Tackling the Intractable

Depression is one of the most common and debilitating illnesses worldwide, especially because many sufferers do not respond adequately to any of the currently available treatment options. Picture/Credit: SanderStock/iStock.com

Depression is one of the most common and debilitating illnesses worldwide, especially because many sufferers do not respond adequately to any of the currently available treatment options. Picture/Credit: SanderStock/iStock.com

 

The scourge of depression affects more than 300 million people worldwide, and is the leading global cause of disability. The Nobel Prize-winning research of Arvid Carlsson, Paul Greengard and Eric Kandel among others, paved the way for effective drugs to treat the condition.

How do nerve cells communicate with each other? This was the question that fascinated Paul Greengard and which led him to unravel the biochemical basis for how dopamine acts as a neurotransmitter between nerve cells. His scientific discoveries provided part of the underlying scientific rationale for drugs such as Prozac that act to increase the levels of serotonin, another neurotransmitter whose levels are implicated in depression. Indeed, several so-called selective serotonin reuptake inhibitors (SSRIs) have been developed for the treatment of depression and other disorders, and they are the most commonly prescribed anti-depressants in many countries.

However, even though these compounds provide relief to many, a substantial proportion of individuals with depression do not respond adequately either to these drugs or to cognitive behavioural therapy, the other common first-line treatment for depression.  In fact, about one third of people with severe depression do not initially respond adequately to any currently available therapy. Recently revived research into the medicinal potential of psychedelic drugs, which include LSD and psilocybin from mushrooms, indicates that such substances, when combined with appropriate psychiatric care, may be an effective tool in combatting depressive disorders. The stage is now set for the largest ever clinical trial examining the effectiveness of a psychedelic substance to treat depression.

Although psychedelic drugs may revolutionise the treatment of depression, at a molecular level, their mode of action is very similar to that of traditional SSRIs: they decrease the amount of serotonin that is “resorbed” by the signalling neuron and thus increase the amount of the neurotransmitter that can be taken up by the neuron which is receiving the signal. The key difference is that psychedelics primarily engage different serotonin receptors, which means that different regions of the brain are affected leading to very different physiological effects. Thus, while traditional SSRIs act to reduce stress, anxiety and aggression and to promote increased resilience and emotional blunting, the goal of treatment with psychedelics is rather to dissolve rigid thinking and provide environmental sensitivity and emotional release. The proponents of psychedelics thus claim that the cumulative effect is to increase well-being, while more traditional medications seek to rather simply decrease the symptoms of depression.

The potential of psychedelics to tackle depression head-on and “wipe the slate clean” instead of simply addressing the symptoms almost sounds too good to be true. Psychedelic drugs are strictly prohibited in most countries around the world. In the UK, for example, both LSD and psilocybin are classified as Class A drugs (those whose consumption is deemed most dangerous). With good reason: in particular, LSD abuse is linked with a range of adverse consequences, including panic attacks, psychosis and perceptual disorders. Many users apply Paracelsus’ maxim: “The dose makes the poison.” The regular ingestion of LSD at amounts that are not sufficient to elicit full-blown hallucinations, but which users claim improves focus and creativity, referred to as micro-dosing, has attracted a huge amount of attention in recent times, in large part due to anecdotal evidence that the practice is rife in Silicon Valley. Micro-dosing with psilocybin is also increasing in popularity. The use of psilocybin, found in “magic mushrooms”, was an element of some pre-historic cultures, and, as with other psychedelics, its use both recreational and medicinal was popular in the 1960s. Prohibitive anti-drug legislation across the globe meant that in subsequent decades research into the drug was severely curtailed. However, the last 20 years have witnessed a gradual renaissance of psilocybin research.

 

Psilocybin, a psychedelic substance found in “magic mushrooms”, has shown promise in tackling treatment-resistant depression and in alleviating the anxiety and depressive symptoms of cancer patients. Picture/Credit: Misha Kaminsky/iStock.com

Psilocybin, a psychedelic substance found in “magic mushrooms”, has shown promise in tackling depression and in alleviating anxiety. Picture/Credit: Misha Kaminsky/iStock.com

 

While regular small doses appear to be one potential approach, most recent clinical studies that have tested the effects of psilocybin for depression in a controlled set-up have adopted a strategy in which a single higher dose of the substance or several such doses are administered over a short period of time. This approach is in sharp contrast to the one taken for classical anti-depressants, which are consumed daily. The single high dose strategy has yielded promising results for patients with treatment-resistant depression and also for those suffering from the anxiety and depression often experienced by individuals with cancer. The majority of patients treated with psilocybin in this way exhibited an improvement in the symptoms of depression for up to six months. However, even though these recent studies have shown positive results, there remain a number of significant caveats: firstly, one of the most recent trials was open-label, meaning that the participants knew in advance that they would be receiving a psychedelic drug; secondly, most of the studies to date have been small with only 50 subjects or less; finally, as in most other trials of this kind, the reporting measures are very subjective in nature and rely upon observation by health care professionals, friends or self-reporting by the patients themselves.

It is thus still too early to draw any definitive conclusions regarding the efficacy of psilocybin in alleviating the symptoms of depression. This might be about to change, however: the British start-up company Compass Pathways is close to sealing final approval to carry out what would be the largest clinical trial to date looking at the efficacy of psilocybin in treating depression. As well as incorporating far more subjects than in previous trials (approximately 400) the scientists involved also aim to use more objective digital tracking methods to monitor the effects of psilocybin. In common with previous smaller-scale studies, careful psychological support and monitoring will be crucial in future trials. Research has shown that simply administering psychedelic drugs without providing a proper supportive environment, including counselling, greatly reduces the efficacy of psychedelics against depression and may even be counter-productive.

Even though the first clinical data suggest promising effects of psychedelic drugs in the treatment of depression, several questions remain open: it is unclear how representative the study populations have been, as there may have been a bias toward recruiting those who are more favourably disposed to using psychedelics, and positive prior experiences with such substances may affect treatment outcome. Furthermore, it has yet to be determined at which point substances should be introduced as therapy – as a front-line therapy before depressive symptoms become too ingrained and before long-term therapy with classical anti-depressants, or rather as a treatment of last resort when all else fails.

Neysan Donnelly

About Neysan Donnelly

Neysan Donnelly is a science writer and editor based in southern Germany. He completed his doctoral research at the Max Planck Institute of Biochemistry in Martinsried near Munich.

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