Psychedelics and Hallucinogens in Psychiatry – Mechanisms of Action and Clinical Application

HISTORICAL AND CONTEMPORARY RESEARCH

LSD was first synthesized by Sandoz in 1938 and by 1943 was shown to have psychoactive properties. By the mid-1960s there were >1000 clinical papers on psychedelic drug therapy with >40,000 patients. [Nichols 2016]

Many people remember vaguely that LSD and other psychedelic drugs were once used experimentally in psychiatry, but few realize how much and how long they were used. This was not a quickly rejected and forgotten fad. Between 1950 and the mid-1960s there were more than a thousand clinical papers discussing 40,000 patients, several dozen books, and six international conferences on psychedelic drug therapy. It aroused the interest of many psychiatrists who were in no sense cultural rebels or especially radical in their attitudes. [Greenspoon L & Bakalar J., 1979]

However, in the 1960s and 1970s, political parties in the USA blamed anti-war attitudes and the countercultural revolution as a consequence of drug use.

Use of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD) and marijuana by so-called hippies who demonstrated against the Vietnam War during the 1960s created great consternation among authorities and legislative bodies, both at the federal and state levels. Antiwar attitudes and rejection of conventional social norms by adolescents and college students were often perceived by the mainstream culture to be a consequence of drug use; hence, these substances were often believed to be “perverting” the minds of our youth.

Furthermore, the outspoken Harvard University professor and firebrand Timothy Leary encouraged young people to “turn on, tune in, and drop out,” essentially coaching them to take drugs, discover their true selves, and abandon convention. Such messages did not play well with the mainstream culture, all while the mass media fanned the flames of public hysteria with greatly exaggerated reports of drug-induced insanity, chromosomal damage, attempts to fly, and so forth. [Nichols D , 2016]

• Therefore, the 1970 the Controlled Substances Act was passed, which classified LSD and other psychedelics as Schedule 1 drugs thus effectively restricting all medical research into these drugs.
• Furthermore, in 1971 the UN Convention on Psychotropic Substances placed global restrictions on psychedelic drugs across 183 countries.

These laws effectively prohibited legitimate experimental research into whether these psychoactive compounds may have potential therapeutic effects. It wasn’t until the mid-1990’s that more research was performed with some experimental data produced on psilocybin and DMT. [Strassman et al. 1994]

However, it would take until 2014 for the first modern human trial to investigate LSD-assisted psychotherapy. [Gasser et al. 2014]

As of 2006, the US Religious Freedom Restoration Act now permits certain psychedelic concoctions to be used in various religious practices, including mescaline.

PSILOCYBIN

The prodrug psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine) is found in several types of mushrooms and, when ingested, is metabolised to the serotonergic receptor agonist psilocin.

Psilocybin (4-phosphoryloxy-N, N-dimethyltryptamine) is most accurately characterized as a prodrug. It is dephosphorylated by hepatic first-pass metabolism into the 5-HT2A, 1A and 2C receptor agonist psilocin (Presti & Nichols, 2004), with subjective effects lasting between 4 and 6 hours.

According to the RElaxed Beliefs Under pSychedelics (REBUS) model, psychedelics appear to relax the weighting of internal models, particularly at a high hierarchical level in mind and brain facilitating the occurrence of insight and perspective change.

Proof-of-principle studies in healthy individuals showed that psilocybin-assisted psychotherapy elicited long-lasting positive changes to behaviour, attitudes, and personality. [Griffiths et al. 2008] Volunteers in these experiments also reported that while under the influence of psilocybin, there were challenging and frightening experiences to overcome; however, these were manageable and resolvable with interpersonal support.

• The Good Friday experiment in 1963 was a landmark trial in the study of psychedelics. This experiment showed that a 30 mg dose of psilocybin induced self-reported feelings of mysticism and enhanced personal meaningfulness and spirituality. [Leary et al. 1963]
• In 1969, Timothy Leary’s Concord Prison Experiment investigated psilocybin-assisted psychotherapy in 32 felons. Although there was no reduction in recidivism, a follow-up revealed major flaws in the researchers’ methodology, including the absence of any follow-up psychosocial support. [Doblin et al. 1998]
• However, in 2014, Hendricks et al. showed that hallucinogen use was significantly associated with a reduced likelihood of recidivism in a longitudinal observational study that investigated the outcome of >25,000 felons with a history of substance abuse. [Hendricks et al. 2014]

Pilot studies have since suggested that when used in conjunction with CBT, psilocybin may be useful for smoking cessation [Garcia-Romeu et al. 2014]; [Johnson et al. 2014] and treating alcoholism. [Bogenschutz et al. 2015]

More recently, research into psilocybin’s efficacy in treatment-resistant depression revealed that 10-25 mg significantly reduced Quick Inventory of Depressive Symptom scores and resulted in the complete remission in 67% of patients as measured using the Beck Depression Inventory. [Carhart-Harris et al. 2016]

In 2021, the results of phase 2, double-blind, randomised, controlled trial involving patients with long-standing, moderate-to-severe major depressive disorder comparing psilocybin with escitalopram over a 6-week period were published. The study was a small study with a total of 59 patients. The study showed:

On the basis of the change in depression scores on the QIDS-SR-16 at week 6, this trial did not show a significant difference in antidepressant effects between psilocybin and escitalopram in a selected group of patients. Larger and longer trials are required to compare psilocybin with established antidepressants. [Carhart-Harris et al., 2021]

The long-term brain effects are unknown, but a reliable biomarker of depression and effective response to an antidepressant treatment – the amygdala response to emotional faces – shows an augmented amygdala response to emotional stimuli with psilocybin therapy, particularly to negative stimuli, the effect of which correlates to treatment response. [Carhart-Harris et al. 2017]

A phase 2 double-blind trial for adults with treatment-resistant depression where they received a single dose of psilocybin 25 mg, 10 mg, or 1 mg (control), along with psychological support showed: [Goodwin, 2022]

• Psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects.
• Adverse events occurred in 77% of participants and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups.

Read more on the therapeutic mechanisms of psilocybin in psychiatric disorders.

LYSERGIC ACID DIETHYLAMIDE (LSD)

LSD is a semi-synthetic tryptamine that acts primarily as a serotonergic agonist as well influencing other neurotransmitter systems via dopaminergic and adrenergic receptors. LSD causes increases in cortisol, oxytocin, and adrenaline levels. The predominant effects induced by LSD included visual hallucinations, audiovisual synesthesia, and positively experienced derealization and depersonalization phenomena. [Schmid et al. 2015]

Schmid et al showed that a robust dose of LSD (200 µg) induced pronounced perceptual and audiovisual hallucinations as well as strong empathogenic mood effects more commonly associated with MDMA. LSD was also shown to disrupt prepulse inhibition of the acoustic startle response (neurological phenomenon whereby a weaker stimulus inhibits a subsequent stronger response) similar to what is observed in patients with schizophrenia. [Schmid et al. 2015]

• LSD has repeatedly been shown to be an effective therapy for the treatment of alcoholism, even after a single dose. A meta-analysis of six double-blind placebo-controlled trials showed that alcohol misuse was significantly reduced in 59% of patients after a single LSD dose of <50 µg (p=0.0003). [Krebs and Johansen 2012]
• LSD has also been successfully used in conjunction with psychotherapy to treat anxiety linked to a life-threatening disease such as cancer. [Gasser et al. 2014] A 12-month follow-up of this investigation showed that the effects of LSD were sustainable with 66.7% of patients reporting an increase in quality of life and 77.8% reporting reduced anxiety. [Gasser et al. 2015]

MESCALINE

Mescaline (3,4,5-trimethoxy-β-phenethylamine) was the first naturally occurring psychedelic alkaloid to be isolated in the laboratory. It was isolated from Lophophora williamsii, a small cactus native to northern Mexico and the southwestern United States, in 1896 by German chemist Arthur Heffter. It is also found in the San Pedro cactus (Echinopsis pachanoi), and derived from the amino acid phenylalanine.

The Lophophora williamsii cactus is used by indigenous peoples of North and South America, and in Nahuatl is known as péyotl (aka peyote; Prue, 2013). Religious use of peyote has been estimated to extend back more than 5,700 years.

Although mescaline has a similar effect as LSD or psilocybin, it is generally believed to be 1,000 to 3,000 times less potent. [Cassels and Saez-Briones 2018]

Aldous Huxley wrote of his experiences with the mescaline in The Doors of Perception (Huxley, 1954). Mescaline is a non-selective 5HT2 receptor agonist.

Research is in mainly observational stages; however, studies in native Americans shows the potential of mescaline in alcohol addiction.

N, N- DIMETHYLTRYPTAMINE (DMT)

DMT is known to act on the following receptors:

• 5HT- 2A
• 5HT-2C
• 5HT-1A receptors
• Sigma-1
• Trace amine-associated receptors (TAARs)

The sigma-1 agonist effect confers immunomodulatory and anti-inflammatory properties. [Szabo A., 2015]

DMT has been implicated as a mediator of consciousness and perception, particularly visual perception, via interactions with trace amine-associated receptors (TAAR). [Wallach 2009]

There are as of yet no clinical studies using DMT as a therapeutic agent.

AYAHUASCA

Ayahuasca is a  Quechua term for “vine of the soul” and was first described in the 19th century by botanist Richard Spruce after an expedition to the Amazon.  [[McKenna D.,  2004], [Spruce R,  1873].

Ayahuasca is thought to contain more than 90 different plant species from 38 plant families.

The majority of ayahuasca brews contain:

• DMT (the only major alkaloid present in the leaves of Psychotria viridis)
• β-carboline alkaloids harmine, tetrahydroharmine, and harmaline present alongside additional trace alkaloids in the bark and stems of the vine Banisteriopis caapi. 

Ayahuasca may have potential in addiction and depression; however, more methodologically robust studies are needed.

MDMA

3,4-Methylenedioxymethamphetamine (MDMA) possesses properties of both methamphetamine and mescaline.

While MDMA is not a classic psychedelic we cover MDMA as it is classified under entactogens which influences emotional connectivity.

MDMA is a potent releaser of catecholamine neurotransmitters (i.e., epinephrine, norepinephrine, and dopamine) and serotonin by blocking the reuptake of these neurotransmitters.

Activity at 5HT -1A and 5HT-1B  receptors attenuates feelings of depression and anxiety, reduces the amygdala fear response and increases levels of self-confidence.

Effects at alpha-2 receptors may result in a paradoxical relaxation/sedation effect, which could be beneficial in the context of trauma-induced hypervigilance.

MDMA has been shown to facilitate the release of oxytocin, the hormone associated with early infantile bonding, which may increase levels of empathy and closeness and dampen fear-related amygdala activity, causing a decrease in stress response and social anxiety. [Sessa B et al., 2019]

MDMA increases fear extinction through a mechanism dependent on elevated levels of brain derived neurotropic factor (BDNF) in the amygdala which might account for the observed phenomenon of MDMA psychotherapy allowing for patients’ safe recall of painful emotional memories, that are usually avoided due to the overwhelming negative affect that usually accompanies recall of such events. Increased prosocial feelings , improved tolerance for unpleasant memories and enhanced empathy and self-compassion, can promote a strong therapeutic alliance to effectively process traumatic memories.

More recent clinical MDMA research has largely focused on treatment-resistant posttraumatic stress disorder (PTSD), where MDMA-assisted psychotherapy has shown efficacy at doses of 125 – 187.5 mg. [Romeu et al. 2016]

An RCT (Phase 3) comparing MDMA vs Placebo in severe PTSD showed that three doses of MDMA given in conjunction with manualised therapy over the course of 18 weeks resulted in a significant and robust attenuation of PTSD symptoms and functional impairment as assessed using the CAPS-5 and SDS. MDMA also significantly mitigated depressive symptoms and did not increase the occurrence of suicidality during the study. [Mitchell et al., 2021]

FDA has granted breakthrough therapy designation for MDMA-assisted psychotherapy for PTSD.

In Australia, from 1 July 2023, Psilocybin and MDMA can be prescribed by specifically authorised psychiatrists for the treatment of treatment-resistant depression and PTSD, respectively.  However, the TGA acknowledges that patients may be vulnerable during psychedelic-assisted psychotherapy, requiring controls to protect these patients. [TGA]

Other indications for MDMA for which studies are ongoing and being considered are social anxiety in autism, alcohol addiction and mood disorders.

UPDATES

One of the largest placebo-controlled study (n=191) used a ‘self-blinding’ citizen science initiative, where participants were given online instructions on how to incorporate placebo control into their microdosing routine without clinical supervision.

All psychological outcomes improved significantly from baseline to after the 4 weeks long dose period for the microdose group; however, the placebo group also improved and no significant between-groups differences were observed. Acute (emotional state, drug intensity, mood, energy, and creativity) and post-acute (anxiety) scales showed small, but significant microdose vs. placebo differences; however, these results can be explained by participants breaking blind. The findings suggest that the anecdotal benefits of microdosing can be explained by the placebo effect. [Szigeti et al., 2021]

The human brain is characterised by a large number of cortical neurons, especially in the upper part of the cortex, known as the transmodal association cortex pole.

This region also shows the highest concentration of 5-HT2A receptors, which are the primary targets of psychedelics.

A recent study investigated the effects of DMT on the brain using EEG-fMRI. [Timmermann et al, 2023]. 

The results revealed significant dysregulation of brain activity in the upper cortex, along with increased connectivity between this region and the rest of the brain. They reduce the hierarchical differentiation of the unimodal (older limbic regions) and transmodal cortex (evolutionary new part).

This suggests that psychedelics may promote expanded information processing and a style of cognition characterized by hyperassociation.

The study also found changes in brain wave patterns, such as reduced alpha power and increased gamma power and signal diversity, which were associated with increased global functional connectivity in the upper cortex.

These alterations in brain activity may explain the distinct phenomenology of psychedelics.

Additionally, increases in delta power were correlated with increased global connectivity, indicating a significant alteration of consciousness.

The study further suggested that limbic disinhibition, affecting memory and emotion processing, may play a role in the emergence of psychedelic phenomena.

Overall, the findings demonstrate that psychedelics, particularly DMT, dysregulate high-level cortical activity and limbic activity, collapsing the principal gradient of the brain and promoting integration between different regions.

These effects seem to be specific to classic psychedelics and share similarities with brain states observed during meditation, schizophrenia, and infancy.

SAFETY AND ADVERSE REACTIONS

The recent clinical interest in the therapeutic use of serotonergic psychedelics is primarily based on earlier anecdotal evidence [Nichols 2016]; [Romeu et al. 2016] as well as some recently published high-profile articles [Griffiths et al. 2016]; [Sanches et al. 2016]; [Carhart-Harris et al. 2017]; [Johnson et al. 2017] that have shown remarkable efficacy and few adverse events in comparison to other CNS drugs such as opiates and stimulants.

• In comparison to other CNS drugs, psychedelics are not classed as addictive and do not induce dependency, particularly when administered in a controlled setting. [Romeu et al. 2016]; [Nichols 2016]
• Acute adverse reactions can include dysphoria and panic attacks, but these usually only occur at higher dosages. [Studerus et al. 2010]
• In unsupervised and recreational settings, questionable purity, dosage, and quality are more likely to influence acute and long-term drug toxicity.
• Use of high doses of psychedelics can lead to vascular problems because the 5-HT_2A receptor is associated with vascular smooth muscle contraction, platelet aggregation, thrombus formation, and coronary artery spasms.
• Case reports of severe side effects have been reported [Nichols D, 2016]
• Hallucinogen persisting perception disorder (HPPD) is characterised by flashbacks or re-experiences of the perceptual effects induced by a hallucinogen. However, it has also been observed that HPPD is less common when the hallucinogen is provided in a carefully monitored research environment. [Halpern and Pope 2003]

MDMA administration was overall safe in physically and psychiatrically healthy subjects and in a medical setting. However, the risks of MDMA are likely higher in patients with cardiovascular disease and remain to be investigated in patients with psychiatric disorders. [Vizeli P & Liechti M, 2017]

• Extensive animal data has shown reduced levels of serotonin (5-HT), the 5-HT metabolite 5-hydroxyindoleaceticacid (5-HIAA), 5-HT transporter (SERT) and damage and/or loss of serotonergic axon fibres after exposure to MDMA. [Biezonski D & Meyer J, 2011].
• Newer synthetic phenethylamine psychedelics are more potent designer drugs that are addictive and have a significantly more serious toxicity profile, including psychosis, tachycardia, hyperthermia, seizures, and aggressively violent behaviours. [Fratantonio et al. 2015]
• These compounds have strong hallucinogenic properties even at doses as a low as 50 µg due to their significantly higher affinity at the 5-HT2A receptor. [Halberstadt and Geyer 2014]

GUIDELINES FOR SAFETY

Selection, supervision, set and setting form the basis of a carefully constructed safety guideline for psychedelic-assisted psychotherapy. [Johnson et al. 2008]

This guideline aims to provide psychiatric screening criteria that will ensure patient safety as well as the psychiatric applicability of administering psychedelic-assisted psychotherapy:

1. Psychiatric interviews to determine traits and factors that will help predict a patient’s response to psychedelic therapy.
2. To ensure that the patient has a positive prior expectation of psychedelic therapy and is fully engaged and willing in the therapeutic process to experience a positive outcome.
3. The presence of two clinical monitors with medical experience as well as an in-depth knowledge of the altered state of consciousness.
4. A safe and comfortable environment i.e. the physical setting.
5. The individual feels safe and secure in the company of the clinical monitors who are friendly, welcoming, respectful, and compassionate.
6. Signed consent forms and adequately detailed information about the preparation and the procedure.
7. The presence of a physician as a medical precaution.

CONCLUSION

• Despite the controversial history of psychedelic therapy, clinical studies have described the therapeutic benefits of psychedelic experiences in a safe and supportive environment.
• Reclassification of psychedelics as a schedule II drug will enable further clinical research and the possible discovery of novel benefits of psychedelic administration in psychiatric disorders.
• Worldwide, about 100 psychedelic trials are currently active for the treatment of depression and anxiety in the terminally ill, alcohol and drug use disorders, dementia, anorexia and chronic pain.
• The UK, Canada, the United States and Israel are active research hubs, and research is informed by international collaboration. The first psilocybin-assisted psychotherapy trial has been approved in Australia, targeting depressive and anxious symptoms in terminal patients, and is hosted at St Vincent’s Hospital, Melbourne. [Clinical Memorandum, RANZCP]
• In Australia, from 1 July 2023, Psilocybin and MDMA can be prescribed by specifically authorised psychiatrists for the treatment of treatment-resistant depression and PTSD respectively.  However the TGA acknowledges that patients may be vulnerable during psychedelic-assisted psychotherapy, requiring controls to protect these patients. [TGA]
• Further research is required to assess the efficacy, safety and effectiveness of psychedelic therapies to inform future potential use in psychiatric practice.

Learn More: 

Watch Dr Sanil Rege’s interview with Prof David Nutt on psychedelics in psychiatry.

Psychedelic therapy – A beginner’s guide. 

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