Depression: Why microdosing psychedelic drugs could be the cure

Depression, according to one of the world’s leading authorities on the illness, is a “cancer of the self” that’s now at “pandemic” levels, exacerbated by the stresses of modern life.

It’s not hyperbole to call Dr Philip Gold the most knowledgeable scientists on Earth when it comes to depression.

Dr Philip Gold

He has just collated 50 years of groundbreaking research into a new book which he hopes will revolutionise how the world sees the illness.

Gold offers hope, too, for those in the grip of depression. His work points towards new cures which could see the illness “one day defeated”. His book, Breaking Through Depression, is described by scientists as “a masterpiece”.

His CV is intimidating. Since the early 1970s, he’s been a leading light at America’s National Institutes of Health, heading research into mental health and neuroendocrinology – how hormones affect the nervous system. He led a 30-strong team of scientists – including psychiatrists, endocrinologists, molecular biologists, immunologists and neuroanatomists – studying depression’s “biological basis”.

A biological psychiatrist, he’s also a psychoanalytic psychotherapist who spent thousands of hours treating depressed patients. He has been appointed to the Library of Congress Council of Scholars and showered with academic awards.

Despite his world-beating academic pedigree, you couldn’t meet a more charming man. He’s the definition of compassion, a trait essential in the therapy room.

He wants the public to know two important findings. Firstly, new drugs are coming that will improve treatment. “That’s the good news. The bad news is: depression is a much worse disease than we thought.”

Lifespan

Depression, it has been discovered, leads to neurodegeneration – a decline in the nervous system, especially neurons in the brain.

The result? “Cognitive function is markedly impaired.”

However, depression also causes serious physical problems – increasing the risk of heart disease, stroke and diabetes. “Depression has multiple physiological functions that predispose premature systemic illness in depressed patients that reduces lifespans by seven to 10 years,” Gold says. “It’s a major public health problem that’s really under-recognised.”

Depression is “the second greatest cause of disability worldwide, and the greatest cause of disability worldwide in people under 45”. It’s a “lifetime illness”, often starting in childhood. Evidently, depression also destroys “interpersonal relationships, and our capacity to love and to work”.

The key to depression is understanding it’s a “stress-response run awry”. Depression is effectively the body trapped in a permanent state of stress. Partly, that’s down to genetics, but it’s also due to “environmental factors” – in other words, life events. A root cause is often childhood trauma. That doesn’t necessarily mean abuse. Unloving parents can be just as damaging as violent parents.

Divorce, redundancy and grief can all be accelerants. However, depression doesn’t need major triggers. Some of us are just predisposed to it genetically. Gold talks of Nobel Prize winners becoming depressed even as they’re celebrated globally.

Depression can devastate relationships 

One frightening aspect of depression is that its effects on the body create a feedback loop of greater depression. The brain, Gold explains, “gives birth to new neurons that help promote successful stress responses, but in depression the birth rate of new neurons is markedly diminished. That impairs the stress response”.

There are two types of depression: melancholic and atypical. Melancholic involves states of “hyper-arousal, and anxiety directed at the self. The cardinal manifestations are feelings of worthlessness, decreased capacity to experience pleasure, decreased appetite, decreased interest in sex, alterations in sleep, and marked accentuation in the secretion of stress hormones like cortisol and norepinephrine”.

“This represents a stress system that’s stuck in the ‘on position’,” says Gold.

Atypical depression involves decreased activity, increased sleep, increased appetite, detachment from self and others, and feelings of loneliness and emptiness. “This represents a stress system that’s been ‘turned off’.”

Gold adds: “For the first time, we now know that stress is at the bottom of major depression, and it’s the stress system that encodes the clinical and biochemical manifestations of depression.”

When Gold talks about “stress”, he means how the body reacts to unsettling events and “potential dangers or losses”. That could be anything from threats to life to “encounters with other people which cause upset or decrease self-esteem”, ranging from bullying to romantic heartbreak.

Think of the “fight-or-flight” response, caused by hormones like norepinephrine, which the body experiences during extreme events like an assault, or during more common events like rows with partners or colleagues. In depressed patients, that stress experience remains “turned on” – it doesn’t dissipate the way it would in others.

Crisis

Information overload can be a “stressor”. Gold adds: “The internet stresses many people, especially adolescents.” That partly explains the teen mental health crisis. Young people, Gold suggests, suffer enormous social pressure from images of glamorous lives online.

We also live in “an unstable world, with tremendous political divisions. There’s a great deal of poverty. That’s an enormous stress. Poor people are especially prone to depression”.

The “threat of abandonment”, however, is “the most disturbing stress for many”: the fear of “losing an important figure – parent, sibling, spouse or dear friend”. Loneliness, another 21st-century epidemic, is also key.

It sounds like he’s saying depression goes hand-in-hand with how we’ve shaped modern life. “Yes, I agree,” Gold adds.

The link between stress and depression goes right back to the birth of humanity. One of our ancient ancestors’ “most important mechanisms for survival was the capacity to generate anxiety when in danger. There’s elaborate structures in the brain to promote anxiety”. Those same structures trigger when modern humans do tasks as mundane as public speaking.

In some, though, that natural stress response to challenging or threatening events just doesn’t turn off. That lies at the heart of depression. Gold uses the example of someone caught in a forest fire. They must get anxious to survive. “They’re hyper-aroused. They’re not going to stop to sleep or eat or have sex. The capacity for pleasure is diminished to prevent distraction. Their heart rates and blood pressure go up. The inflammatory system is activated in case injuries have to be repaired.”

Depressed people are in the same physiological state as the forest fire survivor. Activation of the inflammatory system sees blood-clotting ability increase. White blood cells and platelet production rise in case we’re wounded, as the body knows highly stressful situations can lead to deadly injury. Inflammation stimulates the body’s immune system. But activation of the inflammatory system also damages organs. So inflammation essentially shortens life. Depressed patients have a stress system that’s switched inflammation on.

Inflammation, therefore, “is among the factors that promote premature coronary disease, diabetes, stroke and osteoporosis in patients with depression”. Gold has researched how depressed patients exhibit “pathological loss of bone” due to inflammation.

Depressed patients should be treated with anti-inflammatory drugs, he says: “The medical consequences of depression shorten life significantly.” Not enough doctors are aware of these risks.

Many GPs are not aware of the role inflammation can play in depression

Peak

Depression is now at a “pandemic” level, Gold says. Humanity is currently living at a crescendo moment with depression reaching a global peak. The rate of depression worldwide, he says, is possibly higher than 20%.

Gold thinks it’s “conceivable” that there’s a “cascade effect” from depression: the higher the number of people depressed, the more society splinters, and the more society splinters the more depression rises. It’s a runaway train, like climate change.

“Depression begets depression,” he says. “If mothers become depressed then their children and spouse may become depressed. There’s some cascading effect.”

Despite the previously unknown horrors of depression that have now been uncovered, Gold says we shouldn’t lose hope.

Until recently 40% of all those treated with antidepressants didn’t respond. “We’re moving beyond that point,” he says. “We’re developing new drugs that are rapid-acting. Instead of taking three weeks to work, they work within hours, and cause less side-effects. That’s reason to be optimistic.”

However, doctor shortages mean there are not enough medics “to diagnose and treat depression. Resources must be made for people to get treatment”.

Genetics

LIKE heart disease, depression is down to a mix of “genetic susceptibility and a predisposing environment”. For heart disease, the predisposing environment is “inactivity, being overweight, and smoking. For depression, the predisposing environment is early loss and stress at critical periods when the stress system is developing”.

That “sets” the way our stress system responds to “multiple stressors throughout life”, meaning some of us can deal with hits to our self-esteem or “the inevitable losses and disappointments in life”, while others can’t.

Although the understanding of what depression does to the body is new and startling, the profound effects on the sense of self are perhaps the most corrosive.

Depression causes intense feelings of “worthlessness. That’s a tremendous assault on the self”. It means we can’t experience pleasure, lose concentration, have decreased cognition, suffer memory loss, and learning ability declines.

“It represents a cancer of the self that causes tremendous suffering”.

Gold says that “most” suicides are due to depression. About 700,000 people annually kill themselves around the world. It’s an “epidemic”.

We must ditch the notion that depression is just hyper-sadness. Someone can experience grief, and be extremely sad yet never lose their sense of self-worth. Depressed patients, however, can be so numbed they “lose the capacity for complex feelings. Depressed patients get trapped in a litany of self-disparagement and hopelessness”. Happy memories become meaningless and there’s “decreased activity of the imagination”.

Gold and other scientists are only starting to understand “the neurobiology of resilience” to depression: why some suffer extreme trauma yet don’t experience the illness. To some extent, says Gold, resilience is down to “the inherited characteristics of the stress system: a stress system where areas aren’t active that ordinarily control anxiety and promote the capacity to experience pleasure”.

He adds: “Some people can experience enormous stressors and losses and not become depressed. Others who have a lot of genetic-loading for depression can experience what might seem puzzlingly minor disappointments or losses that precipitate depression.”

Suffering

CRUCIALLY, though, “depression isn’t a reflection of someone’s capacity to deal with life. It’s not an index of inadequacy. In fact, people who feel this cancer of the self are really able to endure enormous amounts of suffering and loss of hope, yet still survive. That’s impressive. They’re strong”. Those who recover often emerge stronger as they’ve endured such battles, Gold believes.

Studies of identical twins show that “if one has depression the chance of the other having depression is 50%”. That means, says Gold, that depression is down to 50% environmental causes and 50% genetics. “It’s very genetically influenced.”

Genetic predisposition means minor negative life events may cause someone to feel that the distress they’re experiencing is due to their own “inadequacy”, triggering a depressive cycle.

Self-loathing is depression’s “cardinal manifestation”. Stress effects the brain’s prefrontal cortex, “involved in self-assessment, self-esteem and the capacity to feel good about oneself”. In depressed patients, the prefrontal cortex, which also regulates anxiety, “is diminished in size and function by up to 40%”. Yet with effective antidepressants “that can be restored”.

Parents

“This cancer of the self is partially biologically-driven, and it’s driven by the experience of the individual in terms of whether they grew up in a nurturing, supportive environment or one that left them feeling they weren’t good enough.” Parenting “can certainly influence the propensity for depression in later life”.

One “very highly qualified professional” patient who Gold treated received little love from his father as a child. The patient wasn’t athletic, but academically gifted. His father valued sport over education. “The father disparaged him continually.” The patient became workaholic, putting his wife and children second. “It was a way of assuaging the wound of not being valued by his father.” The patient even became depressed when he achieved professional accolades.

“No matter how successful he was, it wasn’t going to take away the feeling that he wasn’t good enough.” The same has happened to Nobel laureates, Gold says. “Awards didn’t take away the feeling that they were only valued for their talents, rather than the person on the inside.”

That’s why psychotherapy – the talking cure – is as important as drugs. Without psychotherapy, “even if [someone] responds to antidepressants, they’ll probably eventually become depressed again. The optimal treatment is both medication, which clears up the biological components, and psychotherapy which addresses the existential components”.

Currently, too many doctors “only provide pharmacological interventions. That’s inadequate”.

Anti-depressants and psychotherapy, though, is an expensive combination. “It takes a lot of effort and resource. We’re nowhere near the capacity we need.”

LSD

THE game changer, though, is psychedelic drugs: psilocybin – the active component in magic mushrooms, similar to LSD – and the club drug ketamine. “They’re profoundly important in treating depression,” Gold says. They can even “ameliorate anorexia, which was previously unresponsive to medication”.

However, in Britain, with psilocybin a Class A drug, it’s difficult for researchers and medics to access it. Effective medical use would require changes to its legal status. These drugs work within hours. A single doses can “give remission for three weeks”. Taken regularly, “they promote sustained responses”. Patients won’t get “high”, though – drugs are administered in “extraordinarily low” doses.

Psilocybin works on the serotonin receptor 2A, which affects mood. Ketamine affects the glutamate system, a major neurotransmitter, and has rapid antidepressant effects. Another new treatment is “transcranial magnetic” stimulation, not to be confused with electroshock therapy which causes patients to convulse and can cause harm.

There’s no pain or distress, Gold explains. Magnetic waves are passed through the prefrontal cortex and have been found to produce antidepressant effects in up to “80% of patients otherwise treatment-resistant to most other antidepressants”.

As conventional antidepressants can take weeks to work, they do little to reduce acute suicide risk. “You can give ketamine to suicidal patients and six hours later they’re no longer suicidal.”

In depressed patients, areas of the brain related to sleep, appetite, self-esteem, and the ability to enjoy pleasures like music are “relatively unconnected from each other”. Psychedelics work on chemicals like serotonin to “cause reconnection, so they modulate each other more effectively”.

Although there’s no “high” with the current tests of psilocybin and ketamine, there’s speculation that doses strong enough to induce highs could be more effective by making patients feel “connected to the world and closer to people.

“It could make them take a broader view than just a catastrophic one. These factors may be important, but remain to be demonstrated in the future.”

Work is under way on drugs which “activate the dopamine system”. Dopamine, Gold explains, “is very involved in the capacity for pleasure. It’s activity is reduced in all forms of depression”.

Studies are also under way into the kappa receptor, which is “abnormal in depression”, and how that might be effected by endorphins which improve wellbeing when released. In depressed patients kappa receptors are “overly active”.

Within 10 years, genetic therapy could be available. “That’ll be the real clincher,” Gold says. “It’s coming. The outlook for someone with depression will be profoundly different than it is for those who develop it now.”

Bedlam

TREATING depression has been a long march. As Gold explains, in medieval times, patients were seen as possessed, and even burned as witches. In the 1700 and 1800s, they were confined to prison-style asylums, like Bedlam. Finally, treatments emerged in the 20th century and scientific understanding of depression took root.

Today, thanks to the work of scientists like Gold, we understand what depression is, its causes, and how to treat it. In the future, he says, “we can theoretically end depression”.

“Even 10 years from now, things are going to be significantly different,” Gold adds. “I just hope that people who are feeling terribly depressed and hopeless, those who are suicidal, will hang on.”

Gold knows just how important hope is: as a young man he faced depression himself. A romantic breakup assaulted his sense of self. There was a history of depression in his family which left him genetically predisposed to the illness, he explains.

But Gold was one of the lucky 60% who respond to existing treatments. A mixture of antidepressants and psychotherapy helped him recover.

“For the last 30 years, I’ve been free of depression and able to work, and have a good family and lots of friends. I’m very sorry for people who don’t have the access to help I had to change their lives. I’m very grateful because really I’ve had a wonderful life.”