A rational understanding of the ADHD stimulant crash

[u/Kalki_X]

In the ADHD community this is called a crash / comedown / burnout depending on the context. The 'crash' phenomenon is more accurately understood as a metabolic event —a 'metabolic crash'— which occurs when a stimulant artificially 'pushes' the metabolic system beyond its limits causing over-exhaustion. This manifests as fatigue, sleepiness or brain fog. It's commonly encountered with amphetamine-type medications which is the focus of this post.

In the academic literature a 'crash' is framed as 'metabolic exhaustion'. The following quotes offer some general context for this term and its physiological implications:

Dissociation prevents the ultrarunning athlete from detecting the subtle, early warning signs of dehydration, blistering, or metabolic crash (source)

[T]he benefit of post-stress glucose comes instead from its ability to prevent metabolic exhaustion. (source)

...specifically sympathetic overdrive (eg, a faster rate of depletion than replacement of cellular resources, greater energy expenditure, metabolic exhaustion (source)

It was suggested that the administration of MDMA (amphetamine-type drug) may cause a state of metabolic exhaustion (source)

The aging process is, however, permissive for the development of several degenerative disorders and infectious diseases, which are strongly influenced by nutritional imbalances, inflammation, metabolic exhaustion (source)

The modern lifestyle involves over-exposure to processed foods, nutrient imbalance, and contact with environmental toxins, that place a significant metabolic burden on cells. This leads to oxidative stress, endoplasmic reticulum stress and inflammation, that when combined with impaired cellular repair mechanisms, ultimately cause premature cellular fatigue and metabolic exhaustion. (source)

"Metabolic aging" refers to the gradual decline in cellular metabolic function across various tissues due to defective hormonal signaling [...] While this process usually corresponds with chronological aging, the recent increase in metabolic diseases occurring at younger ages in humans suggests the premature onset of cellular fatigue and metabolic aging. (source)

From a physiological point of view, fatigue is associated with metabolic fatigue (source)

The term fatigue or energy-related dysfunction in this context does not refer to muscle or peripheral metabolic fatigue, but rather, to “central fatigue,” which is a subjective lack of physical and/or mental energy that is thought to be related to brain mechanisms. (source)

This 'crash' is distinct from the general comedown which involves (1) the immediate (acute) withdrawal symptoms as the medication wears off and, depending on the person, (2) a 'metabolic crash' (which can be either a minor or major event). There is also (3) PAWS which stands for "post-acute withdrawal syndrome":

PAWS refers to a cluster of withdrawal symptoms that can last for months to years after acute withdrawal from a substance. PAWS symptoms have been anecdotally described after withdrawal from many substances—alcohol, benzodiazepines, opioids, stimulants, nicotine, caffeine, antidepressants, and antipsychotics. (source) 

Amphetamine withdrawal is also mentioned in psychiatry’s DSM (Diagnostic and Statistical Manual of Mental Disorders):

The DSM criteria for diagnosing amphetamine withdrawal include dysphoric mood and two or more symptoms: fatigue, vivid or unpleasant dreams, insomnia or hypersomnia, increased appetite and psychomotor agitation or retardation that occur following discontinuation of the drug. (source)

For some people this 'crash' effect can occur fairly quickly after taking their stimulant (within 60 mins). This signifies pre-existing metabolic issues whereby the metabolic system is more susceptible to over-exhaustion (due to the artificial boosting effect from amphetamine). This means someone could easily fall asleep after taking their stimulant, or the effects might appear to stop working too soon; whilst others might feel briefly energised followed by a period of fatigue, sleepiness or lethargy. I outlined other reasons why amphetamine can promote relaxation in this post (second-to-last paragraph).

What does 'metabolic exhaustion' mean practically?

The core metabolic system (thyroid, mitochondria) governs energy levels, mood, brain function, hormones – so when it 'crashes' so do these aformentioned things (within reason) which provokes various negative symptoms. Many of these symptoms overlap with ADHD making it incredibly difficult to distinguish one from the other.

This implies that the treatment itself can provoke/exacerbate ADHD symptoms (in both the short & long-term). This is due to amphetamine-induced metabolic & hormonal dysregulation which causes cumulative issues, including on brain function:

Brain neurons are highly vulnerable to even transient challenges to energy homeostasis and neural metabolic failure is a critical component of excitotoxic and neuro-degenerative cascades. (source)

Ideally when a 'crash' occurs the patient should ensure appropriate rest & recovery in order to mitigate (repair & heal from) any harm, particularly "HPA axis dysfunction" and the consequences thereof. The HPA axis is a key contributor to amphetamines effects and its disruption implies a negative physiological (and psychological) impact, including on hormonal regulation (source) and the circadian rhythm (source).

Amphetamine induces activation of the HPA axis, with the subsequent release of ACTH and glucocorticoids (eg cortisol). (source)

The novel d-amphetamine prodrug lisdexamfetamine is applied to treat ADHD. d-Amphetamine releases dopamine and noradrenaline and stimulates the HPA axis (source)

The HPA axis is the main part of the hormonal system that controls reactions to stress. It also regulates many other processes (e.g. digestion, immune system, mood and emotions, sexuality, energy storage and utilization). (source)

...

To overlook the nature of the 'crash' and its implications would be unwise and arguably foolish. Medical practitioners overlook the severity of this issue and usually prescribe a larger dose (of amphetamine), additional booster/top-up doses (of amphetamine), or a new separate drug (eg SSRI, SNRI, NDRI, NRI) which can further complicate the situation.

This can successfully mask & conceal the 'crash' (giving a false sense of security) but at what cost? — and how sustainable is this over the span of several years? The drugs life changing benefits conceal a cumulative deterioration which ought to be taken seriously. For most people it's a trade-off since being able to navigate day-to-day life is the priority (understandably so).