Novel rapidly acting drugs to treat depression and other psychiatric disorders: psilocibin and LSD

by J.E - Newcastle University

Psychedelics are believed to exert their effect via serotonin receptors called 5-HT_1A and 5-HT_2A. Common effects reported include alterations of sensory perception changes to a person’s sense of “ego”, an increased awareness of the present - leading to sometimes profound personal insight, and sometimes a mystical experience [1]. Some other symptoms experienced include:

• Vivid imagery
• Visual alterations (such as hallucinations)
• A feeling of disembodiment (being separated from your body)
• Impaired thinking
• Anxiety
• Audio visual synaesthesia
• Changed meanings of perceptions.
• Religious experience.
• Experience of “unity” with nature and the surrounding world.
• Blissful state.

Abnormalities in neuroplasticity contribute to the pathogenesis of mood disorders. Psychedelics are believed to enhance neuroplasticity and modulate neural circuits[2]. By doing this, they offer a novel approach to the treatment of mood disorders.

It appears that a mystical type experience has a key role in the therapeutic outcome in psychedelic therapy [3-6]. Administered in a controlled environment with appropriate support, psychedelics have a favourable safety profile [7].

Psychedelics can produce a wide range of effects depending on:

• The individual
• The individual’s expectations of what will happen
• Settings in which the drug is taken
• Drug dose

There is very limited evidence that psychedelics cause dependence or addiction. Tolerance however develops quickly. There is no known withdrawal syndrome and there is a low potential for abuse-unlike other psychoactive substances [8] [9]. Long term benefits appear to be greater for those whose psilocybin session leads to a mystical type experience [10]. This may include feelings where there is a direct connection with the divine; a sense of timelessness; pure bliss, joy, or gratitude; a sense of holiness or sacredness about the nature of reality, and a sense that the experience cannot be fully or properly described in words.

By the end of the 1960’s many papers described the use of psilocybin and LSD in clinical populations with non-psychotic mental health problems [11]. The recreational use of psychedelics increased as did the unethical and covert(secret) use of these drugs. A decision was made to classify these drugs as Schedule1 drugs. As a result, doctors were no longer permitted to prescribe psychedelics and their use quickly ceased. In the 21^st century interest in these drugs has been renewed due to several promising studies.

PSILOCYBIN (Magic mushrooms)

This drug activates 5 HT_2A receptors. It is a natural substance found in over 100 different types of mushrooms. It has low physiological toxicity and low abuse liability. Psilocybin can be administered along with psychotherapy. Studies of this drug have usually excluded patients with psychosis. There is a moderate risk of elevated blood pressure - so patients with heart problems may be excluded from taking this drug. It can produce a profound state of altered consciousness and there is a risk of overwhelming anxiety, fear, and confusion that may lead to dangerous behaviour in unmonitored settings [10]. As a result, they should not be prescribed for self-monitored use at home. Therapy sessions require supervision in a healthcare environment/hospital and patients receive support and guidance prior to drug administration and after the drug has been administered.

A single dose of psilocybin has been found to be of use in treating depression and anxiety in patients with terminal cancer or another life threatening illness [12-14]. In these studies, many of the patients had an immediate improvement in depression and anxiety and 60-80% had a clinically significant sustained reduction in depression and anxiety at 6 months follow-up.

Psilocybin with psychological support was also studied in a very small study by Carhart-Harris [15] for Difficult-to-Treat Depression Depression was found to be reduced at week 1 and at 3 months post-treatment, with 8 out of 12 patients meeting the threshold for complete remission. Carhart-Harris (2021) also did a study comparing psilocybin and escitalopram and found no significant difference. Large studies on psilocybin are ongoing.

Similar to the situation in depression, Moreno [16] showed that patients with Difficult-to-Treat obsessive-compulsive disorder had a reduction in symptoms following psilocybin use. However, it should be noted that in this study, even very small doses of the drug had an effect -suggesting that the effects seen could perhaps be a placebo effect.

Psilocybin has also been studied for effects in other situations, including helping to stop smoking and reducing alcohol use. Johnson [17] carried out a study on 15 treatment resistant smokers using 2 treatments of psilocybin and cognitive behavioural therapy. At 6 months follow up 80% were abstinent from smoking and at 2.5 years 75% were abstinent from smoking. Bogenschutz [18] showed that 1-2 treatments of psilocybin, along with therapy, was effective in reducing the number of days that drinking alcohol occurred.

A psychiatrist with a schedule 1 licence (glossary) is required to prescribe and administer psilocybin, manage other medications and provide assessment and management of the patient’s mental state. A psychological session is essential to prepare the patient for the likely effects of psychedelics- long forgotten, unknown or emotionally charged material may become apparent. Psilocybin has an onset of action of 30 mins and peaks at 90 mins, subsiding after 4-6 hours. This means that patient can potentially receive the treatment as “day-case patients”.

Changes in mood, confusion, anxiety, agitation, panic, and paranoia are all expected reactions - although usually mild and respond to reassurance. If the symptoms are more significant a “rescue medication” such as lorazepam may be prescribed, and the patient may need to stay in the hospital setting overnight.

LSD (Lysergic Acid Diethylamide)

LSD can cause perceptual distortions and hallucinations. It can enhance self–awareness and can facilitate the recollection and release from emotionally loaded memories[19, 20]. This appealed to psychiatrists as a unique property that could facilitate the psychodynamic process during psychotherapy. This is when the primary focus is to reveal a deeply seated hidden emotion within a patient’s psyche, in an effort to alleviate psychic tension. The client has an increased self–awareness of their inner world and understanding of the influence of the past on present behaviour. In 1970 LSD was widely popularised as a drug of abuse and highly dangerous and it was classified as a Schedule 1 drug. Research was limited and funding restricted. Neuroimaging and brain mapping increased the understanding of the molecular mechanisms of action of psychedelics and has renewed interest and research in humans

Gasser [21] showed that LSD was effective for anxiety associated with terminal illness. Two thirds of cancer patients given LSD had reduced anxiety and reduced fear of death [22, 23]. Lysergic Acid Diethylamide (LSD) has a relatively long duration of action. This is one reason why most of the current research into therapeutic effects of psychedelics is on psilocybin and LSD.

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