- What is a hallucinogen?
- What is a dissociative drug?
- What is a psychedelic drug?
- How long have people used psychedelics?
- How was LSD discovered?
- Why were psychedelic drugs made Schedule 1?
- Who has the power to reclassify psychedelic drugs from Schedule I?
- How do drug laws vary around the word?
- How has the ban on psychedelics affected scientific research on them?
- Did the CIA really sponsor a secret mind control program?
- Are psychedelics actually as dangerous as their Schedule I status suggests?
- How do psychedelics affect the brain?
- Could LSD be used in mental health therapies to relieve anxiety?
- Could psilocybin be used to treating mental illnesses like OCD?
- Could ketamine be used to treat depression?
- Could ketamine be used to treat opioid addition?
- Is there any evidence that DMT, the active ingredient in ayahuasca, has therapeutic effects?
- Is ecstasy (MDMA) really a breakthrough therapy for PTSD?
- How common are non-psychedelic hallucinations in the general population?
- Do psychiatric patients experience hallucinations differently than the general population?
- What’s the overlap between biological and drug-induced hallucinations?
- How are dopamine, glutamate, and serotonin related to hallucinations?
- How were mental disorders with hallucinations treated in ancient times?
- When were the first hospitals for those with mental illnesses established?
- How has the treatment of mental disorders changed in modern times?
- How are mind-altering mental illnesses treated today?
- How are medications used to treat mind-altering mental illnesses today?
- Is psychotherapy still being used to treat mental illnesses?
- What are brain stimulation techniques? Is electroshock therapy still used today?
- What is Transcranial Magnetic Stimulation (TMS)?
- Are hallucinations a disease?
- What is reality?
- Where is the current debate about psychedelics and hallucinations, and where is it heading?
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Hallucinogens are a diverse group of substances collectively defined by their ability to disrupt the ways in which we perceive the world. Though there are many varieties, all act primarily on the brain chemistry involved in that perception.
Several similar hallucinogenic substances are grouped together as "dissociatives," for their ability to separate sensory inputs from perceptions, allowing a user to feel like they have removed themselves from their body, dissociated from their physical form. These trances or "out-of-body" experiences are the effects desired by those taking these drugs recreationally, but they also can be medically useful. Dissociative drugs such as ketamine are regularly used as anesthetics during surgery. Generally, these substances block NMDA receptors, which mediate communication in the brain, resulting in lost connections between the conscious brain and its sensory inputs. Other dissociatives can also be used medically, such as dextromethorphan (DXM), the drug which gives Robitussin its cough-suppressing ability, or they can be used illicitly, such as phencyclidine (PCP).
The most well-known group of hallucinogens are undoubtedly the psychedelics. The name comes from the Greek for “mind manifesting,” since these drugs are known for expanding the mind and dissolving the ego. This group includes Lysergic Acid Diethylamide (LSD), psilocybin (the active ingredient in magic mushrooms), and mescaline (often from the peyote cactus).
Scientists have used carbon dating and archaeological evidence to show the use of naturally occurring psychedelic compounds in the Americas and Europe since prehistoric times, as far back as 3780–3660 BC. Indigenous people of North and South America used psychedelic plant extracts in various spiritual and cultural ceremonies. These most commonly include ingesting peyote, a cactus containing the hallucinogen mesca; ayahuasca, a drink made from plants containing DMT and monoamine oxidase inhibitors; and mushrooms containing psilocybin. Scientists have even found over 5,000-year-old dried peyote buttons and ground peyote samples that were recovered from the Shumla Caves in Texas, an area known for vivid cave paintings.
Like their counterparts using psilocybin mushrooms in the western hemisphere, the indigenous people of Siberia used fly agaric mushrooms (Amanita muscaria) containing two psychoactive compounds, muscimol and ibotenic acid, which have hallucinogenic proper-ties. In Africa, ibogaine, the active ingredient in iboga tree bark, was heavily used far before Europeans be-came aware of its hallucinogenic properties in the late 1800s.
A scientist named Albert Hofmann at Sandoz Laboratory (now part of Novartis) first synthesized Lysergic acid diethylamide, or LSD-25 (named in part for the virtue of being the 25th drug that Hofmann synthesized). Hofmann originally thought that LSD-25 might be useful to treat circulatory and respiratory depression, because it was similar in molecular structure to another drug that improved breathing and stimulated blood flow. But disappointingly, LSD-25 failed to change circulation or respiration in animal studies, and was deemed ‘uninteresting’ by Sandoz. The compound was put aside, but Hofmann suspected there was still some-thing about it worth investigating.
Five years later, while Hofmann was re-synthesizing LSD-25 to carry out more tests, he accidentally ingested a minute quantity of the compound and experienced colorful hallucinations, discovering its psychedelic properties. A few days later, Hofmann made a more rigorous self-experiment. He took a 250-microgram dose of LSD-25 — guessing how much to take based on his knowledge of other ergot derivatives, but which turned out to be 10 times higher than what would become the recommended dose for LSD-25. Overcome by hallucinations, Hofmann attempted to travel home with the help of a lab assistant. Because this was 1943 — the height of World War II — use of cars was restricted, and he had to attempt the trip home by bicycle. Hofmann experienced intense hallucinations and distortion of his sense of self — a “bad trip,” figuratively and literally.
Fearing for his life, Hofmann summoned his family doctor. But after the doctor reported that his life was in no imminent danger, and Hofmann started coming down from the peak of his trip, he began to enjoy the hallucinations. Sandoz patented LSD, and made it available to researchers as an experimental drug under the trade name Delysid in 1947, with a recommendation for use in psychotherapy. Sandoz also recommended that experimenting with the drug themselves could aid psychiatrists in better understanding psychosis in their patients.
By the late 1960s, when the Controlled Substances Act was percolating, psychedelic drugs like LSD and psilocybin mushrooms had become symbols of the rebellious youth.
The increase in complaints about accidents resulting from recreational use of LSD coincided with the expiry of Sandoz’s patents for the drug in 1963. This combination made LSD suddenly unprofitable, and Sandoz ceased production shortly after. Laws passed by the US Congress in 1965 tightened the regulations on psychedelic research, and investigators without explicit approval were required to surrender their LSD to the government.
Meanwhile, with the 1968 “Summer of Love,” psyche-delic use moved firmly into the counterculture. Media sensationalized reports of terrible LSD-induced side effects, despite scientific evidence that serious side effects of LSD are very rare. In response, the US banned LSD later that year. Two years later, Congress passed the Comprehensive Drug Abuse Prevention and Control Act, including the Controlled Substances Act. The Controlled Substances Act focused on the criminal enforcement of drug regulation, and created five schedules, or categories of drugs. Psychedelics were placed into Schedule I, the designation reserved for the most dangerous substances.
In retrospect, the push to include psychedelic drugs in Schedule I is seen to be mostly the result of social considerations and pushback against recreational use, particularly since the scheduling system was implemented close to the discovery of LSD and the movement of natural psychedelics into mainstream use, while research in their therapeutic potential was still underway. In contrast, other scheduled drugs such as cocaine and morphine, which pose a greater risk of dependence and adverse effects, had been medicinally used for decades before the Controlled Substances Act and that likely played a role in their designation as Schedule II drugs.
Since the original Controlled Substances Act, the process of adding, changing, or removing drugs from their schedule lies mainly with Congress. Congress can add an amendment to the Controlled Substances Act which can affect the scheduling of drugs or the penalties for possessing them.
In 1971, the United Nations followed in the footsteps of the US, introducing a treaty broadly banning drugs, including psychedelics, across their member nations. The UN Drug Control Conventions organize drugs into four classifications or schedules, which are largely similar to the first four schedules in the United States. Like in the United States, psychedelics are a Schedule I drug by UN standards — considered to have high abuse potential and no therapeutic value.
Because UN member nations decide for themselves how to define criminal penalties for personal possession of controlled substances, there is great variability in how drug policies play out around the world. Countries like China, Iran, Malaysia, and Singapore have strict drug laws where distribution and even possession over a certain amount can carry the death penalty. On the other end of the spectrum, countries like the Netherlands and Uruguay have more liberal drug policies, where possession of small amounts of drugs has been decriminalized. In the Czech Republic possession of not more than “a small amount” of most drugs (including marijuana, cocaine, methamphetamine, and LSD) is a misdemeanor with a fine about equal to that of a parking ticket. But the country with the most liberal drug policy is Portugal, which became the first European country to abolish criminal penalties for drug possession in 2001, and in doing so has drastically reduced the death rate of drug users.
Throughout the 1950s, the potential therapeutic effects of LSD were studied in the United States and in Europe. After the Controlled Substances Act became law in 1970, the main agency providing grants for research on psychedelics, the National Institute of Mental Health (NIMH), stopped funding studies into their therapeutic potential. At the same time, getting approval from the Drug Enforcement Agency (DEA) to possess some of the drug, even for preclinical studies, became nearly impossible to obtain. As a result, research into the therapeutic uses of psychedelics including LSD stopped abruptly — to the surprise of many people. Even US Senator Robert Kennedy was startled by the sudden halt of research into the therapeutic potential of LSD, perhaps because his wife, Ethel, had reportedly received LSD therapy.
Kennedy started a congressional probe into why psychedelic research was being stopped, and is quoted addressing the predecessor of the DEA with the question: “Why if [clinical LSD projects] were worthwhile six months ago, why aren’t they worthwhile now? I think we have given too much emphasis and so much attention to the fact that it can be dangerous and that it can hurt an individual who uses it that perhaps to some extent we have lost sight of the fact that it can be very, very helpful in our society if used properly.” He did not receive an answer, and the efforts continued to stop LSD research.
Due to their scheduling regulations, psychedelics like LSD and psilocybin are still difficult to get approval to study, and face pushback from grant funding agencies and the public due to perception that drugs are dangerous. Preclinical research on psychedelics can sometimes circumvent these restrictions by instead studying a drug that is not scheduled, like 2,5-Di-methoxy-4-iodoamphetamine (DOI). But research compounds like DOI don’t have the same established history of therapeutic potential for humans as LSD and psilocybin do.
The inclusion of psychedelic drugs in Schedule I and the end of research into their medical applications have contributed to the public perception that the drugs are dangerous. Among young adults, the perceived risk of trying LSD once or twice in their lifetime is higher than that of binge drinking weekly, in stark contrast to the actual biological risks. This discord between perceived and actual risks is especially striking considering that serious side effects from LSD are extremely rare, while alcohol directly contributes to 88,000 deaths per year in the US alone.
The CIA began a secret project codenamed MKUltra in 1953. Against a backdrop of Cold War paranoia, the CIA set out to identify avenues of mind control to use for espionage, interrogation, and psychological torture. Increasingly, MKUltra focused on the use of psychedelic drugs — particularly very high doses of LSD — in illegal experiments where people in universities, hospitals, or prisons in the US and Canada were given the drug unknowingly or against their will. The program was disbanded in the 1970s, but not until after most of the documentation was destroyed in a post-Watergate frenzy, making it difficult to know the full extent of the damage done to unwilling participants. In 1977, a Senate Subcommittee chaired by Ted Kennedy investigated MKUltra, and called a final halt to the project.
Any drug that impacts the brain’s reward system can theoretically be addictive and abused. However, with the exception of LSD, most hallucinogens do not act through the dopamine reward pathway in the way that opioids do. That’s why scientists think that they might be less addictive.
But to make that thought scientifically waterproof, science protocols demand completing reproducible, dose-dependent addiction studies in animals. It’s worth noting that these studies show animals do not self-administer hallucinogens like they do stimulants and sugar, which further suggests that these set of drugs function differently in the brain — and that they don’t cause addiction.
Another thing that causes drugs to be classified as harmful is if their use causes brain damage later in life. As of now, psychedelics don’t appear to do this. A population study in 2013 looked at whether classical psychedelics such as LSD, psilocybin, and mescaline use was correlated with mental impairment later in life. Out of 130,000 participants, 13 percent reported psychedelic use, and researchers found no association between lifetime use of the drugs and increased rate of any mental health issue. In several cases, psychedelic use was associated with lower rates of mental health problems.
However, caution is essential until there are many more studies addressing the effect, if any, psychedelics has over time. One such study looked at the effects of consuming peyote (which contains mescaline) on 61 Navajo Native Americans. When compared to 79 individuals with a history of minimal drug history, a mental health survey showed that the Native American people had no deficits in memory, attention, and other cognitive functions. Similar results have been shown for ayahuasca use in 22 Spanish participants.
Ideally, we’d pursue this research on long-term side effects and the research on efficacy of psychedelics in treating psychological illnesses, since they seem to have promise for helping ease a variety of mental health conditions. This two-pronged approach would ideally validate their use as medication or show that the long-term consequences outweigh the benefits. For now, there’s a lot we still don’t know.
The brain is constructed of billions of interconnected brain cells, or neurons, which signal to each other both electrically and chemically. Each cell can transmit information by sending electrical signals from one end of the cell to the other cell. Unlike the electrical wiring in our homes, however, neurons aren’t physically connected to each other. Between each cell there are minuscule gaps called synapses. In order to bridge these synapses and communicate with its neighbors, neurons release chemical signals into the gap which pass information to the next cell in line.
This chemical signaling system is comprised of neurotransmitters like dopamine or serotonin being released from the “sending” neuron, and then binding to specific receptors on the “receiving” neuron. Each neuron releases a different neurotransmitter, which fits into a receptors perfectly like a lock into a key, enabling many trillions of these electrochemical handshakes to occur simultaneously in the crowded confines of our brains. The release of neurotransmitters onto many varieties of sensitive receptors allows each signal to be fine-tuned and manipulated as it passes from cell to cell.
All psychoactive drugs, those substances that change perception, mood, and consciousness, affect neurotransmitter signaling in one way or another. Cocaine blocks the protein that hauls extra dopamine out of the synapses, causing a build-up of the neurotransmitter and increased firing of reward cells. Opioids mimic a different natural neurotransmitter, endorphins — the ones that give you a runner’s high — by blocking pain perception. People become addicted to these drugs because, over time, the brain adjusts to these altered chemical levels and becomes dependent on them, resulting in significant physiological and psychological symptoms called withdrawal when the substances are removed.
Classical psychedelics — LSD and psilocybin, as well as new “designer drugs” — are generally chemically similar to the neurotransmitter serotonin, and bind to a specific type of the serotonin receptor called 5-HT2A. In fact, these external molecules bind the receptor more tightly that the neurotransmitters we produce in our bodies. As a result, the drugs disrupt the normal signaling pathways in which these receptors play a role in mediating proper communication between neurons. Masquerading as serotonin, LSD or psilocybin bind tightly to the 5-HT2A receptor in synapses primarily in the prefrontal and visual cortices, and cause nearby cell populations to speed up and slow down their usually regular firing. Like an out-of-tune violin playing in the front row, this disruption throws off the entire concerto of brain activity.
Early research conducted from the 1950 to 1970s suggested that LSD may have therapeutic effects similar to antidepressants and anti-anxiety medication. Today a myriad of studies are corroborating the evidence for the potential of LSD in treating certain mental health problems.
In light of such results, medical professionals in countries such as Switzerland now have limited use of LSD-assisted psychotherapy for benefits in patients with drug and alcohol addiction, depression, and those with terminal illnesses. Patients generally undergo psychotherapy for a couple of months, and then receive two doses of LSD, four to six weeks apart — the ideal number of doses and duration are still being tested.
Patients with terminal or life-threatening illnesses tend to suffer from profound cases of anxiety, and LSD has shown promising results, like decreased anxiety levels, and an increase in the quality of life with no adverse reactions to the drug. Since 2014, the Swiss Office for Public Health has given permission for 10 patients who suffer from anxiety associated with life-threatening illnesses to receive LSD-assisted psychotherapy. (In the United States, no patients have currently been approved to use LSD for this purpose.)
There have been US-based studies investigating the naturally occurring hallucinogen psilocybin in the treatment of PTSD. Accumulating evidence suggests that psilocybin, like LSD, can also be safely used to accompany therapy in treating end-of-life anxiety in diseases such as cancer by acting like an influx of serotonin in the brain. Various studies are further shaping the possibility that psilocybin can help mitigate treatment-resistant depression, alcohol, and tobacco addiction.
A 2006 study done in Arizona additionally showed that, when psilocybin was given once a week for a month at escalating doses (non-hallucinogenic to hallucinogenic), there was a marked reduction in OCD symptoms that lasted for 24 hours. This is a significant finding because all nine patients were previously not responsive to any treatment. These findings echo pre-ban findings in the 1960s, where a study showed that psilocybin could be effective in treating OCD.
Ketamine isn’t exactly considered a psychedelic; scientists usually classify it as a “dissociative anesthetic.” It’s typically used to put animals (and humans) under during surgery, but it can also produce psychedelic effects, like altered perception and feelings of detachment.
In the 1990s, several preclinical studies found that many antidepressants work by reducing activity of proteins that recognize glutamate, the principle neurotransmitter in mammals’ brains. These findings suggested that ketamine could be a potential antidepressant, because it reduces activity of glutamate-related proteins. Initial findings supported this claim, but most of the human studies were performed with a small number of participants.
However, a 2013 study on 73 people with treatment-resistant major depression furthered the evidence for ketamine as an antidepressant. Half of the individuals were given the placebo midazolam, an anesthetic that has similar effects but is not thought to be an anti-depressant, while the rest received ketamine. The group who were administered one dose of ketamine had significantly reduced depression symptoms after 24 hours, and lingering effects lasted a week.
The fast-acting nature of ketamine could be particularly beneficial for patients suffering from major depression with suicidal ideations. Studies have found that a single ketamine infusion can reduce suicidal thoughts within 24 hours. Most conventional antidepressants can’t reduce mortality risk, because they take a long time to kick in, usually taking two to three weeks to take effect. One reason for this could be because ketamine treatment is usually administered intravenously, which increases the speed at which the drug acts on the brain, while most depression medications are taken orally. Preliminary evidence suggests that depression medication in a similar manner could also fasten their actions on the nervous system.
Ketamine is also being studied as a potential treatment for opioid addiction. Using one type of drug to treat addiction to another drug might seem like a counter-productive idea. But here’s why it might work: withdrawal from any addiction is difficult — withdrawal from heroin, for example, can include nausea, diarrhea, vomiting, depression, and major drug cravings. This is an important distinction because drugs such as heroin are more addictive, which is synonymous with abuse of the drug. However, chemicals like methadone are strictly prescribed to manage the debilitating and painful symptoms of withdrawal. That said, patients can still become dependent on these prescription medications.
Ketamine’s anesthetic properties can help reduce symptoms as people wean off painkillers, and could therefore be useful for managing opioid withdrawal. In a 2002 clinical trial, 70 heroin addicts received one low or high dose of ketamine after 10 hours of psychotherapy. Follow-up studies on each patient over the next two years revealed that a significant amount of them had a higher rate of abstinence, reduced craving, and a positive emotional attitude. Since ketamine does have the potential to become addictive itself, it is integral that studies assess proper dose regimens and take necessary precautions. Still, that risk is less than that of addiction to methadone, one of the main standard medications dispensed daily to addicts in recovery.
Quechuan people in South America gave the term ayahuasca to Banisteriopsis caapi, long-stemmed vines endemic to the Amazon and Orinoco river basins. The ayahuasca brew (water infused with stems of B. caapi and other ingredients) has played a pivotal role in ancient shamanic rituals and rites of passages within indigenous communities in northwestern South America for centuries.
In the western world, there is an increase in the use of ayahuasca, mainly due to its “mystical” and visionary effects, usually, though not always, thought to be caused by its active ingredient DMT. Though the research is somewhat sparse, anecdotal evidence suggest that some find the experience therapeutic. In 2014, a widowed teacher, who drank Ayahuasca with other Brooklynites looking to cleanse, went on to say, “I find ayahuasca to be a purifying psychological journey.”
With the recent renewed interest in psychedelic research, there have been new studies examining the therapeutic potential of ayahuasca. Two studies performed in 2015 and 2016 found that a single dose of ayahuasca can rapidly reduce depressive symptoms in treatment-resistant patients, with remarkable improvement in symptoms seen for up to three weeks. The only adverse effect, seen in 47 percent of the patients, was vomiting.
Back in the 1970s, before the drug was deemed illegal, MDMA (the active ingredient in ecstasy) was used to enhance the effects of psychotherapy, like during couples therapy or spiritual awakening exercises. More recently, there’s been a resurgence of clinical trials on MDMA-assisted psychotherapy. It is perhaps the single best example of the need for relaxed regulations for potentially beneficial uses of psychedelic substances.
Most famously, MDMA has the ability to reduce PTSD-related symptoms. Studies performed in 2012, 2013, and 2018 show that patients with severe and treatment-resistant PTSD who receive three psychotherapy sessions accompanied by three doses of MDMA, and extended psychotherapy thereafter, have significantly reduced negative symptoms, with effects lasting over two months. Results have been so striking that the FDA approved MDMA as a “breakthrough therapy” for PTSD in 2017. Preliminary clinical trials started in 2012, and the final round of trials are currently underway.
Scientists think that MDMA helps PTSD patients feel less afraid when they recall past traumatic events because it triggers release of dopamine, serotonin, and other neurotransmitters associated with positive emotions. In MDMA-assisted psychotherapy, patients are given MDMA and asked to recall past experiences. Instead of the typical rush of fear, the drug helps them feel positive emotions. Over time, positive associations with these memories outweigh the previous traumatic associations. This could have tremendous impact in the group that are affected by PTSD the hardest: soldiers. General Loree Sutton, who was the highest ranking psychiatrist in the US army until 2010, encouraged the use of MDMA as a potential treatment option, saying, “If this is something that could really save lives, we need to run and not walk toward it. We need to follow the data.”
For the purpose of diagnosis, hallucinations were once assessed as simply being ‘present’ or ‘absent.’ Over the last few decades, however, evidence has mounted that hallucinations occur widely in many different ways and intensities, and often outside the bounds of sickness and health.
Sometimes, people without a history of mental illness experience situational hallucinations. People going through a bereavement report hearing or seeing deceased loved ones soon after their passing. People who are sleep deprived can also experience hallucinations. For this reason, hallucinations cannot be considered as an in-variable “all-or-nothing” sign of illness, but rather, exist on a symptomatic continuum between nonclinical individuals and those with certain clinical disorders.
In 2015, psychiatrist John McGrath, director of the Queensland Centre for Mental Health Research, published a study on 31,261 adults across 18 countries and reported that 5.2 percent of participants had experienced a hallucination at least once in their lifetime. The most common overall type was visual hallucinations (3.8 percent), followed by auditory (2.5 percent). Lifetime prevalence estimates were higher for middle- and high-income countries than low-income countries and higher in women than men.
Another study showed that hallucinatory experiences were more common amongst people living in urban areas compared to those living in rural areas. Another study went further, showing that neuroticism, victimization experiences, and below-average IQ are also possible risk factors for the experience of hallucinations among clinical and non-clinical groups.
Various self-report questionnaires have been developed to explore the prevalence and characteristics of hallucinations in both clinical and non-clinical groups. One of the most popular is the Launay-Slade Hallucinations Scale (LSHS), created in 1981 by Gilles Launay and Peter Slade. Over the years, it has been adapted and now includes five main components: sleep-related hallucinations, vivid daydreams, intrusive or vivid thoughts, auditory hallucinations, and visual hallucinations.
Thirty years of studying hallucinations in clinical and non-clinical populations using this scale has revealed a number of differences in how clinical and non-clinical groups experience the same hallucinations, supporting the “continuum hypothesis” of hallucinations. One study, for example, found that non-clinical participants experienced more hallucinations relating to sleep like “I’m half asleep, not quite asleep nor fully awake, and I hear people calling me by my name,” whereas clinical participants experienced more auditory verbal hallucinations like “I hear a voice that asks me to do something or tells me something about someone.”
Numerous studies suggest that similar mental processes are behind hallucinations in psychotic and non-patient populations. Auditory hallucinations, for example, likely happen when inner speech is mistaken for that of another person.
In one study, schizophrenia patients with auditory verbal hallucinations were asked to read single adjectives aloud under different conditions: reading aloud by themselves, reading aloud with acoustic distortion of their own voice playing back into headphones they were wearing, someone else’s voice played back, or someone else’s voice with distortion played back. They were then asked to identify the source of the speech as ‘self’ or ‘other.’ Compared to a non-psychiatric control group, the schizophrenia patients were particularly prone to mistaking their own distorted voice for someone else’s.
A similar attribution bias has been described in otherwise healthy hallucination-prone participants too. In another study led by Professor Frank Larøi at the University of Liège in 2004, participants were given a reality monitoring task, in which they were asked to identify the source of presented words that had either been previously presented by the experimenter, generated by the subject, or were entirely new. People that were more hallucination-prone made significantly more errors identifying the source of the words.
In an interview with the BBC, neuroscientist Kelly Diederen at the University of Cambridge explains how research using brain-scanning techniques on “healthy hallucinators,” has revealed differences between this group and a control group of individuals who do not experience hallucinations. Individuals who do not experience hallucinations have activity on the left side of the brain, which is more often involved in language production. However in people with auditory hallucinations it’s switched: there’s much more activation on the right, where language formation is limited and engaged more in automatic language production, like reciting lyrics to a song or cursing when you hurt yourself. This increased activity in the brain’s right side may explain why this population finds it difficult to distinguish the source of their own voices. Diederen has also published work to show that brain activation patterns during auditory hallucinations are similar in psychotic and non-psychotic individuals.
One way to explore the biology behind hallucinations is by studying hallucinogenic drugs. While some people naturally experience hallucinations, others induce them chemically. By applying what we know about the mechanisms of chemical hallucinations, we might find clues as to how hallucinations occur in healthy people and those with mental disorders.
A lot! There are three major biological models (serotonin, glutamate and dopamine) of how hallucinations happen in humans, based on the major neurotransmitter involved. They seem to involve some similar, overlapping neurological processes that can lead to hallucination as well as other psychotic symptoms. It is likely that the brain areas and extent to which these different pathways are active gives each hallucination its distinct characteristics. Another important point to consider is whether or not we can distinguish hallucinations from the other symptoms that constitute psychosis, such as delusions. It’s unclear whether these symptoms are separate or combined states, resulting from the same or different chemical pathways and cognitive means.
Dopamine seems to be involved in hallucinations related to schizophrenia, and perhaps other psychotic states. Imaging studies in the brains of people with schizophrenia suggest that they have increased dopamine activity in an area called the striatum, which is involved in various things, such as movement initiation, the feeling of reward, and social behaviors. By reducing the level of dopamine, symptoms like hallucinations are reduced. Thus, the dopamine model suggests that hallucinations in schizophrenia result from abnormally high dopamine in the striatum. Some scientists insist that dopamine is the logical explanation for all psychotic states, whether experienced as part of a mental illness or neurodegenerative disease, or as a non-disease related phenomenon in healthy individuals. As such, psychostimulant drugs like amphetamine can induce hallucinations by in-creasing dopamine levels in the brain.
Glutamate is the most abundant neurotransmitter in the brain. It is responsible for increasing the trans-mission of electrical impulses between neurons, and is involved in most brain functions including cognition, memory, and learning. In the 1950s, a new class of anesthetic drugs such as PCP were developed, which could induce hallucinations by blocking one of the receptors that glutamate binds to, and disrupting glutamate signaling in the brain. Further research into the effects of drugs like PCP led to new ideas about what cause not only symptoms like hallucinations (“positive symptoms”) in schizophrenia but other symptoms which are not explained by the dopamine model, like losing the ability to find pleasure in things that were once pleasurable (“negative symptoms”) too. By better understanding how these drugs lead to different, specific behavioral effects, we can hopefully design smarter treatments.
Oliver Sacks described his own personal experience of taking LSD, and recalled a particularly vivid hallucination of a huge pear-shaped blob of pure indigo, appearing on the wall and then disappearing. Unlike the dopamine and glutamate models, the pharmacological mechanisms behind these hallucinations are less clear, but there is evidence to suggest that it involves the overstimulation of serotonin receptors (5HT2AR) on cortical neurons. Overstimulation of this system is thought to disrupt the way we process information, resulting in neurological “glitches” that create aberrant perceptions. However, applying this knowledge to the role of the serotonin receptor in schizophrenia is problematic, because psychedelic-induced hallucinations differ from those in schizophrenia: visual hallucinations are typical of psychedelics, but auditory hallucinations more rare. Having said that, second-generation antipsychotics do target the serotonin receptor, suggesting that there are some similar underlying mechanisms.
Ancient Egyptian, Indian, Greek, and Roman writing describe mental illness as being caused by the wrath of the gods or evil spirits. Hippocrates, a Greek physician who was born in 460 BCE (where the Hippocratic Oath comes from), described physical and mental illness as stemming from an imbalance of what he thought were the body’s essential elements — black bile, yellow bile, phlegm, and blood. In Hippocrates’ writing, mental disorders were classified as Mania, Melancholy, Phrenitis (inflammation of the brain), Insanity, Disobedience, Paranoia, Panic, Epilepsy, and Hysteria. Hippocrates knew these disorders could have different presentations depending on their cause. Mania, for example, was attributed to either excess phlegm or yellow bile — excess phlegm was thought to lead to a quieter mania, while excess yellow bile led to a more frenzied and mischievous mania. Back then, treatment entailed releasing what was considered excess fluid through bloodletting, or by ingesting herbs to induce vomiting or diarrhea.
In the Middle Ages — from the fifth to 15th century — the first mental hospitals and asylums were founded in Baghdad and Cairo, followed later by hospitals in England and Spain. Many were initially privately run, and often religiously affiliated. They were generally described as caring institutions that provided entertainment for the patients (although some have still been described as restraining patients with chains). But mental hospitals didn’t really become common in Europe until the 18th and 19th centuries, when public institutions were opened. The first hospital with psychiatric care in the United States — back when it was actually still a colony of Britain — was the Pennsylvania Hospital, which was founded in 1752.
The growth of cities in the 1800s led to a fear of people with mental illness as a threat to public safety and a created a boom in mental asylums as they were built to separate people with mental illness from the rest of society. As more patients became institutionalized, it also, however, allowed physicians to make close clinical observations, and new diagnostic categories were created. For example, Emil Kraepelin, a German psychiatrist, is credited with popularizing the diagnosis of “dementia praecox,” which would later be called schizophrenia, and “manic depression,” now known as bipolar disorder. The poor generally found themselves in public asylums, while the wealthy were able to attend private asylums with a retreat-like qualities including private parks, greenhouses, and sun parlors.
Wealthy patients with less severe mental health problems such as hysteria, sleep disorders, or alcoholism were able to see doctors instead of being placed in an asylum. One of the commonly used treatments of the 1800s was hypnosis, or putting patients in a trance-like state where they became highly suggestible, and using this to suggest more pleasant thoughts and behaviors. This led to the development of other interventions based on relaxation and suggestion collectively known as “psychotherapy.” The term psychotherapy became used to describe any therapy that involves talking about psychological problems as a means of treating them.
Probably the best-known psychotherapy of the time was detailed by Josef Breuer and Sigmund Freud which they outlined in “the talking cure,” a case study about a patient called Anna O. In it, they had the patient guide the treatment (which was unusual at the time) by talking freely about whatever was on her mind. Although it was unclear how effective the treatment was, the approach caught on and became refined into a form of psychotherapy called psychoanalysis, which explores how unconscious motivations and drives im-pact current functioning. This type of therapy became popular among the upper-middle-class in Vienna and is still used today.
In 1937, over half of all hospital beds were used for psychiatric care, so there became a push to develop new treatments. In the early- to mid-1900s new procedures were developed for patients especially those in psychiatric hospitals. One such development was psychosurgery, most (in)famously the prefrontal lobotomy, in which surgeons severed connections in part of the frontal lobe. Although the practice won a Nobel Prize at the time, it was soon recognized as largely harmful to patients, and less effective than subsequently discovered psychiatric medications.
In the 1950s, the “psychopharmacological revolution” in psychiatry began with the identification of two medications called chlorpromazine (a chemically-synthesized compound that affects dopamine signaling in the brain), and reserpine (a natural substance obtained from the root of a flower that affects norepinephrine, dopamine, and serotonin). These medications were found to be effective in treating psychosis, calming patients without making them unresponsive. The success of these treatments stimulated interest in psychopharmacological research and led to an explosion of new discoveries. There are now a number of broad categories of psychiatric medications available to treat psychiatric conditions
Mental disorders are much more common than previously thought. By age 38, eight out of every 10 people will have met criteria for a mental disorder at some point during their life. And more and more, mental health is being viewed along a continuum, recognizing that there is no single ideal or “normal” state. That being said, there are many instances when treatment can have a significant positive impact in a person’s life.
In the case of altered perceptions (especially psychosis, which generally includes the inability to sense reality and can include hallucinations), mental health professionals can either aim to directly treat the disordered thinking or can treat other aspects of the disorder with the hope that once those aspects are treated, then the disordered thinking will go away. The particular approach depends both on the characteristics of the disorder and of the needs of an individual patient.
Overall, there are three common approaches to treatment: psychiatric medications, psychotherapy, and brain stimulation techniques. Oftentimes a combination of approaches are used for best results. For people experiencing mental disorder symptoms, it’s important to see a mental health professional to get an accurate diagnosis. Then, the clinician will prescribe one or several of these evidence-based treatments.
We’ve covered each approach in detail as a separate entry in this Q&A.
The general categories of common medications for mental health conditions include antidepressants, anti-anxiety medications, stimulants, antipsychotics, and mood stabilizers. Generally in the case of schizophrenia or schizoaffective disorder, the primary treatment of choice is with antipsychotic medications. Antipsychotic medications do not cure these disorders, but can make it so that people don’t experience psychotic symptoms while they are taking the medication and/ or make it so the hallucinations and delusions are less frequent and distressing. There are two general classes of antipsychotic medications that are split into “first generation” or typical antipsychotics (also called neuroleptics) and “second generation” or atypical, antipsychotics.
First-generation antipsychotics were discovered in the 1950s when chlorpromazine was used during surgery to augment anesthesia. In the course of these surgeries, it was serendipitously found that when the patient undergoing surgery had psychosis, that their psychosis seemed to improve as well. Doctors began giving the medication to psychotic patients and found that people who had been completely unresponsive would within hours begin having normal conversations with others. It was hailed as a miracle drug and began being used broadly in psychiatric hospitals around the world. Later studies would find that first-generation antipsychotic medication either eliminates psychotic symptoms or at least reduces them to a tolerable level for about 70 percent of patients.
Common first-generation antipsychotics include chlorpromazine (better known by the brand name Thorazine), haloperidol (Haldol), and fluphenanize (Prolixin). They work by blocking dopamine D2 receptors in the brain. Dopamine is a chemical that is used by the brain in communicating between neurons, and is used in a wide range of functions from movement to motivation to thinking and problem-solving. The problem with typical antipsychotic medication is that they can cause significant motor-related side effects similar to the symptoms of Parkinson’s disease. This led researchers to search for medications without these side-effects. These medications were called second-generation antipsychotics.
Second-generation antipsychotics were developed in the 1960s but didn’t come on to the market until 1990. These drugs generally impact dopamine as well as an-other neurotransmitter -- for example, blocking serotonin 5-HT2A receptors or noradrenaline receptors in addition to dopamine receptors. Overall, these drugs seem to make it so that just enough dopamine receptors are blocked in a part of the brain called the basal ganglia that is involved in motivation and movement, leading to therapeutic effects without causing motor side effects (although these drugs tend to have greater metabolic side effects). Common second-generation antipsychotics include aripiprazole (Abilify), clozapine (Clozaril) risperidone (Risperdal), quetiapine (Sero-quel), and olanzapine (Zyprexa).
Since these approaches treat symptoms, but do not cure the illness, over 40 percent of people end up needing to be re-hospitalized. There is a push to find longer-acting treatments and to help people to stick to taking their medication regularly long-term. Psychotherapy approaches have shown some promise in this regard.
In addition to antipsychotics, there is evidence that antidepressants can be an effective treatment for depression with psychotic symptoms. Many antidepressants are SSRIs (Serotonin Selective Reuptake Inhibitors) which block the removal of serotonin in the synapse, leading to more serotonin that is available to affect neuronal signaling. Mood stabilizers can also be an effective treatment for the psychosis that sometimes accompanies bipolar disorder. For example, lithium, is a common mood stabilizer used in the treatment of bipolar disorder, has been found to be similarly effective for bipolar disorder with and without psychosis. It both decreases excitatory neurotransmitters such as dopamine and glutamate, and increases inhibitory neurotransmitters such as GABA.
Many of these medications are non-specific, meaning that they affect more than one chemical in the brain, in more than one area of the brain. This may also be why some of these medications can be used to treat more than one disorder and also why they have side effects. Pharmacological treatment should not be “one-size-fits-all,” and sometimes it’s necessary to switch medications, with the guidance of a psychiatrist, until an effective medication regimen with minimal side effects can be found.
Yes! There are a number of effective psychotherapy approaches for disorders with alterations in perception or cognition. In fact, it might be said that many if not all disorders include distorted thinking in some way. For example, in depression (even without psychosis), many people tend to have negative biases where they focus on sad or angry facial expressions instead of happier expressions, and have better memory for sad words over happier words. In fact, a major theory about depression is that it is maintained by overly negative interpretations of events, and that by carefully examining the evidence for or against these interpretations through a form of therapy called Cognitive Behavior Therapy (CBT), a person can develop skills to notice and interrupt these negative biases.
Other alterations in perception can also be helped with psychotherapy approaches. For example, people with PTSD can have flashbacks where they feel like they are re-experiencing a traumatic event and may even lose touch with where they are in the moment. Two common psychotherapy approaches for PTSD are called Prolonged Exposure (PE) Therapy and Cognitive Processing Therapy (CPT). PE involves recounting the traumatic memory multiple times and processing the experience with a therapist, as well as confronting trauma-related stimuli that are safe, but that the patient is avoiding (e.g. avoiding all public transportation if a traumatic event happened on public transportation). In CPT, the patient and therapist explore why the trauma occurred and how the trauma has impacted the patients’ beliefs. These therapies may work by re-activating fear memories in such a way that they feel less overwhelming, leading to increases in regulatory regions of the brain such as the prefrontal cortex that are involved in planning and problem-solving and decreasing activity in areas that react to our environment, such as the amygdala. A 2015 study found that 49-70% of military vets going through these gold-standard psychotherapy approaches had clinically mean-ingful improvement in their symptoms, but 60-72% still met criteria for having PTSD after treatment ended, so there is still a need to improve our treatment approaches.
The alterations in perception that can result from sleep deprivation can be helped by another form of therapy called Cognitive Behavior Therapy for Insomnia (CBT-I). CBT-I, like other forms of CBT, aids patients in identifying unhelpful thoughts about sleep and working on developing alternative interpretations. CBT-I also includes other techniques such as teaching good sleep behaviors (e.g. not looking at a phone or tv while in bed, having a bedtime routine, etc.) and limiting the amount of time in bed.
The therapies listed above all fall under the umbrella of “CBT,” but have different names depending on the specific techniques that are used. All CBT therapies have some things in common though, in that they look at the relationships between thoughts, behaviors, and emotions, and also are very active treatments (tracking thoughts and emotions, setting goals, etc.). Overall, many CBTs can be helpful either alone or in combination with medications for treating disordered thinking in its various manifestations.
Other treatments are used when medications and psychotherapy have not led to adequate results. These therapies generally fall under the category of brain stimulation therapies, because they use electricity or magnets to affect signaling of the brain. They are most commonly used in severe depression, but may also be used to treat bipolar disorder and schizophrenia. The brain uses both chemicals and electrical signals to communicate, so by influencing the electrical signaling of the brain, specially trained clinicians can enhance the functioning of particular brain regions or inhibit the functioning of other regions.
One brain stimulation is Electroconvulsive therapy (ECT). ECT has been around since the 1930s, and is often negatively portrayed in popular culture. This may be because it was initially more dangerous than it is today, and was historically used in abusive ways. The treatment is now much improved, and when used ethically, can lead to much-needed relief of symptoms for patients.
ECT is conducted by a psychiatrist and anesthesiologist. During ECT, the patient is first sedated with general anesthesia and a muscle relaxant. Then electrodes are placed either on both temples, or on one temple and the side of the forehead. (Generally, the temple and forehead combination is associated with fewer side-effects while achieving similar results). ECT creates a controlled seizure that lasts for about a minute across the brain. Then the patient is woken up about five minutes later. The process is often repeated about three times a week for several weeks, for a total of six to 12 treatments. Side effects may include headaches and some memory loss. While there are a number of hypotheses as to why ECT works, the bottom line is that scientists don’t yet know the mechanisms of action.
Transcranial Magnetic Stimulation, on the other hand, is a targeted treatment that works by placing a magnet over a part of the brain. Generally, it targets the region on the upper forehead that is involved in problem-solving and mood regulation, called the dorsolateral prefrontal cortex (DLPFC). Short electromagnetic pulses are then applied to the skull to stimulate nerve cells in the DLPFC. The session lasts about half an hour, and does not require anesthesia. Depending on results, patients may have a single treatment or a number of sessions. Common side-effects include dizziness and headaches. It’s important to be supervised by a medical professional to avoid the risk of accidentally inducing a seizure.
Scientists are still determining how TMS works for treatment. Repeated TMS is thought to impact the brain in multiple ways, from subatomic changes in neuron structure to changing synaptic plasticity. One study found that TMS decreases activity in a brain net-work referred to as the Default Mode Network (DMN), which is involved in mind-wandering and seems to be over-active in depression and other disorders (hallucinogenic drugs like ayahusca have a similar quieting effect on the DMN). This may explain why TMS is effective at reducing hallucinations in schizophrenia, particularly auditory ones.
As late as the 18th century, hallucinations in their various forms were considered independent diseases or syndromes. In 1821, Alexis Vincent Charles Berbiguier de Terre-Neuve du Thym, a French author and demonologist published a three-volume book entitled “The Imps; or, All the demons are not from the other world,” in which he described frequent torments by small mischievous devils. In 1816, Berbiguier became a patient of the French physician Philippe Pinel, a pioneer of psychotherapy.
In his book, Berbiguier recounted his meeting with Pinel, saying “After listening with great attention, this doctor told me that he knew of the type of disease affecting me, and that he had successfully treated people with it.” However, Berbiguier continued feeling tormented by the imps and accused Pinel of making false claims.
Berbiguier wasn’t wrong. The concept that hallucinations were not a disease per se but a “symptom” of different diseases developed in the 19th century after what one leading psychiatrist called a “long and barren” debate. Although hallucinations are now regarded as symptomatic of a number of disorders, they are not themselves necessarily harmful. As a symptom, they can indicate that the brain is not functioning properly, which may lead to other harmful symptoms, but hallucinations are not categorically good or bad.
The consequences of experiencing hallucinations vary from one experience to the next. For example, “low-level” auditory hallucinations experienced in the general population are usually mundane and cause little distress, while auditory hallucinations experienced by some schizophrenia patients during episodes of psychosis can be violent and extremely distressing, perhaps even leading to dangerous behavior that could harm the individual or others. (That said, violent behavior is rare, and the idea of people with schizophrenia being dangerous is largely a myth perpetuated by ill-informed media.)
Some people, both those with and without mental illness or a neurological disorder, actually enjoy their hallucinations. People who experience visual hallucinations following a bereavement, for example, can find them comforting. In one study, 86 percent of widowers described their hallucinations as good or helpful. Individuals with Charles Bonnet syndrome, a common condition among people who have lost their sight which causes them to see things that are not there, report mixed experiences. According to the late Oliver Sacks, seeing faces — which are sometimes deformed — is the single most common hallucination, an experience many people with the condition are averse to. The second most common hallucination is cartoons, which some patients do not mind.
Furthermore, many people deliberately induce hallucinations. In recent years, people in the west have start-ed taking part in ayahuasca ceremonies, a traditional practice among indigenous groups of the Amazon, as a way to experience a “spiritual awakening” through experiencing visions. The use of hallucinogenic drugs have also been used as inspiration and a way to reach new levels of creativity. The book Riding So High, The Beatles and Drugs by Joe Goodden, describes how LSD greatly influenced The Beatles’ music between 1965 and 1968, leading to the creation of the 1966 and 1967 albums, Revolver and Sgt Pepper’s Lonely Hearts Club Band.
Hallucinations force us to question the very nature of reality. Unlike imagination, hallucinations don’t seem to be of our own creation, are often outside of our control, seem to come from the outside world, and mimic perception. One might argue that it is easy to define reality in a way that rules out hallucinations by considering “normal” to be what appears to a large group of people. However, hallucinations can be experienced by large groups of individuals. Take Koro for example, a culture-bound syndrome in South East Asia that is characterized by a panic anxiety state that one’s penis is shrinking or retracting into the abdomen, or even disappearing. Just because lots of people perceive something does not make it real. So what does?
We can think of reality as our constructed perception of the world, or the ground truth about how the world actually is. The only problem is that the definition of reality lies at the center of fundamental philosophical, spiritual, psychological, and scientific questions which we do not have all the answers to.
Nonetheless, two broad ideas about what reality is seem to dominate. The first is that reality is everything that would remain even if we were not here to perceive it. But, we do exist and many things in the world only exist because of us. The other view is that reality is the most fundamental thing in the universe — matter, or, better, the time and space that matter occupies, which is really just mathematics, a universal concept that exists in our minds. Thus, it is impossible to consider reality without consciousness, and consciousness is different for all of us. Clearly, defining reality is not easy, but a good place to start is understanding the processes involved in how the brain perceives it.
The brain, hidden inside our skull, cannot see, hear, smell, taste, or touch. That is the job of our sense organs, which contain receptors that relay information via electrical impulses, through sensory neurons to the brain. These sensory organs allow us to detect the physical world. It is then up to our brain to interpret the information, allowing us to perceive reality.
The question is: how does the brain create a reality from this information, which is only indirectly related to the physical world? An old answer is that the brain behaves as a sophisticated prediction machine. It has evolved to combine the signals that it receives from our sensory organs with prior expectations about the world, which are deeply engrained into our neuronal circuitry, to make an informed “best guess” about reality — the state of things as they actually exist. Numerous illusion tests, designed to challenge our perception, support this idea. In recent years, different approaches, based on the same idea have emerged including; predictive coding, the Bayesian brain and the free-energy principle. In a recent TED Talk, Anil Seth, a British professor of Cognitive and Computational Neuroscience at the University of Sussex, argues that our whole reality is a hallucination, only one we can agree on. The hallucinations we ascribe to drug taking, mental illness, and neurological disorders are just uncontrolled hallucinations as a result of misfiring mechanisms, the cause of which boil down to an imbalance of neurotransmitters in our brain. In other words, the perceptual predictions made by the brain in these conditions may be too strong or not strong enough, causing sensory information to be distorted.
There has been a steady shift in how hallucinations are being used for the diagnosis of mental illness and other brain disorders. No longer are they considered to be an exclusively medical phenomenon. Nonetheless, hallucinations still carry a stigma in the general public, and therefore remain largely unreported.
For some people, reporting their hallucinations is simply unnecessary, because they consider them a normal part of their life that do not warrant seeking help. New research suggests that the mental health implications of experiencing hallucinations depend on the interpretation of the experience by the person experiencing them. Some of this interpretation is influenced by the way in which hallucinations are viewed culturally and therefore changing the culture around the experience of hallucinations may have an impact on the level of distress they induce. An important clinical consideration is how in the absence of stigma — shifting the focus from having or not having hallucinations to understanding their nature — may provide insight into what they mean to the person, something that could be incorporated into treatment.
By focusing on their true chemical nature, rather than simply painting them as good or bad, hallucinations can help us to better understand how the brain works normally, what goes wrong in disease, and in turn help move the field of psychedelic medicine forward.
The magnitude of people suffering from mental illnesses within the US is staggering. Approximately 40 million adults have anxiety disorders, 16 million have had at least one major depressive episode, and half have experienced one or more traumatic event in their lives. In 2016 the estimated number of deaths from drug overdoses was 64,070, or 176 per day. These numbers characterize an epidemic of mental health issues, which has not been mitigated by pharmaceutical companies designing complex drugs that have high-dependency and vast adverse effects.
Critical evaluation and study of psychedelics are opening a door to their potential use as therapeutic tools in mental illnesses. As regulations change, and we continue to learn more, clinically validating studies on psychedelics could reshape mental health worldwide.