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Safest Psychiatric Drugs: Low Risk, Effective Medications

Reports suggest that nearly 20% of all people in the United States are taking a psychiatric drug.  This means that 1 out of every 5 people you see is on some sort of mind-altering medication.  Although many of these drugs are marketed as being “safe and effective” for conditions like ADHD, anxiety, bipolar disorder, depression, and schizophrenia – many are not as safe as you may think.  For years doctors assumed that benzodiazepines like Xanax were safe, but now know that benzos may cause dementia and permanent memory impairment.

If you have a mental illness, it is always best to exhaust alternative treatment options before subjecting yourself to a pharmaceutical.  That said, many people don’t respond well to alternative treatments and have no choice but to opt for a pharmaceutical psychiatric drug.  Individuals that are going to subject themselves to psychiatric treatment should attempt to find the drugs with the lowest risk and highest potential benefit.

In other words, the drugs should have: favorable side effect profiles, minimal unwanted long-term effects, minimal or no withdrawal symptoms, and tolerance should be slowly established.  In an ideal world, all drugs would fit this criteria.  Unfortunately there are many problems with psychiatry and many dangerous psychiatric drugs are utilized before lower risk, safer options.

Determining the Safest Psychiatric Drugs

While psychiatrists are likely to tell you that all approved drugs are “safe” – the interpretation of “safe” is very subjective.  One practitioner may have been spoon fed the “safety risk” information by a sales rep, while another may assume that since a drug is approved and on the market, that it must be safe.  Below is a list of psychiatric drugs that tend to be relatively low-risk when compared to the majority.

Keep in mind that there is often significant individual variation in response to many of these drugs.  No person is guaranteed to have a favorable response to the substances listed below.  However, the psychiatric drugs listed below tend to be recognized by psychiatrists and patients as having lower-risk, safer substances than other pharmaceutical options.

Criteria for Safety of Psychiatric Drugs…

Unfortunately there is not a formally established criteria for the safety of psychiatric drugs.  This means that many patients may be exposed to risky drugs (associated with severe discontinuation symptoms and/or side effects) earlier than necessary.  Below is some generalized criteria that may help you analyze the safety of the medications you take.

Abuse / dependence / addiction likelihood

When considering any psychiatric drug, you should consider its potential for abuse, dependence, and whether it is addictive.  A psychiatric drug should be regarded as safer if it has a low potential for abuse, dependence, and is unlikely to have addictive properties.  In other words, it shouldn’t be classified as a “controlled-substance” in the United States.

All drugs classified as “controlled-substances” (regardless of their schedule) have potential for abuse.  Should you abuse a drug, become addicted, or dependent upon it for functioning – it may harm your brain and/or physiology more than you expected.  Recovery from prescription drug addiction can be costly in regards to finances and time spent towards rehabilitation efforts.

Long-term effects

People with serious psychiatric illnesses like major depressive disorder aren’t often concerned about long-term effects.  They want immediate relief from their depression because without relief, they feel as if they’re already dead.  If you have suicidal thoughts and feel like you want to die all the time, you’ll take whatever drug is suggested to help without considering the long-term effects.

Should the drug work, you may feel as if it has saved your life.  But what if you develop a severe health condition caused by the drug after 10 years?  Sure it may have been worth it, but what if there was another drug that would’ve worked just as well, but wouldn’t have resulted in development of a severe health condition?  Chances are you’d have preferred the drug with the least long-term risk.

Side effects / Adverse Reactions

Many people are happy with the initial symptomatic reduction experienced after they start taking a psychiatric drug, but become unhappy with the side effects.  Sure they feel happier, but now they are unable to orgasm, are gaining weight, and their hormone levels are out of whack.  Some people gain so much weight that it becomes a health concern of its own – so they’re left in a catch-22 paradigm: take the drug and look like a beached whale OR stop the drug and feel super depressed.

In order to prevent these unfavorable catch-22 scenarios from occurring, it would be recommended to thoroughly analyze the potential side effects of various drugs.  Therefore drugs with favorable side effect profiles should be considered before they’re prescribed.  Keep in mind that side effects are not prone to physical phenomena, they may be mental such as “brain fog” or cognitive impairment – which could impair work performance and cost someone a job.

Tolerance onset

Most psychiatric drugs with a very slow tolerance onset are considered safe.  Many drugs aren’t associated with significant tolerance, but in reality – every drug causes tolerance over time when taken on a daily basis.  Your brain and nervous system will adapt over time to the effects of a drug.  Your goal should be to find a drug that works as long as possible without tolerance.

Drugs that have a slower tolerance onset means you can take the minimal effective dose for a longer duration with sustained efficacy, rather than having to constantly increase the dose to maintain efficacy.  Each time you increase the dosage of any foreign, exogenous substance – the likelihood of side effects and adverse reactions increases.  Your goal should be to find the drugs without a recognized “tolerance” or the ones people can take for years at low doses with the same effect.

Withdrawal symptoms

Many psychiatric drugs have severe withdrawal symptoms that are so debilitating, people cannot cope with work, family, and are seemingly unable to function.  In many cases these symptoms are protracted – meaning it can take months before a person starts to feel even a little bit better.  Even more concerning is that it may be difficult to distinguish withdrawal symptoms from the returning mental illness; there is often significant overlap.

In effort to cope with these symptoms, many psychiatrists play psychotropic roulette, often with various augmentation strategies.  This attempts to cover up the antidepressant-induced chemical imbalance that the person has endured from discontinuation of the drug they had been taking, but usually creates an even bigger neurochemical mess for the future.  With proper recovery efforts, the person will eventually revert back to physiological homeostasis.  The safest psychiatric drugs should be considered those with the least debilitating withdrawal and quickest transition back to homeostatic functioning.

Safest Psychiatric Drugs: Low-Risk, Clinically Effective Options

The drugs listed below are considered safe based on the criteria outlined above.  Understand that the list below is in alphabetical order – not based on degree of safety.  Keep in mind that the safest drug for you may be different than that for someone else.

1. Buspar (Buspirone)

  • Type of drug: Anxiolytic (Anti-Anxiety)
  • Mechanism of action: Buspar acts as a serotonergic 5-HT1A receptor partial agonist. This means that the drug stimulates the 5-HT1A receptor and it reduces anxiety by tricking the brain into thinking that it has more serotonin than in actuality.  It also acts as a presynaptic dopaminergic antagonist (at D2, D3, and D4 receptors) and as a partial Alpha-1 adrenergic receptor agonist.  The drug is able to suppress serotonergic activity and increase firing of norepinephrine and dopamine.
  • Conditions it treats: Anxiety disorders

If you struggle with anxiety and have already pursued natural cures for anxiety with limited success, it may be time to test a pharmaceutical option.  If you’re going to try any anxiolytic, perhaps the safest to test first is Buspar (Busprione).  This is a drug that was approved by the FDA in 1986 for the treatment of generalized anxiety disorder (GAD).

Buspar has been on the market for an extensive period of time and is well-researched.  In fact, most scientific evidence suggests that the drug has no significant side effects.  Some psychiatrists have gone as far as to hypothesize that there are no Buspar withdrawal symptoms.  That said, even though reports suggest that there are in fact withdrawals – they appear to be milder than SSRIs.

On my hierarchy of anxiety treatments, this drug is near the top due to the fact that it will not impair cognitive function and carries no significant side effects like weight gain or sexual dysfunction.  It isn’t associated with rapid-onset of tolerance and some people have reported taking it for over a decade at the same dose with efficacy.

2. Clonidine

  • Type of drug: Antihypertensive
  • Mechanism of action: Clonidine functions by stimulating Alpha-2 adrenergic receptors in the brain as an agonist, including: Alpha-2A, Alpha-2B, and Alpha-2C receptors. In addition, it acts as an agonist of the imidazoline receptor.  Its mechanism on these receptors reduces activation of the sympathetic nervous system, which lowers blood pressure.  The drug also increases norepinephrine in the prefrontal cortex via action on postsynaptic Alpha-2 adrenergic receptors to improve attention. (Read: Clonidine for ADHD).
  • Conditions it treats: ADHD (Attention-Deficit/Hyperactivity Disorder)
    • Off-label: Anxiety disorders, Drug withdrawal, PTSD, Sleep disorders

Clonidine is a drug that’s been approved for the treatment of hypertension (high blood pressure) since 1974.  The fact that it has been on the market for a long-term means that we have a good idea of its side effect profile and long-term effects.  The drug is considered an effective ADHD medication and may be preferred over stimulants due to the fact that it has no significant side effects or withdrawal symptoms.

The drug is also ubiquitously used off-label for the treatment of:  anxiety disorders, withdrawal symptoms (from opioids or alcohol), sleep disorders (i.e. insomnia), and even post-traumatic stress disorder (PTSD). Most psychiatrists consider Clonidine as being among the safest drugs on the market.  It is not associated with any tolerance or addiction, has no significant unfavorable long-term effects, and there are negligible documented Clonidine withdrawal symptoms.

Despite the fact that it is an older drug, there is significant evidence to suggest its efficacy in treating a multitude of conditions.  Though it may be less potent than a psychostimulant for the treatment of ADHD or a benzodiazepine for anxiety, it is still clinically effective.  Plus users of Clonidine won’t likely need to worry about developing tolerance or unwanted cognitive impairment upon discontinuation.

3. Guanfacine

  • Type of drug: Antihypertensive
  • Mechanism of action: Guanfacine functions as an Alpha-2 adrenergic agonist, specifically the Alpha-2A adrenergic receptor. This means that the drug selectively binds to the Alpha-2A receptor to elicit its effect.  By stimulating the Alpha-2A receptor, it inhibits activation of the sympathetic nervous system, ultimately reducing blood pressure.  It also increases norepinephrine in certain parts of the prefrontal cortex, which results in improved attention span. (Read: Guanfacine for ADHD).
  • Conditions it treats: ADHD (Attention-Deficit/Hyperactivity Disorder)
    • Off-label: Anxiety disorders, Drug withdrawal, PTSD, Sleep disorders

Guanfacine is similar to Clonidine in that it functions as an Alpha-2 adrenergic agonist.  It is slightly different than Clonidine in that it is highly selective for the Alpha-2A receptor, whereas Clonidine acts on the Alpha-2A, Alpha-2B, and Alpha-2C receptors.  It was approved by the FDA in 2010 for the treatment of ADHD and is regarded as a clinically effective option.

This drug has been on the market since 1986 for the treatment of hypertension – long before its approval to treat ADHD.  Since it has been on the market for nearly 3 decades, it has been subject to significant research.  It is well-known that the drug has minimal withdrawal symptoms, a favorable side effect profile (no weight gain, sexual dysfunction, etc.), and isn’t associated with any tolerance.

Furthermore, the drug can be used off-label for a variety of conditions including: anxiety disorders, drug withdrawal, PTSD, and sleep disorders.  It reduces sympathetic activation (e.g. the physical symptoms of anxiety), while simultaneously ramping up cognitive function via bolstering of noradrenergic activity in the prefrontal cortex.  This is considered one of the safest psychiatric drugs on the market.

4. Nuvigil (Armodafinil)

  • Type of drug: Eugeroic
  • Mechanism of action: Nuvigil has an undeciphered mechanism of action, but is believed to elicit diverse cortical effects. It is thought to function as a dopamine reuptake inhibitor (DRI) and D2 receptor partial agonist. The drug also is thought to increase histamine in the hypothalamus and boost concentrations of norepinephrine and serotonin.  Additionally, the drug may stimulate orexin receptors (OX1 & OX2), increase NDMA (glutamate), reduce GABA, and facilitate “electronic coupling.”
  • Conditions it treats: Obstructive sleep apnea, Narcolepsy, Shift work sleep disorder
    • Off-label: ADHD, Chronic fatigue syndrome, Depression

Nuvigil is a drug that hit the market in 2007 as an improved version of its predecessor Provigil.  It is formulated with solely the R-stereoisomer of racemic modafinil, hence being known as “Armodafinil” (R-modafinil).  The predecessor formulation of Provigil (Modafinil) consisted of 50% R-modafinil and 50% S-modafinil; the S-stereoisomer isn’t considered to have an effect and was therefore eliminated. (Read: Nuvigil vs. Provigil).

Some speculate that Nuvigil is simply a cleaner version of Provigil and ultimately an upgrade.  The drug is considered to be twice as potent, longer-lasting, and is thought to have less side effects than Provigil due to the fact that it contains only the S-enantiomer.  Although the drug is considered a “Schedule IV” controlled-substance, it is considered to have a very low potential for abuse.

Additionally, most users are able to take the drug for extended periods of time without developing tolerance.  Most evidence indicates that side effects aren’t usually troubling and may even be favorable including: weight loss (Nuvigil and weight loss), increased sex drive, and increased cognitive function.  A majority of experts consider Nuvigil withdrawal symptoms to be minimal and/or nonexistent, making it a safe drug for off-label conditions like ADHD, chronic fatigue syndrome, and dperession.

5. Provigil (Modafinil)

  • Type of drug: Eugeroic
  • Mechanism of action: Provigil is thought to function primarily as a dopamine reuptake inhibitor (DRI). It has been shown to increase histaminergic activity in the hypothalamus region and increase other neurotransmitters such as norepinephrine and serotonin.  It also activates orexin peptides, and may stimulate glutamate, inhibit GABA, and increase “electronic coupling.”
  • Conditions it treats: Obstructive sleep apnea, Narcolepsy, Shift work sleep disorder
    • Off-label: ADHD, Chronic fatigue syndrome, Depression

Provigil is a drug that has been on the market since 1998 and is considered safe.  Although it hasn’t been around for nearly as long of a term as other medications, most evidence suggests that its side effect profile as well as possible discontinuation symptoms are minimal.  Most experts suggest that there are no Provigil withdrawal symptoms – a claim that probably is a bit too good to be true.

The drug elicits widespread cortical effects, with less dopamine reuptake than a psychostimulant and other hypothesized effects such as glutamate stimulation and GABA inhibition.  The drug is effective as a eugeroic or “wakefulness-promoting” agent.  It may be slightly less safe than Nuvigil due to the fact that it contains both the S-enantiomer and R-enantiomer – increasing potential of side effects.

Although some people may experience unfavorable reactions (e.g. skin rashes), most users find the drug effective at the same dose for years without any tolerance.  For most psychiatric patients, Provigil remains a hidden gem.  It is seldom prescribed for off-label conditions, but is considered highly effective and relatively safe when compared to psychostimulants which may rapidly deplete dopaminergic reserves and lead to a downregulation of receptors.

6. Wellbutrin (Bupropion)

  • Type of drug: Antidepressant
  • Mechanism of action: Wellbutrin functions as a weak norepinephrine-dopamine reuptake inhibitor (NDRI). It primarily increases levels of norepinephrine, while increasing dopamine to a very minimal extent.
  • Conditions it treats: Depression, Smoking addiction
    • Off-label: ADHD

Individuals that respond well to the atypical antidepressant Wellbutrin generally don’t struggle with any unwanted side effects.  The drug is stimulating, and many find that it is the best antidepressant for weight loss and maintenance (or enhancement) of sex drive.  Though it is commonly prescribed as an adjunct to an SSRI, it can be an effective standalone option.

In fact, many people that find Wellbutrin effective wish that they would’ve been prescribed this medication first over standard SSRIs.  It has perhaps the most favorable side effect profile of any approved antidepressant.  The only major drawback is that it can provoke seizures in some people and be overly stimulating to the point that it could cause anxiety.

It should also be mentioned that Wellbutrin withdrawal isn’t nearly as unfavorable as discontinuation from other antidepressants.  In fact, most find that withdrawal symptoms subside quickly compared to discontinuation of an SSRI.  If you only have depression without anxiety, this may be one of the lowest-risk, highest benefit psychiatric drugs to try.  There is evidence to suggest that using Wellbutrin for ADHD with comorbid depression may also be effective.

7. Strattera (Atomoxetine)

  • Type of drug: Nonstimulant
  • Mechanism of action: Strattera functions primarily as a norepinephrine reuptake inhibitor (NRI), increasing extracellular levels of norepinephrine.
  • Conditions it treats: ADHD (Attention-Deficit/Hyperactivity Disorder)
    • Off-label: Bedwetting, Binge eating disorder, Depression

Strattera is a unique medication in that it treats ADHD without significantly increasing dopamine.  The drug works as a norepinephrine-reuptake inhibitor, increasing levels of norepinephrine to alleviate attentional deficits and reduce hyperactivity.  Due to the fact that the drug is stimulating via it mechanism on norepinephrine, it is thought to be an effective off-label treatment for pediatric bedwetting, binge eating disorders, and depression.

It isn’t associated with any significant side effects nor unfavorable long-term effects.  Most drugs that act primarily on norepinephrine are considered well-tolerated.  There is some reason to believe that Strattera causes weight loss – making it effective for someone with ADHD who is overweight.  In addition to having favorable side effects, there don’t appear to be any major Strattera withdrawal symptoms.

Clinical trials indicate that there were “no significant discontinuation symptoms” associated with this drug.  Some individuals have also found that Strattera treats depressive symptoms and mitigates depression-induced cognitive impairment.  (For more information read: Strattera for Depression).

Is any drug better or safer than the others?

Of the drugs listed above, it cannot be determined whether one drug is safer than others.  Much of the safety and efficacy associated with these medications is subject to individual variation.  You may want to test your genetics (using a service like Genesight) to determine which drugs are most likely to provide a therapeutic benefit.

It should also be mentioned that it is possible for makers of these drugs to have withheld safety information from the public.  In other words, they may have conducted studies and found withdrawals, but since there were no apparent withdrawals in clinical trials, they withheld evidence.  Realize that no drug is flawless in terms of safety, but the ones mentioned above tend to have lower risk compared to others.

No universally utopian psychiatric drug…

As with any drug, it is important to consider that there is no biological free lunch.  The greater the effect you derive from a substance, the greater the likelihood that you’ll experience equally oppositional effects upon discontinuation.  The aforementioned drugs may be favorable compared to other psychiatric agents due to the fact that they have well-established therapeutic efficacy and are low-risk in regards to: abuse potential, tolerance, long-term effects, side effects, and withdrawals.

That said, there is no utopian pharmaceutical “drug” – each has pros and cons.  The goal of the psychiatric community should be to prescribe drugs that are low risk and effective.  The current mainstream treatment approach seems to be prescribe a potent, new drug – without considering the side effects, long-term effects, and potential discontinuation effects in the future.

Opinion: What’s the safest, clinically-effective psychiatric drug?

Feel free to share a comment mentioning what you believe is the safest (lowest risk, yet effective) psychiatric drug.  Are you basing this on personal experience, scientific journals, or a combination of both?  Based on the criteria listed above for risk including: abuse potential, long-term effects, side effects, tolerance onset and discontinuation symptoms – should any substances be added to this list?

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1 thought on “Safest Psychiatric Drugs: Low Risk, Effective Medications”

  1. What about Lyrica? How safe is that as an anxiety treatment? I have read that it is toxic to the formation of new neurons.


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