-3 gramsDried mushrooms ingested orally (often as a tea)Shrooms, boomers, mushies, capsAcid (LSD)Lab synthesisLysergic acid diethylamide (LSD)10-20 micrograms100-400 microgramsBlotter papers, gel tabs or liquid ingested orallyAcid, hits, tabs, windowpane, microdot, stamps, dots, fryAyahuascaA blend of South American shrub and vineDimethyltryptamine (DMT)Harmaline (and other MAOIs)Undetermined; likely <10mg 25-200mg DMT componentDecoction or tea ingested orallyThe spirit molecule, grandmother, caapiBufoToad venom (endangered) or synthetic (man-made)5-MeO-DMTUndetermined; likely <2mg 2-30mg of 5-MeO-DMT component depending on route takenInhalation – smoking or vaporizing dried toad venom or synthetic 5-MeO-DMT. May also be administered nasallyThe God molecule, bufotoxin, toadPsychedelic CactiPeyote Cactus (endangered), San Pedro cactus, and numerous other cacti Mescaline25-50mg300-500mgCactus flesh, chewed or boiled in water to make a tea; isolate can be vaporized Buttons, peyote, san pedroIbogaRoot of African Shrub (usually Tabernanthe iboga)Ibogaine5-10mg100mgIngested as a drink made from Iboga root, full spectrum extract, or ibogaine isolateKetamineSynthetic (man-made)Ketamine(or Esketamine)Varies by route of administrationVaries by route of administrationIV, IM, oral compounded troche, nasal sprayK, Special K, Kit Kat, Vitamin K MDMA Synthetic (man-made)Methylenedioxy-methylamphetamine (MDMA)Not typically recommended80-125 mgIngested as a tabletX, Ecstasy, Molly, XTC SalviaSalvia divinorum leaf or concentrated extracts Salvinorin AUnknown150-500 micrograms (inhalation). Larger doses needed for chewingInhalation or ingestion (chewing)Diviner’s Sage, Sally-D, Ska Pastora, Magic Mint910111213
Classical psychedelics
Mushrooms
(Illustrative photo by Nick Fewings on Unsplash)
History: Magic mushrooms have likely been consumed as long as humans have roamed the earth – or possibly longer, according to Terrance McKenna’s “Stoned Ape Theory,” which suggests human evolution and language development was expedited by these mushrooms. 14 15
Gordan Wasson, an ethnomycologist and pharmacologist, introduced magic mushrooms to America in the 1950s after participating in a ceremony with healer Maria Sabina in Oaxaca, Mexico. After a brief surge of popularity in the 1960s counterculture movement, the US government criminalized psychedelic mushrooms in 1970 with the signing of the Controlled Substances Act.
Common uses: Mushrooms are used for their mood enhancing, mind altering and healing effects. They are consumed during religious and spiritual ceremonies in many cultures. Socially, mushrooms are often consumed among close friends to heighten experiences and deepen connections. They are also used medicinally for depression, eating disorders, OCD, migraine and cluster headaches, addiction, PTSD and end of life anxiety.
How psychedelic mushrooms work: There are over 200 different species of psychedelic mushrooms, but a species known as psilocybe cubensis is the most common. What makes these mushroom’s “magic” is the primary compound found in psychedelic mushrooms, known as psilocybin. Just as THCA in cannabis flower needs to be decarboxylated into the active compound THC, psilocybin is not active until it undergoes a chemical reaction. The chemical reaction needed to activate magic mushrooms occurs in the body, which makes psilocybin a true prodrug. Psilocybin, once ingested, converts to the active molecule psilocin after it is dephosphorylated in our GI tract before causing the trip.
So it is actually the psilocin which primarily acts on 5-HT2A receptors, not the psilocybin as the mushroom produces it. Dephosphorylation is necessary to feel the trip of mushrooms, and this process naturally occurs in the acidic environment of the stomach.
Citric acid in lemon juice and fresh orange juice is sometimes used to aid this reaction and produce a stronger effect. This makes some sense, as the acid from the citrus can expedite the dephosphorylation and cause the mushrooms to come on faster or stronger. 16
And while psilocybin and psilocin have long been stars of the psychedelic mushroom show, there is increasing interest in other molecules that mushrooms produce. Similar to the entourage effect in cannabis, scientists and mycophiles are beginning to explore the idea that the different species and crosses (golden teacher, penis envy, blue magnolia) could produce unique effects. 17 18
Another fun fact about mushroom varieties is that the term strain, which has long been misused in cannabis, is actually appropriate terminology for the varieties of the same type of mushrooms. So when someone talks about white albinos or golden teachers, they are indeed talking about specific and unique strains of psilocybe cubensis.
Clinical research: Today many scientists are researching the medicinal value of these mushrooms. The results are so compelling that the FDA has categorized magic mushrooms as a “breakthrough therapy” for depression, and is committed to fast tracking its approval. Additionally, there is research supporting mushrooms and psilocybin to improve anxiety and depression, battle alcohol/nicotine addiction, and much more. 19 20 21 22 23
Using mushrooms: Psychedelic mushrooms are usually fruiting bodies that are dried and ingested whole, and can easily be infused into tea or chocolate. In Amsterdam, it’s more common to see magic truffles, which are small underground growths that develop along the mushroom mycelium network.
Microdosing mushrooms: If the goal is not to completely alter your state of mind, but rather to improve performance or mood, microdosing might be for you. Some prefer a more subtle dose (100mg) taken 3-4 times a week rather than every day, to avoid developing a tolerance. The Fadimen microdosing protocol suggests one microdose every three days for four to eight weeks followed by two to four weeks of rest. 24
Macrodosing mushrooms: Around 30-60 minutes after ingesting a psychedelic dose (1-3 grams) you will begin to experience psychedelic effects that typically peak within an hour or two, and last roughly four to six hours. Some common side effects include nausea, runny nose, restlessness, teary eyes, yawning and possible temporary psychosis (a break in the perception of reality).
LSD – Lysergic acid diethylamide (Acid)
History: Swiss natural products chemist Albert Hofmann synthesized LSD and accidentally ingested it on April 19, 1943. He documented his “trip” while riding his bicycle home; now psychedelic enthusiasts celebrate Bicycle Day each year on April 19th.
LSD – lysergic acid diethylamide – is synthesized in a lab from the starting material lysergic acid (LA), which can occur naturally in certain plants and fungi, including a specific rye fungus Claviceps purpurea. LA (the precursor to acid) is itself psychedelic. There is a theory that fungal contamination of rye bread contributed to the hallucinations, magical visions, and convulsions that were mistaken for witchcraft during the Salem Witch Trials in the US. LSD, like mushrooms, was popularized during the 1960s and its usage became illegal in the US in 1970. 25 26
Common uses: While LSD might be best known for intense hallucinogenic and creative effects, it is beginning to be used medicinally for depression, anxiety, alcohol addiction, cluster headaches, and end of life anxiety.
How LSD works: Like mushrooms, LSD acts on 5-HT2A receptors, but with much stronger binding affinity. Compared to mushrooms, LSD seems to deliver a more visually stimulating, uplifting, and much longer trip of 6-10 hours. Side effects of LSD are similar to those of mushrooms, like nausea, dizziness, teeth clenching, and an altered sense of time and space, but also include reports of long-term flashbacks, called “hallucinogen-persisting perception disorder,” at higher doses. 27 28
Clinical research: LSD was researched between 1950 and 1970 for depression, anxiety, psychosomatic diseases, and addiction – but the scientific rigor in these early studies is lacking. The most compelling clinical research to date is using LSD to treat alcohol addiction. 29 30
Using acid: Most commonly known simply as “acid,” LSD is quite potent, and measured in micrograms. It is usually consumed orally as infused blotter papers – small squares of paper with LSD liquid carefully dropped onto them, ideally making for a consistent dose. LSD can also be found as liquid or orally-disintegrating tablets.
Microdosing LSD: Doses can range from 10-20 mcg for very mild effects or even noticeable effects. Regimens for microdosing acid typically recommend taking the drug twice a week, though sometimes it can be as often as every other day. 31
Macrodosing LSD: The typical psychedelic dose is approximately 100 mcg (0.1mg), and can increase all the way up to 300-400 mcg for more intense experiences. One of the biggest differences between acid and other classical psychedelics is the length of the trip – with larger doses having noticeable psychedelic effects for over 12 hours or more. 32
Ayahuasca
History: For centuries, indigenous South American cultures in the Amazonian Basin have used ayahuasca ceremonies for religious sacraments and as healing medicine. The name comes from aya meaning “soul,” and wasca (huasca) meaning “vine or rope,” to give us the “vine of the soul.”
Common uses: Ayahuasca is still used today for spiritual healing, and its use has spread from the Amazon to across the globe. It’s also used medically for depression and addiction.
How ayahuasca works: Most ayahuasca blends contain two key psychoactive ingredients – DMT (Dimethyltryptamine, a classical psychedelic) and a MAOI (monoamine oxidase inhibitor). There are many sources of these molecules throughout nature, but the South American tradition utilizes leaves from a shrub called chacruna (psychotria viridis) that provides the DMT and bark from the ayahuasca vine (banisteriopsis caapi) that contains harmala alkaloids that act as the MAOI. The harmala alkaloids help to protect the DMT within the tea from enzymes in our bodies that want to break it down. 33
Clinical research: Research is currently focusing on how ayahuasca works on addiction, anxiety, and depression. The effects of ayahuasca have also been evaluated for those with eating disorders, PTSD, grief, neurodegenerative disorders like Alzheimers, Parkinson’s and more. In general the results of these studies all show minimal harms and risks, while carrying the potential to improve individual or societal health. 34 35
Using ayahuasca: Ayahuasca is a tea made from a mixture of plants which contain DMT, a MAOI, and many other active ingredients. The chemical composition is dependent on the shaman or curandero who prepares the tea, which makes dosing quantities difficult to report. Microdosing is possible in theory, but there are no current recommendations.
After ingesting the tea, effects are usually felt within 40 minutes, and last about four to five hours. Hallucinations, increased blood pressure, nausea, vomiting, and diarrhea are all common side effects. The vomiting and diarrhea can be intense, and it is often referred to as “purging,” which is an important part of the healing according to Amazonian culture. 36
In traditional Amazonian rituals, the shaman acts as a “trip-sitter” to prepare and protect you, and help you learn from your ayahuasca journey. Profound spiritual experiences, connection, and a sense of being in touch with the unconscious and deeper levels of the mind are common experiences. Ayahuasca users also report a physical healing effect that is hard to explain with science. There are some risks and drug interactions when ayahuasca is combined with other substances like nicotine and antidepressants so preparation often includes a restrictive diet and tapering off other medications. 37 38
What is DMT?
Dimethyltryptamine (DMT) is the psychedelic molecule found in ayahuasca, and in many other plants around the world. Like all classical psychedelics, DMT activates the 5-HT2A receptor to cause most of its psychedelic effects. In addition to consuming DMT as ayahuasca, it is also possible to smoke, snort, or even inject it alone. Consuming DMT (usually by smoking) delivers a shorter, but more intense (and some say more fearful) hallucination compared to ayahuasca.
If you consume DMT orally, nothing much will happen. This is because an enzyme in the body called monoamine oxidase (MAO) breaks down DMT and renders it inactive. But when you combine the DMT in chacruna with the MAOI found in the ayahuasca vine, the DMT is not broken down quickly. This is because the MAOI slows down the bodies’ MAO enzymes, which allows DMT to cross into the brain and cause traditional intense psychedelic effects. 39
Bufo
History: Bufo is a slang term for the poisonous secretions of certain toads. In 1983, Ken Nelson was likely the first person to extract and smoke Sonoran Desert Toad (aka the Colorado River toad, Incilius alvarius) venom. It became illegal in the US in 2009.
Common uses: Bufo is also often called the “God Molecule,” because during this intense trip users tend to lose all concept of self and become one with the universe. It is often described as a near-death experience that will change the user’s outlook on life. Like Ayahuasca, the effects of Bufo are intense and difficult to microdose.
How bufo works: The primary active compound in Bufo alvarius toad venom is 5-methoxy-dimethyltryptamine (5-MeO-DMT). Also a classical psychedelic, 5-MeO-DMT is more intense compared to DMT, but has an even shorter duration. Like most psychedelics, it works on serotonin receptors, specifically 5-HT2A and 5-HT1A. 40
Clinical research: Research is focusing on 5-MeO-DMT use in depression and anxiety. The short duration and strong effect has the potential to be more feasible for in-office administration compared to psilocybin. Current clinical trials are underway using a synthetic nasal spray of 5-MeO-DMT in patients with major depressive disorder. There’s more to come regarding medicinal uses of this potent psychedelic. 41 42
Using bufo: A synthetic version of 5-MeO-DMT is becoming increasingly available. However, purists still prefer the assumed entourage effect of natural toad venom, because it is known to contain numerous psychoactive substances. Bufo is extracted by milking the venom from the toad’s parotoid glands. It is then dried to a powder and smoked.
Dosing, whether microdosing or macrodosing, remains a challenge for bufo users. The dose of toad venom, which is only a small part 5-MeO-DMT and contains other components, will need to be dosed very differently than the synthetic version. Additionally, if not smoking/vaporizing the 5-MeO-DMT, then a much larger dose will be needed. Just like DMT in ayahuasca, 5-MeO-DMT in bufo is very sensitive to enzymes in the GI tract and therefore oral dosing can be challenging and inconsistent.
While the natural source may have more desired effects, there are concerns about overharvesting and the impact on toad populations. The Sonoran Desert toad is found in remote regions of Arizona and northwest Mexico. It hibernates underground for most of the year, only resurfacing during the summer rainy season. Until we can better assess the impact of human consumption on toad populations it may be wise to use synthetic formulations as this is clearly a limited resource. 43
Psychedelic cacti – Peyote & San Pedro (Mescaline)
Mescaline hallucinations can include a “geometrization” effect, in which objects appear flat and distorted, like a Cubist painting (illustrative image by Shutterstock)
History: Mescaline is an alkaloid found naturally in a variety of cacti. In Central America and the Andes mountains, it is extracted from the San Pedro or Peruvian Torch cactus. In the Southwestern United States and Mexico, it’s sourced from the Peyote cactus. Mescaline is known as the OG psychedelic, and is said to have been used in religious ceremonies by indigenous cultures in Peru, Mexico and the United States for over 6,000 years. 44
Common uses: Mescaline is used for religious ceremony and sacrament, and is revered within the psychedelic community for its introspective nature.
How mescaline works: Like most of the classical psychedelics, it binds with 5-HT2A receptors. But unlike LSD and mushrooms, mescaline also has properties of phenethylamines, like MDMA and amphetamines.This gives it a stimulatory effect similar to adrenaline and can cause nausea, increased heart rate, and increased temperature.
Compared to most psychedelics, a mescaline trip is a longer, all-day experience. Effects begin in one to three hours, and the trip can last 10-12 hours. There are some unique visualizations such as a “geometrization” of objects, where the object can appear flat and distorted, like a Cubist painting. It is an experience not to be taken lightly, and is often associated with an intense spiritual journey with vivid hallucinations. 45
Clinical research: Mescaline is not easy to use clinically because of its slow onset and long duration, but clinical trials are being organized for addiction, PTSD, and chronic pain. 46
Using mescaline: Traditionally mescaline is consumed by chewing on Peyote buttons or making a tea with the cactus flesh. The bitterness of the cacti flesh is intense and can be hard to tolerate. However that can be avoided by consuming mescaline as a powder in capsule form, which may also make dosing more accurate.
Microdosing mescaline: The practice of microdosing mescaline looks pretty similar to other psychedelics. The idea is to take about 1/10th of the psychedelic dose a few times a week in hopes of stimulating brain restructuring. There are very few studies evaluating microdosing in general, and none that specifically investigate mescaline.
Macrodosing mescaline: Ceremonial dosing of mescaline usually reaches at least 500mg of mescaline to induce a psychedelic trip, but there’s very limited research on the topic. Because tea can be made using pure mescaline isolate, ground dried cactus powder, or by using fresh or dried cactus flesh, there are plenty of questions remaining regarding the optimal dose of psychedelic cacti.
Obtaining mescaline: Peyote is currently illegal to cultivate or consume in the US unless used for religious ceremonies through the Native American Church. Peyote grows very slowly, and a button can take up to 12 years to mature. Due to habitat destruction, poaching, and unsustainable harvesting, the peyote cactus is now endangered. According to the Multidisciplinary Association for Psychedelic Studies (MAPS), peyote should be reserved for those cultures that consider it a sacred tradition. 47
Other psychedelics
Iboga
History: Iboga is a medicinal shrub found in Central West Africa and is traditionally used by the indigenous Bwiti religion located in Gabon. In 1962, Howard Lotsof, a 19-year-old heroin addict from Staten Island, New York, accidentally discovered that this plant cured him of his addictions. He then conducted an informal experiment on 20 of his friends and found similar anti-addictive results. Lotsof became a strong advocate for the plant’s healing potential, and made it his life’s mission to spread the word of iboga’s therapeutic potential the world over.
Common uses: The active ingredient ibogaine has been reported to have medicinal value in treating substance use disorder or addiction to substances such as opioids, alcohol, cocaine, and nicotine. The Bwiti religion uses iboga ceremonies for healing, communing with ancestors, transitions into adulthood, and as a “truth serum” where one sees the meaning of life and death.
How iboga works: The iboga root contains ibogaine, which is an indole alkaloid and thought to be the primary psychoactive ingredient in iboga. However, like cannabis, the root of this shrub produces many bioactive molecules. Thus, the concept of the entourage effect pattern exists with iboga as well. Most research suggests iboga primarily acts on the adrenergic system, the opioid system, as well as some nicotine receptors in the brain. Because of the hallucinogenic properties, it is presumed that iboga also interacts with the serotonin system, however the exact mechanism is still up for debate. 48
Once consumed, ibogaine is metabolized to noribogaine, which is also a pharmacologically active compound – similar to what happens when you consume edibles and THC is converted in the body to the active metabolite 11-hydroxy-THC. Because the experience of ingesting iboga is so long, often 24 hours or greater, scientists believe noribogaine, an active metabolite, may be an important part of the overall effects delivered from taking iboga root.
After consumption there are three stages of effects, experienced over three days. Stage one lasts between four and eight hours and is described as a “waking dream,” where traditional intense psychedelic hallucinations and recall of past events are experienced. Stage two is more mellow and traditionally seen as the time for evaluation and reflection. This stage lasts for 8 to 20 hours. Stage three lasts up to 72 hours after ingestion, and is characterized by mild stimulation, heightened awareness and disrupted sleep. 49 50
Clinical research: A recent scientific review concluded that ibogaine from the iboga plant has therapeutic potential for substance use disorder, withdrawal symptoms, and reducing cravings. It also shows promise in treating depression and assisting with trauma recovery. 51
Using iboga: Traditionally, the iboga root is processed into a drink that is consumed as part of a ritual involving three sleepless days and nights filled with singing, dancing, drumming, and even self-burial ceremonies. Apart from ceremonial purposes, the root bark is consumed orally via capsules, as well as extracted for a total alkaloid (or full spectrum) extract and purified ibogaine hydrochloride. 52 The duration of effects for larger doses can be longer, often exceeding 24 hours.
Microdosing iboga: Though microdosing is not iboga’s most common use, some psychonauts are exploring this option. A 2022 case report describes a middle aged woman with refractory bipolar depression who started taking 8mg of iboga daily and within 60 days has drastically improved depression scores. More strikingly, depression scores continued to trend down for 30 more days even after stopping the microdose of ibogaine. 53
Macrodosing iboga: Whenever preparing to take a large dose of iboga, it is important that the duration of effects is considered and that one is in a safe, relaxed space for the coming day or two. A large dose of iboga is expected to last longer than 24 hours and is usually described as an unpleasant journey. For this reason, it is often recommended to find a trip sitter to help ground you during the experience.
Iboga safety: Numerous concerns about the safety of iboga have been raised by scientists. There have been a number of deaths associated with using this substance, particularly related to ibogaine’s effects on heart rate and rhythm. Caution should be taken by anyone considering taking iboga, especially those with underlying cardiac conditions. 54
Ketamine
History: Ketamine was first synthesized in 1960. It is a Schedule III controlled substance that was first FDA approved for anesthesia.
Common uses: Ketamine is commonly used in hospital settings and veterinary medicine, and is nicknamed “Special K” when used as a party drug. Ketamine is indicated for anesthesia, pain, and depression (esketamine), but has been used off-label to treat anxiety, PTSD, OCD, migraines, eating disorders, and addiction. Because it is one of the few legal psychedelics in the US, we’re currently seeing a large increase in ketamine infusion clinics for mental health purposes, specifically treatment resistant-depression and addiction.
How ketamine works: Ketamine is not a classical psychedelic. It is a dissociative anesthetic known for producing feelings of detachment from the environment and/or self, and it can create a psychedelic state under certain conditions. Ketamine is a NMDA receptor blocker, which is a fancy way of saying that it blocks excitatory signals in the nervous system. The changes set forth by ketamine affects many complex neurotransmitter systems in the brain, including those involved with the serotonin system.
Additionally, it has been proposed that ketamine has mixed actions in the endogenous opioid system, and stimulates the fight or flight (adrenergic) system. It increases proteins important for neuron growth (Brain-Derived Neurotrophic Factor or BDNF) and like other psychedelics it also decreases activity in the DMN. 55 56
Clinical research: Since ketamine is already approved by the FDA, carrying out research is much easier than Schedule I substances like LSD, MDMA, or even cannabis. As such, there have been numerous clinical trials using ketamine. Recently, research has been focused on the benefits for mental health conditions and understanding its dissociative properties. 57
Using ketamine: Ketamine can be administered through an intravenous injection, an injection into the muscles, via a nasal spray, as a dissolvable lozenge, and as a tablet. Most clinics use intravenous or intramuscular administration, but technically ketamine is not FDA-approved for any psychiatric condition. However, the FDA recently approved a nasal formulation of esketamine (Spravato) which is the S-isomer of ketamine (hence the name) for treatment-resistant depression.
MDMA
History: MDMA was first synthesized in 1912, but it didn’t become popular until 1970, when therapists began to utilize it to enhance openness in therapy sessions. It earned the nicknames “molly” and “ecstasy” as it made its way into the party and rave cultures, which prompted the US to make it illegal in 1985.
Common uses: MDMA has possible benefits for treating PTSD, addiction, and anxiety. Using MDMA along with psychotherapy promotes trust and safety, allowing the patient to talk about and process their traumatic experiences or mental health issues.
How MDMA works: MDMA is an amphetamine derivative that has both stimulant and psychedelic effects. Users report an increase in empathy, energy and alertness, extroversion, emotional warmth, personal insight, mild eurphoria and heightened sensations (especially sexual sensations). It acts on three different neurotransmitters in the brain – increasing serotonin, norepinephrine, and to a lesser extent, dopamine. MDMA causes these neurotransmitters to flood the activation sites in the brain and inhibits their recycling – making a more elevated experience across many of the senses. It also increases oxytocin, the hormone associated with bonding, empathy, and closeness. 58 59
Clinical research: Based on strong clinical research results, the FDA designated MDMA as a breakthrough therapy for PTSD. It is expected to be approved as a medicine after current Phase 3 clinical trials are complete. 60
Using MDMA: Doses are typically 80-125mg, but doses over 200mg are often used for a more intense experience. Dosing is often done gradually, about every 1-2 hours, in an attempt to keep the peak effects of the MDMA going. Side effects include difficulty regulating temperature, jaw clenching, loss of appetite, disorganized thoughts, and feelings of depression for a few days after ingestion, often referred to as the “comedown.” The side effects of MDMA can be minimized with in-office administration and monitoring, and are usually dose dependent.
Salvia
History: Salvia divinorum or salvia is an herb in the mint family. It has been used by the Mazatec Indians of Oaxaca Mexico for healing and religious purposes for centuries. Believed to be the reincarnation of the Virgin Mary, this plant is often seen as sacred, and not traditionally for everyday consumption. 61
Common uses: Salvia is used as a short-acting psychedelic, dissociative, and pain reliever. Despite the short duration, the effects of salvia can be quite intense and include hallucinations, slurred speech, and loss of coordination.
How salvia works: The major active ingredient in Diviner’s Sage is salvinorin A, a terpene-like molecule (a diterpenoid) made by the salvia plant. Its mechanism of action is unique compared to classical psychedelics, in that it acts on kappa-opioid receptors rather than serotonin receptors. There is also speculation that salvia’s effects may be intertwined with the endocannabinoid system. 62
Clinical research: While only recently becoming a focus of clinical research, salvia is quickly becoming a focus for clinical researchers. A 2021 study from The Johns Hopkins found that salvinorin A had profound effects on the DMN, despite not having classical psychedelic qualities.This was a surprise to the researchers and opens up questions about the true mechanisms underlying the benefits of psychedelics. Salvia is currently being explored for its effects on mood, depression, pain, and interestingly, obesity. 63 64
Using salvia: Traditionally, the leaves of the salvia plant are chewed and absorbed buccally, or through the cheek and mouth, in what is known as “the quid” method.
The leaves can also be dried and smoked, similar to cannabis, for a shorter effect, and potent extracts can be made from the leaves. Extracts are marked according to potency (5x or 50x). It is this extract that can be consumed in a drink or smoked. A typical dose is 150-500 mcg.
Unlike most of the substances listed above, salvia has not historically been illegal. It only began to become illegal in 2002, starting with Australia. Today, salvia is prohibited across much of the world, particularly in Asia and Europe. In the US, Salvia divinorum is federally legal but banned in 33 states; Depending on the state you live in, it’s easily accessible. 65
Most modern salvia usage is focused on psychedelic dosing, but it is possible to deliver smaller doses via the chewing method, wherein small amounts of salvinorin A enter the bloodstream through the cheek tissues. This can enhance mood without causing dissociation – effectively delivering a microdose.
The future of psychedelics
Psychedelic medicine is experiencing a modern day renaissance, with research booming and a rediscovery of therapeutic potential. Just like in the cannabis space, we’re seeing advocacy, legalization, and competition among industries to provide these medicines. Hundreds of companies are racing to establish a foothold in this emerging space.
With scientists busy creating exciting novel psychedelic substances and companies collecting patents left and right, it may be wise to look back at the origins of these substances. We still have much to learn from the plants, fungi, and animals that have been on this planet longer than us, and are the source of such healing medicine.
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