Emerging Research: How Psychedelics May Help People With Bipolar Disorder

Mystical visions and hallucinogenic experiences might be what comes to mind when you hear about popular psychedelics such as magic mushrooms containing psilocybin, LSD (lysergic acid diethylamide), and the spiritual medicine ayahuasca and its active ingredient, DMT (N,N-dimethyltryptamine). While these substances can all cause intense trips, or psychological experiences, there is also surging interest in their therapeutic use.

Based on reports from recreational and traditional users, as treatments for psychiatric conditions psychedelics might have fewer side effects yet be more effective than traditional drugs for mental health concerns. This has fueled an interest in research within the scientific community.

New and ongoing investigations into the therapeutic use of psychedelic substances to treat addiction, anxiety, depression, post-traumatic stress disorder (PTSD), and other illnesses are taking place in clinical research settings worldwide. But what about bipolar disorder?

A golden period of research started in the 1950s, but ended when most psychedelic substances were classified as “drugs of abuse” in the early 1970s. With no recognized medical value on the books, there was no way to conduct controlled clinical studies.

This kind of research, designed to assess the therapeutic efficacy and basic psychopharmacological properties of psychedelics as adjuncts to existing psychotherapeutic approaches, is again being conducted. The 6s paradigm that acknowledges the critical influence of factors such as set and setting for facilitating positive outcomes is central to this revival.

Most of what we the public hear and understand about psychedelic drugs has to do with potential harm and “bad trips.” But the source of most of this knowledge is cases in unsupervised nonmedical contexts involving patients who used illicit substances. Emerging research into therapeutic use of psychedelics as adjuncts to counseling or psychotherapy for mental illness is very different—and what we’re covering here.

Types of Psychedelic Drugs

Psychedelic drugs all have powerful effects on the conscious experience but may include a range of substances with differing pharmacological profiles.

Classic psychedelics such as psilocybin, lysergic acid diethylamide or LSD, dimethyltryptamine or DMT, and mescaline act as agonists at the 5-HT2A. Many of these compounds occur naturally in fungi or plants prized for folk healing and spiritual rituals, or their close analogues, such as the Central and North American peyote cactus (Lophophora williamsii), the Eurasian ergot fungus (Claviceps purpurea), and the Amazonian ayahuasca brew (Psychotria viridis and Banisteriopsis caapi).

The entactogens are another class of psychedelic substances with overlapping yet significantly different effects compared to classic psychedelics. This class includes methylenedioxymethamphetamine (MDMA), which primarily acts as a serotonin-releasing agent.

Ketamine is technically a dissociative anesthetic which produces some effects that are similar to psychedelics. We will cover each of these below.

Briefly, scopolamine is an anticholinergic that produces effects similar to psychedelics. It is currently being investigated for therapeutic potential in bipolar patients.

Finally, ibogaine is a natural hallucinogenic substance with a complex neuropharmacology. It has been associated with mania in case studies, but this bears more study.

History and Background: Therapeutic Use of Psychedelics

Psychiatric interest in psychedelics is hardly novel. Thousands of patients in the 1950s and 1960s received various psychedelics experimentally to treat mental health disorders such as alcoholism. Of course, much of this research ground to a halt in 1971 when the US Controlled Substances Act passed. During the Nixon administration, psilocybin—a primary focus of psychedelics studies and the main active compound in “magic mushrooms”—was classified as a schedule I drug.

Since then, researchers have demonstrated relatively low toxicity and abuse potential associated with psilocybin. In 2000, Johns Hopkins University researchers obtained regulatory approval to reinitiate psychedelics studies.

By 2006, the Johns Hopkins team published landmark research in Psychopharmacology. The double-blind study proved psilocybin had positive, sustained effects on behavior and attitudes of healthy volunteers—and that under well-controlled conditions, it was safe.

This fueled a global surge in psychedelic research, most of which has demonstrated that psychedelic substances such as psilocybin, ketamine, ayahuasca, MDMA, LSD, and ibogaine all have some therapeutic benefits. Given that most of these substances have long been used in spiritual and medical practices by indigenous cultures, this is hardly surprising.

However, despite multiple research studies accumulating that overall support the therapeutic use of psychedelics, the broader body of research mostly excludes bipolar patients.

Most ongoing and planned clinical trials of psilocybin and other psychedelics for mental health conditions have strict exclusion criteria surrounding co-occurring disorders including bipolar or schizophrenia spectrum disorders. This is based on the possible risk of inducing psychosis or mania. A first-degree relative with bipolar disorder is another common basis for exclusion, and may extend to any cluster B personality disorder.

Current State of Research: Psychedelics and Bipolar Disorder

The psychedelic science community achieved consensus decades ago regarding bipolar disorder, and the advice was to stay away. Conventional wisdom has it that people with bipolar disorder or manic depression, along with those with a psychotic spectrum disorder or a heart condition, should avoid psychedelics which are unsafe for them and may aggravate their condition.

For those with bipolar disorder, there is a risk that the psychedelic experience can trigger a manic episode, something that has been observed in case studies. Mania, characterized by grandiose thinking and over-extending oneself personally, financially, and otherwise, can prompt behavior that is essentially out of character, and even dangerous, reckless, and intrusive. As a result, people who experience manic behavior can put themselves and others in dangerous situations, and lose control of their own lives. However, there is no research that studies psychedelics in people with bipolar disorder that controls for things such as dose, set, and setting.

Classic psychedelics such as psilocybin, MDMA, and ketamine, affect the serotonin system, and the 5-HT2A receptor in particular. This is not very risky for most people, and unless at super-high doses or mixed with different substances it’s not physically dangerous. But for people with bipolar disorder, that increased serotonergic activity may be what is potentially triggering mania, or perhaps creating the right conditions for mood episodes and making them more likely.

Many people with bipolar depression cannot take SSRI antidepressants because they cause them to experience manic episodes. In fact, some people receive a bipolar diagnosis after an SSRI prescription causes them to feel manic or experience psychotic symptoms.

The fact that an SSRI can cause mania is clearly the reason why many in the psychedelic community feel that it’s unsafe to give people with bipolar disorder psilocybin, MDMA, ayahuasca, or anything like them. Yet people struggling with bipolar disorder often feel unwilling to dampen their hypersensitivity or suppress their creativity with traditional medications.

Traditional pharmaceuticals may not make people with bipolar disorder feel manic or suicidal, but they can also limit how much fun, pleasure, or even arousal that they feel. People with bipolar disorder sometimes report that they lose the ability to be creative or to make spiritual connections, and this can result in feelings of alienation, pointlessness, numbness, and frustration.

Ketamine and Bipolar Disorder

The animal aesthetic and party drug ketamine, also called “special K,” holds promise for treating bipolar disorder. Originally developed in the 1970s, ketamine can induce hallucinations, psychosis, and other psychedelic reactions.

Recreational ketamine users trigger these psychedelic effects by consuming large quantities of the drug, usually 30 to 300 milligrams, ingested orally or snorted. Also called “going down the K-hole,” this is very different from therapeutic use of ketamine, which is typically 0.5 milligrams of ketamine per kilogram.

According to a 2014 study, ketamine appears to have lower risk for inducing mood episodes than either psilocybin or MDMA. The study of 36 subjects with treatment-resistant depression over five years, from the National Institute of Mental Health (NIMH), found that ketamine helps reverse anhedonia: the inability to seek or feel pleasure, and one of the key symptoms bipolar patients experience.

The team found that a single infusion of ketamine treated anhedonia in about 40 minutes, with other depressive symptoms improving within hours. In contrast, most antidepressants take three to six weeks or even longer to take effect. In some patients, ketamine’s antidepressant effects lasted up to two weeks.

Researchers are working to replace ketamine, which can harm cognitive function and damage the bladder, with a replacement drug patients could take periodically. Johnson & Johnson received approval from the Food and Drug Administration (FDA) for a nasal spray that imitates ketamine in 2020.

Unlike other entheogens, ketamine doesn’t work as much on serotonin. Rather, it produces rapid antidepressant effects via its primary action on the glutamate and NMDA receptors. Thus far, even with a history of mania do not appear to develop mania in clinical ketamine treatment.

However, many bipolar patients in ketamine programs likely mitigate the risk of mania by staying on their mood-stabilizing medications, because ketamine is one of the only psychedelics which can safely be taken at the same time. This is important for patients with bipolar disorder who can be destabilized by stopping medication too abruptly.

Ketamine assisted psychotherapy (KAP) is another good option for individuals with bipolar disorder. In KAP, ketamine is offered to the patient at various small to moderate doses in tandem with talk therapy, a sort of formalization of the integration process. A monitoring clinician might increase the number of follow-up sessions for monitoring changes to cognition or mood in bipolar clients.

Psilocybin and Bipolar Disorder

Psilocybin use among those with bipolar disorder was the subject of a fairly exhaustive and systematic review. The team evaluated published case histories and other evidence published through December 31, 2020 found on Web of Science, PubMed, and PsychInfo, focused on classic psychedelics and case histories or studies. The goal was to assess the known risks of using psilocybin as a treatment of depression in bipolar disorder.

The team found 15 case studies reporting some form of mania or manic like behavior that lasted beyond the intoxication event. Of those 15 cases, four involved psilocybin, two involved people with an existing bipolar diagnosis, and three involved people without a history of concurrent polysubstance use or polysubstance abuse.

The authors conclude that although there is some risk of mania from psilocybin and substances like it, the risk is neither overwhelming nor strong. They also argue that study of these substances among bipolar patients is warranted with careful controls.

MDMA and Bipolar Disorder

MDMA seemed poised to become the first prescribable psychedelic after its breakthrough approval from the FDA in 2016. Now the timeline looks promising for 2023—for PTSD patients.

However, because of its action with serotonin, most experts recommend that people with bipolar disorder avoid MDMA.

DMT, Ayahuasca, and Bipolar Disorder

Because of its incredibly short binding time with the 5-HT2A receptor, DMT might hold major benefits for those with bipolar disorder. Most psychedelics including psilocybin, LSD, and DMT, “plug into” the 2A receptor, and the length of a trip is determined by the length of their stay there. LSD is a longer-lasting trip than DMT or psilocybin because it stays plugged in for the longest. It is possible that DMT’s short binding time also poses less risk of mania for bipolar people, LSD and other substances that bind longer present more risk.

The bipolar brain has a malfunction in a key mood regulating function: inositol phosphate metabolism. Rather than being too high or low, due to its missing regulating mechanism, the bipolar mind functions at speeds that are too fast or too slow. Medication like Lithium helps regulate that speed.

Ayahuasca and DMT in carefully curated circumstances can help some bipolar patients feel relief from depression and better awareness of their mania and how it affects others. The feelings of social connectedness and conscience from psychedelics and DMT in particular might offer bipolar patients insight into how behaviors that feel amazing in the moment are actually highly problematic.

Benjamin Mudge, a Flinders University PhD candidate, has created harm reduction guidelines for people diagnosed with bipolar disorder who want to drink ayahuasca. He advises people to wait for research like his to be finished before trying psychedelics, yet hopes if people ignore his advice they will reduce the risk of mood episodes and stay safe by following these guidelines.

For example, the guidelines recommend that bipolar people avoid partaking in the ayahuasca tradition of multiple ceremonies over the course of several days, which places the bipolar brain at greater risk of mania. They also recommend that bipolar patients avoid mixing ayahuasca with other substances, including traditional tolls such as cannabis, rapé, and even anything containing caffeine such as cacao. The bipolar ayahuasca explorer should also avoid fermented ayahuascas that contain alcohol, and aim for brews without Syrian Rue and with more DMT than MAOI inhibitors.

(Fermented ayahuasca is still usable; just brew over low heat for 15 to 20 minutes to steam off the alcohol—avoid boiling. It should smell like a vegetable stew when it is done.)

Psychedelics, Heightened Awareness, and Bipolar Disorder

Deeper insights that support healthier behaviors are a hallmark of psychedelics generally, not just DMT and ayahuasca. Bipolar people who have used psychedelics in a controlled setting may be more aware of my manic episodes as they take place and more quickly able to recognize them. This in turn empowers them to render manic events less severe and shorter. For example, a patient with bipolar disorder may recognize a manic episode after spending $100 online, rather than thousands.

For these kinds of bipolar patients, a single psychedelic experience every few months with the right support and setting could be sufficient to ground them and better allow them to manage and experience their full spectrum of feelings—even without other medications. Certain experts believe that intermittent psychedelic-assisted therapy sessions and skill building work can help some bipolar patients manage mood fluctuations more independently.

It is important to note that unmedicated bipolar people are at much higher risk for suicide. Furthermore, it is dangerous to go off psychiatric medication without a doctor’s supervision and/or too quickly, particularly when combined with other substances, including psychedelics.

Mixing psychedelics and bipolar medications does seem to be contraindicated, although it is difficult to get a clear answer from doctors on this. SSRIs should not be combined with psychedelics for several reasons, including the potential risk of Serotonin Syndrome. There is less available information about common bipolar medications such as lithium and lamotrigine.

Therapeutic Microdosing

Increased interest in microdosing has surged alongside research into psychedelics. Microdosing is the therapeutic consumption of doses of psychedelics that are too small—usually 5 to 10 percent of a standard dose—to produce any perceptible effects. Some evidence suggests that microdosing can offer some of the therapeutic benefits seen with full-dose psychedelic treatment without the sometimes intense and even negative psychotic or hallucinatory experiences.

This might seem ideal, especially to a patient with bipolar disorder, who needs to avoid that kind of experience in particular. Some scientists worry that microdosing may be harmful for these kinds of brains in particular. However, very recent research which includes bipolar patients seems to suggest potentially positive benefits.

Risks and Mitigation

Typically, participation in psychedelic research excludes people with a family or personal history of bipolar disorder or psychosis. The reason for the exclusion is the risk of triggering mania or psychosis. Hallucinogen Persisting Perception Disorder (HPPD) is another risk associated with psychedelic drugs, more commonly known as severe and persistent flashbacks.

The incidence of adverse effects such as HPPD, mania, and psychosis with psychedelic use in the general population is thought to be relatively low, and such bad trip experiences are nearly always associated with illicitly procured psychedelic substances, especially unsupervised use of multiple substances in uncontrolled settings.

Final Thoughts on How Research Shows Psychedelics Can Help People With Bipolar Disorder

New scientific interest in psychedelic drugs as treatments for mental illnesses such as addiction, anxiety, and posttraumatic stress disorder is on the rise, and successful human research in multiple countries proves that this kind of work can be safe, probative, and effective.

Recent findings indicate many successful applications for these treatments, with few if any serious adverse effects and significant clinical improvements. And while too many studies have excluded bipolar patients, we are finally seeing this gap closing with new information.

As more and more people are helped by new therapeutic options, the culture surrounding psychedelics may continue to change. This will hopefully foster more investigation into how psychedelics can help people with bipolar disorder.

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