Issue:March 2023

DELIVERY TECHNOLOGY - NeuroDirect™ Ketamine: Novel, Non-Systemic Topical Therapy for PTSD & Associated Intractable Depression


PTSD, Post-Traumatic Stress Disorder, is a brain memory processing disorder that continues to affect emotions, thought processes, and behaviors such that normal functioning becomes difficult, if not impossible, in affected individuals. Many, particu­larly war veterans, resort to suicide as a means to escape its over­whelming effects.1-5

Patients with PTSD have in common experiences with pro­found associated psychological stress that remains embedded in their memory and continues to playback in various ways, influ­encing their mental well-being and functioning. There may also be associated physical aspects to the event that contribute to the process, such a sexual assault, physical abuse, head injury, or other trauma. But most important are the emotionally traumatiz­ing aspects of the event that remain unresolved in the affected person’s psyche.6-7

Symptoms of PTSD are varied, and pharmaceuticals are gen­erally used to specifically treat them. Counseling and bio-feed­back are also used as augments. Symptoms may include flashbacks and uncontrollable thoughts about the event, night­mares, and severe anxiety. PTSD symptoms are generally grouped into four types: intrusive memories, avoidance, negative thinking and mood, or changes in emotional reactions.1,4,8,9

Although medications benefit in reducing PTSD symptoms, no single effective drug treatment for PTSD exists. Positive symptoms, such as re-experiencing, hypervigilance, and increased arousal, respond better to medication than negative ones of avoidance and withdrawal. As residual symptoms in spite of med­ications are the rule, much research continues in PTSD symptom management.10-12

SSRIs (selective serotonin reuptake inhibitors) have been considered first-line drug treatment. Data exists to support use of the following SSRIs: citalopram, escitalopram, fluoxetine, fluvox­amine, paroxetine, and sertraline. Bupropion and the SNRI ven­lafaxine have the lowest patient drop-out rates due to medication side-effects.13-17

In addition to antidepressants and benzodiazepines, anti­convulsants and other non-traditional compounds have been used in treating PTSD symptoms. Commonly used anticonvulsants include Carbamazepine, Topiramate, Lamotrigine, and Valproic Acid, which help reduce mood swings, agitation, impulsivity, and aggression. Narcotics and opioids are used for physical pain re­lated to physically traumatic events.18-40

From the above, it is apparent the majority of patients with intractable symptoms of PTSD are on several different medica­tions or “poly-pharmacy.” Not only are symptoms not adequately relieved, but side effects and drug-drug interactions can be prob­lematic. This has led many patients to self-medicate with alcohol, cannabis, and off-the-street narcotics and psychedelics. Psyche­delics include LSD, psilocybin (“magic mushrooms”), cocaine, and ketamine (“Special K.”).41-45


Ketamine was primarily developed for induction and maintenance of general anesthesia. It induces “dissociative anes­thesia,” a trance-like state providing pain relief, sedation, and amnesia. It is distin­guished from other general anesthetics in that respiratory functions are preserved. Cardiac status is unaffected with mainte­nance of normal blood pressure, making it ideal for traumatic situations with signif­icant blood loss and circulatory compro­mise. It was extensively used for battlefield surgical anesthesia in the Vietnam War.

Ketamine was first synthesized in 1962 and approved in US in 1970. It has been regularly used on dogs and horses; therefore, called “horse tranquilizer.”46 Be­cause of its safety profile, it is used in pe­diatrics.

At lower, sub-anesthetic doses, keta­mine has shown promise for pain and treatment-resistant depression. However, its antidepressant effect after IV dosing di­minishes with time and long-term re­peated IV use has not been sufficiently studied. Ketamine infusion clinics have popped up at major cities in the US, indi­cating unmet needs in treating PTSD with traditional pharmaceuticals.

Infusions are expensive, ranging from $300-$2000 per IV infusion, depending on dose and indication for treatment. Each infusion lasts an hour or more fol­lowed by an observation period for vital signs and side effects. Psychiatric side ef­fects are frequent as well as elevated blood pressure and nausea. Insurance does not cover the infusions, and therapy can be cost prohibitive.

Ketamine is reported to be a robust and rapid-acting antidepressant, although the effect is transient. IV ketamine in treat­ment-resistant depression usually results in improved mood within 4 hours, reaching peak at 24 hours. The effect is diminished at 7 days, and most patients relapse within 10 days, although for a significant minor­ity, the improvement may last 30 days or longer. The challenge with IV ketamine treatment is what to do when its anti-de­pressive effect wears off. Maintenance IV therapy, from twice weekly to once every 2 weeks, appears promising but is a costly option.

Even at low sub-anesthetic intra­venous doses, psychiatric side effects are prominent. A majority of patients report feeling “strange, spacey, woozy or float­ing” or having visual distortions or numb­ness. Also mentioned frequently is difficulty speaking, confusion, euphoria, drowsiness, and concentration problems. Psychotic symptoms such as “going into a hole, disappearing, feeling melting, expe­riencing colors, and hallucinations” are described by around 10% of people. Dizziness, blurred vision, dry mouth, hy­pertension, nausea, increased/decreased body temperature, or feeling flushed are common non-psychiatric side effects.

Adverse effects are most pronounced near end of infusion. They are significantly reduced by 1 hour and generally resolve by 4 hours. Accordingly, a several-hour period of observation is recommended after ketamine infusion. Patients are not recommended to drive home afterward.

Ketamine has not been approved as an antidepressant in the US, but the Canadian Network for Mood and Anxiety Treatments recommends it as a third line treatment for depression. An enantiomer of ketamine, esketamine, has been ap­proved as a nasal spray for treatment-re­sistant depression in the US and elsewhere. Intravenous ketamine has not been directly compared with intranasal es­ketamine, but a comparative meta-analy­sis of clinical trials suggested IV ketamine’s superiority. There were greater overall re­sponse and remission rates and less dropouts from side effects.

Ketamine is used as a recreational drug in powder and liquid forms for its hallucinogenic and dissociative effects. At sub-anesthetic doses, ketamine produces a dissociative state, characterized by a sense of detachment from one’s physical body and the external world, known as “depersonalization” and “derealization.” At sufficiently high doses, users may expe­rience what is called the “K-hole,” a state of dissociation with visual and auditory hallucinations similar to the effects of LSD.

Because of its ability to cause confusion and amnesia, ketamine has been used for date rape. Liver and urinary toxicities can occur with regular high-dose ketamine use, such as occurs in recreational use. Ketamine is an NMDA receptor antagonist, which may account for most of its actions. Its anti-de­pressive effects remain an area of debate and research. Ketamine is on the World Health Organization’s List of Essential Medicines and is available in generic form.47-50


It is apparent ketamine can play an important role in treating intractable symptoms of PTSD. But, limiting use is ex­pense, inconvenience of infusions, poten­tial systemic side effects, and impracticality of maintenance therapy.

NeuroDirect™ (also known as Direct EffectsTM technology) is a novel, patented delivery of neuro-active compounds as cream applied to skin at the back of neck at the hairline (BONATH). BONATH is crit­ical area of anatomy where access to af­ferent neural input to spinal cord and brain is achieved through Trigeminal and Vagal Nerve Complexes. Free nerve-end­ings under skin surface are activated by topically applied active drug, with neuro-chemical reactions occurring at specific re­ceptors. Action potentials to central nervous system resulting from chemical re­actions provide therapeutic benefit. This occurs without requirement of drug entry into bloodstream, a main source of side effects and drug interactions. The psy­chogenic effects encountered with intra­venous and other systemic ketamine uses are avoided. With NeuroDirect technology, benefits of psychedelic compounds may be achieved without concern for their po­tential systemic effects.51

Neuro-active compounds that have been successfully used with NeuroDirect technology include: triptans, dopamine agonist apomorphine, tizanidine, phenter­mine, 4-amino pyridine; cannabinoids, in particular, CBD,CBG, and beta-caryophyl­lene; as well as opioids, amantadine, tra­madol, and others. In all these topical drug applications, therapeutic benefit was generally noted within 10-15 minutes of application, as nerve impulses from skin-free nerve-endings to brain travel at essen­tially the same rate for all individuals. Such is not so when gastrointestinal absorption and blood flow factors are involved, which even differ in an individual, depending on gastrointestinal and hemodynamic func­tions at the time.

With bloodstream not involved, none of the usual systemic side effects associ­ated with these compounds have been ob­served in patients using NeuroDirect technology. A blood level study with mi­graine drug, sumatriptan/Imitrex™, re­vealed no presence of active compound in blood in all studied patients, suggesting therapeutic mechanism was by direct nerve connections without involvement of bloodstream or blood-brain-barrier.52-54 With sumatriptan pill, injection, or nasal spray, a “therapeutic blood level” is re­quired for efficacy.


Antagonism of NMDA receptor is thought responsible for anesthetic, anal­gesic, and psychomimetic effects of keta­mine. Analgesia occurs through preven­tion of central sensitization in spinal dorsal horn neurons interfering with pain trans­mission to the brain. Ketamine’s antide­pressant mechanism of action is less certain. It is likely the NMDA receptor is not solely responsible and other receptors are involved. NMDA receptors exist on periph­eral nerves and skin-free nerve-endings, allowing receptor antagonism to occur at these sites with topically applied drugs such as ketamine. This allows for keta­mine’s benefits in pain, depression, and anxiety relief associated with PTSD.49-50

In summary, through mechanisms at NMDA receptors, various chemical and neuro-electrical processes responsible for symptoms related to PTSD may be ad­dressed using a single compound, keta­mine. Additionally, using ketamine with NeuroDirect drug delivery technology allows potential undesirable side effects to be avoided, with therapeutic benefits achieved rapidly.


Observational data from an out-pa­tient Neurology and Neuropsychiatry prac­tice in 100 patients with intractable depression, anxiety, and other symptoms commonly associated with PTSD, indicated relief of symptoms with NeuroDirect keta­mine applied as a cream on skin at BON­ATH. Initial dose was 100 mg/ml; but subsequently, with a different formulation, 25 mg/ml was found equally effective. Ini­tial and maintenance dose is now 25-50 mg/ml depending on patient need. Sub­jects were patients with symptoms related to PTSD for a long time, having failed numerous previous other treatments. Many were significantly symptomatic while on several pharmaceuticals as well as herbal products, such as CBD and cannabis.

Discernible improvement in anxiety, depression, paranoia and unrealistic fear, focusing issues, cloudy thinking, neuro­pathic pain, and other such symptoms were noted within 8-10 minutes of topical drug application. Benefit by patients was also noted by family members and other objective observers. In some instances, clinical improvement was documented by objective measures, such as the Hamilton Depression Scale and EEG tracings.

More than 80% of patients trying NeuroDirect topical ketamine found it ef­fective to the extent formal prescriptions were requested for continued use at home. As with any therapeutic intervention, pa­tient selection is key in determining clinical response. No psychogenic effects, such as hallucinations or dissociative phenomena, were experienced by any patient. To the contrary, patients indicated their thought processes were clearer, more focused; and, that they were more keenly aware of surroundings.

Initial ketamine dose was 25-50 mg: 1-2x/day. Less “wearing off” phenomena with return of symptoms was seen with longer continued use, suggesting “de-pro­gramming” of PTSD-related neural cir­cuits. Some patients reduced dosing after 2-3 weeks. After a period, some patients were even able to change to use on “as needed basis.” In more severe chronically affected individuals, 25-50 mg every 2-3 days was generally required as mainte­nance therapy. Using the NeuroDirect top­ical ketamine, a significant number of patients were able to reduce or discontinue prior medications.

Table 1 provides a breakdown of diagnoses of the 100 treated patients. Middle- aged females with PTSD predom­inated; there were 61 females and 39 males. Ages ranged from 12 to 90 years. Table 2 shows top presenting symptoms relieved by ketamine therapy and imme­diate responses noted.

Eight patients had NeuroDirect keta­mine applied during EEG recording. All exhibited EEG improvement 3-5 minutes after treatment. Figure 1 is an example one such patient.

Click image to enlarge

The Hamilton Depression Rating Scale (HAM-D) is a multiple-item question­naire that provides indication of depres­sion and guides in evaluating treatment response and recovery. The questionnaire is self-assessed, with occasional input of a significant other/spouse/family member as corroboration. It rates severity of de­pression, anxiety, and other symptoms that may be associated with PTSD. It evaluates mood, feelings of guilt, suicide ideation, insomnia, agitation, retardation, anxiety, weight loss, and other somatic symptoms.

Figures 2 and 3 show changes in the Hamilton Depression Scale in two patient examples. One is immediately after keta­mine application, and the other, 2 weeks after continuous twice-daily therapy. Six patients studied before and after treat­ment with ketamine, exhibited reduction in HAM-D scores of 40, 22, 13, 11, and 7 points 15 minutes after ketamine application.

Click image to enlarge

Click image to enlarge


In view of the preliminary observa­tional data, formal controlled studies need to be undertaken and steps taken to make this revolutionary product more widely available. It is more cost-effective, conven­ient, and appears more effective than cur­rently available treatments using systemic ketamine for PTSD symptoms. Additionally, there is no concern for psychogenic and other systemic effects.

The following is a testimonial from a patient who used NeuroDirect ketamine: “It was like truth serum! I became aware of thoughts and emotions I had sup­pressed which needed to come out. I found myself crying uncontrollably as I re­leased them. It allowed me to move for­ward as I had been stuck in a rut. I began to feel so much better as I faced how self­ishly and un-lovingly I had treated my ill mother before she suddenly passed away.” Another stated “The usual triggers no longer affected me to go into a panic state…”


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Dr. Ronald Aung-Din practices General Neurology & Neuro-Psychiatry in Sarasota, FL. He is board-certified by the American Board of Psychiatry & Neurology and member, American Academy of Neurology. After earning his Bachelor’s and Master’s degrees in Engineering at Bucknell and Cornell Universities, he worked for a period as a supervising engineer. He then attended Columbia University in New York City for Premedical studies, followed by Medical School at University of Texas Southwestern Medical School, Dallas, TX. Residencies in Neurology and Neurosurgery were at University of Florida. Other studies included a Medical Student Fellowship in Cardiology at Radcliffe Infirmary, Oxford and Clinical Neurology Fellowship at National Hospital for Nervous Disease, Queen Square, London, UK. He has participated in over 60 pharmaceutical industry-sponsored clinical trials, functioning as Principal Investigator in drug research studies in MS, epilepsy, pain, Parkinson’s disease, and other neurological diseases. He is also active in treating varied neurological and psychiatric conditions using delivery of CNS-active drugs with Neuro-Direct™ technology, developed by him for which 13 US and foreign patents have been granted; with others pending. Publications using this novel therapy in migraine, Parkinson’s disease, autism spectrum disorder, and diabetic neuropathy; in addition to articles on the use of cannabidiol, CBD, and the non-cannabis cannabinoid receptor agonist, caryophyllene, have appeared in Drug Development and Delivery. AfGin Pharma, LLC was founded by Dr. Aung-Din in 2009 to advance his unique technology and its goal of “Enhanced Neuro-Therapeutics through Direct Effects Topical Technology.”

Dr. Chantelle G. Martin was born in Zimbabwe, Africa, and attended Medical School at the University of the Free State, Bloemfontein, South Africa, earning her Bachelor of Medicine and Bachelor of Surgery degree in 2016. She later completed 2 years of internship training at Grey’s Hospital, Pietermaritzburg, South Africa; rotating through Surgery, Pediatrics, OB-GYN, Neurology, Internal Medicine, Orthopedics, Anesthesiology, Family Medicine and Psychiatry, where she managed a wide range of medical and surgical conditions. Later, she also did a year of rural community service as a medical officer in Pietermaritzburg. She currently lives in Sarasota, FL, awaiting a residency position. In the interim she is not only gaining valuable clinical experience but also participating in groundbreaking research with the General Neurology and Neuropsychiatry clinical research practice of Sarasota neurologist Dr.Ronald Aung-Din and his AfGin Pharma, LLC research and development bio-pharmaceutical company, founded in 2009. Her recent work with the Direct Neuro Topical use of ketamine for the treatment of PTSD and intractable depression is an example of the value she provides in clinical research, advancing novel non-systemic technologies for difficult neurological and psychiatric disorders. Her passion for finding treatments for diseases of the nervous system using neuro-psychotropic drugs is evident and an added bonus to her contribution to medical pharmaco-therapeutics.