Clinical depression is the most common psychiatric illness in the world, affecting more than 300 million people globally. Antidepressants are currently the most frequently prescribed drug in the Western world; between 2000 and 2014 prescriptions given for antidepressants doubled. However, this huge increase in antidepressant prescription rates has not translated into the expected improvement in public health. So why are these drugs failing?

The most commonly prescribed antidepressants are selective serotonin reuptake inhibitors (SSRIs), which work by fixing a chemical imbalance caused by a lack of serotonin in the brain. Other, less common, antidepressants include serotonin and norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), monoamine oxidase inhibitors (MAOIs). First-line antidepressants are ineffective in about 30% of patients and side effects such as libido loss and weight gain occur frequently in patients who use them. Antidepressants typically only begin to take effect about a month or two after starting treatment. The numerous downsides of conventional depression treatment indicate that treatment needs to evolve past the mainstay regiment of modern psychiatry.

A new wave of antidepressants is beginning to take shape. The application of psychedelic drugs, such as ketamine, LSD, and psilocybin, in the treatment of depression, is experiencing a rebirth in the form of psychedelic-assisted psychotherapy. The medicinal use of psychedelics dates back millennia to the rituals of indigenous tribes. Their effects are described as ‘mind-altering’ or ‘mind-enhancing’, and their use became strongly associated with the ‘hippie’ counterculture of the 1960s, fuelled by psychedelic pop and flower-power.

Research into psychedelics as a potential antidepressant had begun in the 1950s, and was showing promising results. However, this research was promptly halted when psychedelics were made illegal in 1966, a decision prompted by misinformation and irrational political fear because of the popularity of their use recreationally. To this day, the psychedelics psilocybin and LSD are still classed as Schedule I drugs, meaning no currently accepted medical use, but many believe they are undeserving of this designation.

Psilocybin, a naturally occurring drug produced by psilocybe mushrooms (‘magic mushrooms’), has been shown to be effective in patients with depression, especially in treatment-resistant patients. Similar to SSRIs, it increases serotonin levels in the brain. Part of its appeal lies in its very low-risk profile, with largely no side effects and little to no risk for addiction. The FDA recently approved a phase IIB clinical trial to test psilocybin therapy in patients with treatment-resistant depression. LSD which works in a similar fashion to psilocybin, and is the most potent of all psychedelics, has also shown promise as a potential antidepressant.

Ketamine was first discovered in 1962 and has historically been used as surgical anaesthesia, mostly in animals. Ketamine’s emergence as a ‘club drug’, often referred to colloquially as ‘special K’ began in the early 90s, and it is popular for the dissociative, auditory and visual effects it can produce. Ketamine is an antagonist at the NMDA receptor meaning it can boost levels of the neurotransmitter glutamate by blocking its docking port.

In a first of kind study in 2000, Ketamine was shown to be extremely effective at quickly alleviating depression in treatment-resistant patients. Rapid onset is where the appeal of ketamine lies; its effects take place in a matter of hours, as opposed to the weeks that traditional antidepressants require. However, its speed also works to its detriment; its effects are extremely short-lived. Attempts to prolong its antidepressant qualities have yielded modest results at best. Should it be approved for treating depression, patients will be required to frequently top up their dose, opening the door to tolerance, addiction and potentially abuse. Additionally, regular use of ketamine can lead to severe and permanent damage to bladder function.

Times are changing for ketamine; the FDA recently voted in favour of recommending a compound known as esketamine for the treatment of depression. This is a major step in the right direction towards the de-stigmatisation of the drug. If approved, esketamine, which is an isomer of the ketamine compound, will be the first novel antidepressant to join the market in 50 years. But things aren’t changing quickly enough for some people. Independent, unlicensed ‘ketamine clinics’ have begun to pop up all over the US, in which ketamine is infused into patients via an IV. Lack of regulation could prove extremely dangerous, and these clinics take advantage of people who see the drug as a last resort when conventional pharmaceuticals do not work for them.

A major limitation of studies investigating the antidepressant qualities of psychedelics are the inability to conduct blind studies; owing to the profound perceptual effects of these drugs, a control group is simply impossible to conduct. Additionally, a significant roadblock to the implementation of psychedelics as a viable treatment strategy for depression is the means by which they would be administered; they will require the patient to receive the drug in a healthcare provider’s office, as opposed to at home, due to their mind-altering nature. Hallucinogenic drugs are not without risk either; bad trips and flashbacks are potential repercussions of their use.

More robust and long-term studies are required to substantiate the claims as well as to ensure that these drugs can be safe in the long-term. There are many ethical, regulatory and political hoops that these drugs must jump through in order to be deemed safe for the general public. An increase in depression rates and a rise in the incidence of suicide signal that better treatment methods are required. Regulatory bodies have begun to soften their stance on the psychedelic drugs, and the potentially ground-breaking research has begun to pick up once again. Conservative and out-dated views should no longer hinder the potentially life-changing relief these drugs could offer the millions of people worldwide suffering from depression. The future for antidepressants looks promising, and trippy.

By Grace Browne – Science Writer

Featured image is credited to Brian D’Cruz Hypno Plus at